Antiviral Chemistry & Chemotherapy 10:285–314
Review
Non-nucleoside reverse transcriptase inhibitors: the
NNRTI boom
Ole S Pedersen and Erik B Pedersen*
Department of Chemistry, University of Southern Denmark, Odense University, DK-5230 Odense M, Denmark
*Corresponding author: Tel: +45 6550 2555; Fax: +45 6615 8780; E-mail: EBP@chem.sdu.dk
Non-nucleoside reverse transcriptase inhibitors
(NNRTIs) are promising drugs for the treatment of
HIV when used in combination with other anti-
HIV drugs such as nucleoside reverse transcriptase
(RT) inhibitors and protease inhibitors. The first
generation of NNRTIs have, however, suffered
from the rapid development of resistance. This
review discusses the properties of the FDA-
Introduction
The HIV epidemic is still a major concern. Virtually every
country in the world has seen new infections in 1998, and
the epidemic is out of control in many places according to
the World Health Organization (WHO) and the Joint
United Nations Programme on HIV/AIDS (UNAIDS).
The introduction of highly active antiretroviral therapy
(HAART), which has been used mainly in North America
and Western Europe, has reduced the number of deaths
caused by AIDS. However, because new infections continue
to occur and infected people are kept alive with HAART
and other combinations of anti-HIV drugs, the number of
people living with HIV has increased in North America
and Western Europe. Combinations of anti-HIV drugs
often contain a non-nucleoside reverse transcriptase (RT)
inhibitor (NNRTI), a nucleoside RT inhibitor (NRTI) and
a protease inhibitor. This review will concentrate on the
NNRTIs, of which the first, nevirapine (Viramune,
Boehringer Ingelheim), was approved as a drug for the
treatment of HIV-1 infection by the US Food and Drug
Administration (FDA) in 1996. Nevirapine was followed
by delavirdine mesylate (Rescriptor, Pharmacia & Upjohn)
and efavirenz (Sustiva, DuPont), approved for the treat-
ment of HIV-1 infection by the FDA in 1997 and 1998,
respectively. A further three compounds, MKC-442
(Triangle Pharmaceuticals), Calanolide A (Sarawak
MediChem Pharmaceuticals) and AG 1549 (Agouron
Pharmaceuticals) are in clinical trials according to the
Pharmaceutical Research and Manufacturers of America
(PhRMA) 1998 survey report. Because of the increasing
©1999 International Medical Press 0956-3202/99/$17.00
approved NNRTI drugs and focuses on the recent
efforts being made to produce second genera-
tion inhibitors that circumvent this resistance
problem.
Keywords: HIV-1; non-nucleoside reverse
transcriptase inhibitors; HEPT; nevirapine;
delavirdine; efavirenz; trovirdine
interest in NNRTIs we intend to review this class of com-
pounds, especially the second generation of NNRTIs, using
a chemical approach. This review will focus on the recent
and most interesting published results. The NNRTIs syn-
thesized before 1996 are covered by reviews by Artico
(1996) and Tucker et al. (1996). A review focusing on the
role of NNRTIs in the therapy of HIV-1 infections has
been published by De Clercq (1998a).
Non-nucleoside reverse transcriptase
inhibitors
NNRTIs are bound in a hydrophobic pocket proximal to
the catalytic site of RT in HIV-1 (Tantillo et al., 1994). X-
ray crystallographic studies of NNRTIs in complex with
RT (Ren et al., 1995; Ding et al., 1995) have shown that the
NNRTIs maintain a very similar conformational ‘butterfly-
like’ shape and appear to function as π-electron donors to
aromatic side-chain residues surrounding the binding
pocket (Kroeger et al., 1995; De Clercq, 1998b).
The major problem in the development of new
NNRTIs is the rapid emergence of resistant strains of
HIV-1 in cell culture and patients. In patients receiving
monotherapy with nevirapine, drug resistance developed
rapidly owing to mutations in the RT; particularly signifi-
cant is the Y181C mutation (Cywin et al., 1998). Cross-
resistance is also a contributing factor and
pyridinone-resistant strains containing the Y181C, K103N
or both mutations (Nunberg et al., 1991) have been found
285
OS Pedersen & EB Pedersen

Figure 1. The structure of nevirapine
O include metabolic stability, clearance rates, the ability to
H3C 5H
N
4
11
2 N N N
1 10
to confer resistance to both TIBO R82150 (Pauwels et al.,
1990) and nevirapine (Merluzzi et al., 1990). It has been
shown that NNRTIs rapidly select for resistant mutant
HIV-1 strains when selection pressure is applied by drugs
in vitro (Kleim et al., 1995; Nunberg et al., 1991) or in
monotherapy (Cywin et al., 1998; Miller et al., 1998).
Cross-resistance has been observed between many
NNRTIs in development (Miller et al., 1998). Mutations
commonly selected for by NNRTIs occur at amino acid
positions 98 to 108, 179 to 190 and 230 to 236 (Miller et
al., 1998). Cross-resistance is one of the obstacles that has
to be overcome for the next generation of NNRTIs, new
drugs that have a resistance profile that differs from the
resistance profile of the already known drugs.
Many aspects beside selectivity and activity against
mutant strains of HIV-1 have to be considered in the devel-
opment of new NNRTI drug candidates. These aspects
cross the blood–brain barrier and protein binding. Protein
binding is a complex issue; a high protein binding could
reduce the metabolism of the drug, the clearance rates and
maintain high concentration of the drug in the blood.
However, too strong protein binding may reduce the con-
centration of the free drug available for inhibitory action.
Some of the currently most interesting subclasses of
NNRTIs are described below. Tables showing the antiviral
activity and activity against purified RT are presented. The
presentation of each drug begins with the subclass with an
FDA approved drug, followed by a subclass with a drug in
clinical trials according to the PhRMA 1998 survey report,
and ends with a description of some additional characteris-
tic subclasses.
Nevirapine
Nevirapine (Viramune; Boehringer Ingelheim) (Figure 1)
was approved for the treatment of HIV in combination
with nucleoside analogues in 1996 in the USA, and in 1998
in the European Union.
Nevirapine has a good potency against wild-type RT,
with a 50% inhibitory concentration of 84 nM (Hargrave
et al., 1991), good metabolic stability, good bioavailability
(Cywin et al. 1998) and crosses the blood–brain barrier eas-

Table 1. The activity of some nevirapine analogues against wild-type RT and two mutant strains of HIV-1 RT

H3C O
N

N N
N
R1
R2

IC50 (µM) HIV-1 RT*

Compound R1 R2 WT† Y181C Y188L Reference
1 Cl Et 0.08 0.21 ND‡ Proudfoot et al. (1995a)
2 N-pyrrolyl Et 0.09 0.21 ND Proudfoot et al. (1995a)
3 2-furanyl Et 0.11 0.16 ND Proudfoot et al. (1995a)
4 3-furanyl Et 0.04 0.11 ND Proudfoot et al. (1995a)
5 2-pyrrolyl Et 0.07 0.07 ND Proudfoot et al. (1995a)
6 3-pyrrolyl Et 0.033 0.050 ND Kelly et al. (1997)
7 3-pyrrolyl c-Pr 0.05 0.06 ND Proudfoot et al. (1995a)
8 4-pyrazolyl Et 0.02 0.06 ND Proudfoot et al. (1995a)
9 4-pyrazolyl c-Pr 0.06 0.05 ND Proudfoot et al. (1995a)
10 4-NH2-phenyl Et 0.04 0.12 ND Proudfoot et al. (1995a)
11 indol-3-yl Et 0.028 0.028 0.090 Kelly et al. (1997)
12 5-azaindol-3-yl Et 0.044 0.098 0.384 Kelly et al. (1997)

*Inhibitor concentration to give 50% inhibition of incorporation of [3H]dGTP into a [(poly)rC•(oligo)dG] template.
†Wild-type HIV-1RT.
‡ND, Not determined.

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 The NNRTI boom

Table 2. The activity of some nevirapine analogues against wild-type RT and two mutant strains of HIV-1 RT
H3 C O
N
R2

N N
N
R1

IC50 (µM) HIV-1 RT*

Compound R1 R2 WT† Y181C Y188L Reference
13 Cl (3-ureidophenyl)ethyl 0.06 0.08 0.23 Klunder et al. (1998)
14 Cl (3-anilinyl)ethyl 0.12 0.23 0.25 Klunder et al. (1998)
15 Cl (4-(2-aminopyridyl))ethyl 0.02 0.07 0.16 Klunder et al. (1998)
16 F (4-pyridyl)ethyl 0.05 0.08 0.25 Klunder et al. (1998)
17 I (4-pyridyl)ethyl 0.09 0.18 0.43 Klunder et al. (1998)
18 Cl (4-pyridyl)ethyl 0.08 0.12 1.85 Klunder et al. (1998)
19 Cl (phenylthio)methyl 0.02 0.01 0.03 Cywin et al. (1998)
20 Cl (phenyloxy)methyl 0.11 0.06 0.64 Cywin et al. (1998)
21 Cl (2-methyl-4-pyridinyl-oxy)methyl 0.03 0.03 0.23 Cywin et al. (1998)
22 Cl phenylethyl 0.05 0.15 0.96 Cywin et al. (1998)
23 Cl (3-(aminocarbonyl)phenyloxy)methyl 0.13 0.28 0.34 Cywin et al. (1998)
24 Cl (3-aminophenyloxy)methyl 0.05 0.10 0.37 Cywin et al. (1998)

*Inhibitor concentration to give 50% inhibition of incorporation of [3H]dGTP into a [(poly)rC•(oligo)dG] template.
†Wild-type HIV-1 RT.

ily (Glynn & Yazdanian, 1998). Like all current NNRTIs,
nevirapine selects for mutations in the RT, the most com-
mon resistant strain of HIV-1 being characterized by the
Y181C mutation. Mutations appear rapidly in response to
treatment with NNRTIs administered as monotherapy,
and the focus of researchers working with nevirapine ana-
logues has been to develop drug candidates that retain
activity against both wild-type HIV-1 and known
NNRTI-resistant HIV-1 strains.
The substitution pattern of the dipyridodiazepinone
ring system in the search for new derivatives was changed
from C-4 and N-11 to N-5 and N-11, as this appears to be
optimum for activity against both wild-type RT and
Y181C RT (Proudfoot et al., 1995a). Molecular modelling
of the X-ray crystal structure of nevirapine bound to wild-
type RT has revealed a lipophilic cavity proximal to the C-
4 position, which allows for placement of an aryl group at
this position. Although the placement of an amino group
in the para position of this aryl group produced derivatives
conferring activity against the Y181C mutant enzyme, the
activity was not strong (Kelly et al., 1995). Adding an aro-
matic substituent at position 2 afforded several analogues
with activity against both wild-type RT and Y181C
mutant RT (Proudfoot et al., 1995a) and some have also
shown activity against the Y188L mutant RT (Kelly et al.,
1997) (Table 1). Changing the position of the aromatic
substituent from position 2 to position 8, and introducing
an ethyl linker, have afforded new analogues with anti-
HIV activity against both wild-type RT and a broad spec-
trum of mutant RTs (Klunder et al., 1998). The aim in the
synthesis of these derivatives has been to achieve multiple
interaction points with the enzyme or to achieve interac-
tion between the compound and some more conserved
residues of RT. Some of these residues include the catalyt-
ic aspartic acid residues, Asp-110, Asp-185 and Asp-186.
Mutation of these residues results in inactive RT enzymes
(Larder et al., 1987). Further research has investigated the
linker between the aryl substituent and the dipyridodi-
azepine system (Cywin et al., 1998). The preferred substi-
tution at the 8 position was with an aryloxymethyl or an
arylthiomethyl, the arylthiomethyl derivatives being the
most active compounds (Table 2). The aryloxymethyl com-
pounds though, were metabolically more stable, less toxic
and yet possessed good activity, and are thus the choice for
further development rather than the thio analogues (Cywin
et al., 1998).
Several derivatives of nevirapine with changes in the
ring system have been synthesized and tested. Some of
these are the dipyrido[2,3-b:2′,3′-c]diazepinones
(Proudfoot et al., 1995b), pyridazinobenzodiazepines
(Heinisch et al., 1997a; Barth et al., 1996) and pyridoben-
zodiazepines (Hargrave et al., 1991). However, none of
these have shown an improved anti-HIV potency.
Dibenzoxapinones and pyridobenzoxazepinones (Tables
3 and 4) are analogues of nevirapine that have shown activ-
ity against HIV-1 RT in the nanomolar range (Klunder et

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Table 3. The anti-HIV-1 RT activity of some Table 4. The anti-HIV-1 RT activity of some
dibenz[b,f][1,4]oxazepin-11(10H)-ones pyrido[2,3-b][1,5]benzoxazepin-5(6H)-ones
R1 O
R1 O
N 1
9 N
7 4
2
8 3
8
R2 R3
7
O 3 R3
6 4 R2 O 2
9 N
1
Compound R1 R2 R3 IC50 (nM)*
1 CH3 7-CH3 2-NH2 30 Compound R1 R2 R3 IC50 (nM)*
2 CH2CH3 9-CH3 2-NH2 60 8 CH2CH3 8,9-(CH3)2 3-NH2 71
3 CH3 7,9-(CH3)2 2-NH2 20 9 CH(CH3)2 8,9-(CH3)2 3-NH2 45
4 CH2CH3 7,9-(CH3)2 2-NH2 43 10 CH3 7,9-(CH3)2 3-NH2 46
5 CH3 7,9-(CH3)2 H 57 11 CH2CH3 7,9-(CH3)2 3-NH2 27
6 CH3 7,9-(CH3)2 2-CN 50 12 CH2CH3 7,9-(CH3)2 H 29
7 CH3 7,9-(CH3)2 2-OH 63 13 CH2CH3 7-NO2, 9-CH3 H 31
14 CH2CH3 7-CN, 9-CH3 H 19
*Inhibitor concentration to give 50% inhibition of incorporation of
[3H]dGTP into a [(poly)rC•(oligo)dG] template. 15 CH3 7-CN, 9-CH3 H 55
Data from Klunder et al. (1992). 16 CH3 7-NO2, 9-CH3 H 23
17 CH3 7-CO2CH3, 9-CH3 H 22

al., 1992). As a class, oxazepinones are less potent HIV-RT
inhibitors than the diazepinones. This problem has been
partly solved by substituent optimization. However, solu-
bility is a problem for this class of compounds because
oxazepinones have the disadvantage of being less soluble
than diazepinones. Replacing a phenyl ring with a pyrimi-
dine ring in the dibenzoxazepinones may increase the sol-
ubility, but is often accompanied by a decrease in the
inhibitory effect on RT (Klunder et al., 1992).
BHAP
Bis(heteroaryl)piperazine (BHAP) RT inhibitors form a
class of compounds, discovered by the Upjohn laboratories
(delavirdine, atevirdine; Pharmacia & Upjohn) (Romero et
al., 1991). This subclass of NNRTIs contain delavirdine
mesylate (rescriptor), which was given FDA approval in
April 1997 for therapeutic use against HIV-1. Atevirdine
mesylate is another compound of this class that was chosen
*Inhibitor concentration to give 50% inhibition of incorporation of
[3H]dGTP into a [(poly)rC•(oligo)dG] template.
Data from Klunder et al. (1992).
for clinical evaluation (Romero et al., 1994). The structures
of delavirdine mesylate (U90152S) and atevirdine mesylate
(U87201E) are shown in Figure 2.
Later work has led to new analogues, the (alky-
lamino)piperidine BHAPs (AAP-BHAP). This has pro-
duced compounds with activity against RT containing the
Y181C and P236L mutations. The proline to leucine
mutation at position 236 appears in RT after several HIV-
1 passages in vitro in the presence of increased concentra-
tions of atevirdine or delavirdine (Romero et al., 1996).
Some AAP-BHAPs have, in a structure–activity relation-
ship programme, demonstrated excellent activity against
the wild-type virus (Romero et al., 1996) (Table 5).
Delavirdine has been found to block the replication of 25

Figure 2. The structures of delavirdine mesylate and atevirdine mesylate

HN
HN H3CO
H3CSO2-NH

N N
N N
N
N N
N H
H .CH3SO3H
.CH3SO3H O
O

Delavirdine mesylate Atevirdine mesylate

U90152S U87201E

DLV ATV

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 The NNRTI boom

Table 5. The in vitro inhibition of recombinant HIV-1IIIB RT mutants

R2

R3 HN

N
R4 N N N
H
O R1

IC50 (µM)*
Compound R1 R2 R3 R4 WT† P236L Y181C
Atevirdine mesylate 2.3 >60 >60
Delavirdine mesylate 0.26 18.0 8.32
Nevirapine 3.1 0.32 >60
1 mesylate Me i-Pr H H 0.23 0.74 0.80
2 Me i-Pr H (OCH2CH2)OH 0.3 0.41 0.77
3 Me i-Pr CH3SO2HN H 0.5 1.5 1.1
4 Me i-Pr CH3NHCONH H 0.18 NT‡ 1.6
5 c-Pr i-Pr H H 0.70 0.59 2.31
6 Me i-Pr H HOCH2 0.17 0.37 0.49

*IC50 (µM), concentration that inhibited the RNA-dependent DNA polymerase activity of RT by 50% using a rA.dT template:primer.
†Wild-type HIV-1 RT.
‡NT, Not tested.
Data from Romero et al. (1996).

primary HIV-1 isolates in peripheral blood lymphocytes
(PBL), including variants that are highly resistant to 3′-
azido-3′-deoxythymidine (zidovudine) and 2′,3′-dideoxyi-
nosine (didanosine), with a mean 50% effective dose (ED50)
of 0.066±0.137 µM (Dueweke et al., 1993). The mutations
Y181C and K103N conferred some resistance to delavir-
dine, as for many other NNRTIs. However, delavirdine has
been shown to inhibit the Y181C mutant RT with the
rA.dT template:primer at a 50% inhibitory concentration
(IC50) of 8.3 µM, whereas nevirapine and L-697,661 failed
to achieve 50% inhibition at 60 µM. This, together with
good oral bioavailability and good serum drug levels in ani-
mals, made the mesylate salt of delavirdine a candidate for
clinical trials (Dueweke et al., 1993).
These compounds did not, however, possess the desired
pharmacokinetic profile, primarily due to high clearance
rates. This afforded a new structure–activity relationship
programme focusing on compounds with increased activi-
ty against mutant RT (P236L and Y181C) with the appro-
priate pharmaceutical properties. These included alteration
of the 3-pyridine substituent because N-dealkylation of the
pyridine 3-alkylamino substituent is a predominant path-
way for metabolism of the BHAPs (Romero et al., 1996).
Work included varying the lipophilicity and introducing
polar water solubilizing groups. Because delavirdine also
underwent hydroxylation at C-6 of the pyridine ring, this
position was targeted for blocking. This was done by syn-
thesizing compounds containing a halogen at C-6 and one
compound containing a pyridazine ring where nitrogen
replaced C-6 (Romero et al., 1996). Substituting an ethyl
for a methyl group on the aminopiperidine spacer
enhanced the activity against Y181C and P236L mutant
RTs (Romero et al., 1996). Some of the most active com-
pounds in this series are presented in Table 6.
Replacing the 3-alkylamino in both BHAPs and AAP-
BHAPs with alkoxy groups has also been investigated
(Genin et al., 1996). Incorporation of a 3-alkoxy sub-
stituent has been shown to be beneficial on the metabolic
stability, evaluated in the presence of hepatic microsomal
cytochrome P450 in vitro, thus providing analogues with
similar or greater metabolic stability than delavirdine.
Some of these compounds possessed good activity against
wild-type and P236L RT enzymes, but the activity against
Y181C RT was diminished (Genin et al., 1996).
Benzoxazinones
Benzoxazinones are the third class of compounds from which
a non-nucleoside inhibitor has been approved by the FDA.
Efavirenz (DMP-266; DuPont) (Table 7) was approved in
September 1998 by the FDA for once-daily dosing to be used
in combination with other anti-HIV drugs in both adult and
paediatric patients.
Efavirenz is a very potent inhibitor against a wide range
of mutant HIV-1 RTs. Its activity against some of these are
presented in Table 8. In cell culture efavirenz selects for a
double mutation (L100I plus L103A) following 10 serial
passages at increasing concentrations (Young et al., 1995a).
However, no single RT substitution has yielded a mutant

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Table 6. Antiviral activities of selected compounds against resistant viruses

HN
CH3SO2HN 1. R = Et, Y = t-Bu and X = H

2. R = n-Pr, Y = t-Bu and X = H

N N N X 3. R = Et, Y = Et and X = H
N
H R 4. R = Et, Y = i-Pr and X = F
O
5. R = Et, Y = t-Bu and X = F

Y
H3C
N HN
H
N 6. Z = CO, Y = i-Pr and X = H
N
Z 7. Z = CO, Y = t-Bu and X = H
N N N X
8. Z = SO2, Y = t-Bu and X = H
N Et
H 9. Z = CO, Y = t-Bu and X = F
O
10. Z = SO2, Y = t-Bu and X = F

EC90 (µM)*
Compound HIV-1MF (P236L)† HIV-1IIIB (L100I, M230L)† HIV-1IIIB (Y181C)‡
Delavirdine mesylate >10 >10 5.2
1 0.19 0.08 0.03
2 0.32 0.11 0.03
3 0.31 0.08 0.18
4 0.3–1.0 0.11 0.14
5 0.22 0.12 ≤0.03
6 0.24 0.11 0.05–0.1
7 0.16 0.16 ~0.05–0.10
8 0.34 0.14 <0.03
9 0.16 0.14 0.13
10 0.29 0.29 0.15
*EC90, concentration of drug that inhibited p24 production in the antiviral assays by 90%.
†Delavirdine was used for the selection of BHAP-resistant MF and IIIB HIV-1 variants.
‡L-697,661 was used for the selection of the resistant IIIB HIV-1 variant.
Data from Romero et al. (1996).

Figure 3. The structure of 1-[(2-hydroxyethoxy)methyl]- virus for which the EC95 for inhibition by efavirenz has
6-(phenylthio)thymine (HEPT) and the benzyl been >1.5 µM. Most mutants are inhibited by efavirenz at
analogue MKC-442 EC95 values of 50 nM or less (Table 8). The lowest con-
centration of efavirenz that has yielded evidence of cyto-
O toxicity, both in primary cells and in T cells, is 80 µM,
O
giving a selectivity index of approximately 80000 (Young et
5
HN 3 HN al., 1995a).
1
O 6
N S O N HEPT derivatives
1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine,
O O HEPT (Figure 3), is the lead compound of this class of
HO NNRTI and was described in 1989 (Miyasaka et al., 1989).
HEPT was synthesized as an acyclonucleoside and was
expected to be a member of the nucleoside class of RT
HEPT MKC-442 inhibitors, which act as competitive inhibitors by mimick-
ing the natural substrate for the enzyme (Tantillo et al.,

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 The NNRTI boom

Table 7. The activity of selected benzoxazinones against HIV-1 RT and against a strain of HIV-1 with a double
mutation in RT

X R

Cl
O

N O
H

Configuration X R IC50 (nM)* WT IC50 (nM)† A17 RT ClC95 (nM)‡

(–) Efavirenz CF3 2 85 6

(–) CF3 8.6 69 12

(+/–) CF3 25 480 6

NC

(+/–) CClF2 12 350 ND§

CH
3
(+/–) CF3 N
CH
43 1950 100
3

*Inhibitor concentration to give 50% inhibition[(poly)rC•(oligo)dG] in wild-type RT.

†Inhibitor concentration to give 50% inhibition[(poly)rC•(oligo)dG] in A17RT, which is a mutant with double mutation: K103N and Y181C.
‡Concentration of inhibitor that reduced the spread of infection by at least 95% in MT-4 cells. HIV-1 p24 accumulation was directly
correlated with virus spread.
§ND, not determined.
Data from Young et al. (1995a).

1994). However, in antiviral testing it was found only to
inhibit HIV-1 and not HIV-2. From this it was deduced
that HEPT was different in its mechanism of inhibition of
HIV than the known nucleoside inhibitors zidovudine,
stavudine and didanosine.
Studies of the structure–activity relationship of HEPT
analogues have led to the synthesis of MKC-442 (I-EBU;
Triangle Pharmaceuticals) (Figure 3), which has entered
Phase III clinical trials. The importance of the substitution
pattern of the thiophenyl ring in the 6 position and the sub-
stituent at the 5 position were among the first characteris-
tics to be studied (Tanaka et al., 1992a). Substituting the
methyl group in the 5 position of HEPT with ethyl or iso-
propyl gave a marked increase in potency (Tanaka et al.,
1992a), whereas substitution with a hydrogen atom resulted
in loss of activity. Also, the substitution pattern of the 6-

Table 8. Inhibition of wild-type and mutant HIV-1 infection in cell culture by efavirenz*

EC95 (nM)‡ EC95 (nM)‡

Virus or amino Virus or amino
acid substitution† Efavirenz L-697,661 acid substitution† Efavirenz L-697,661
Wild-type IIIB 1.5 100 V108I 3 400
Wild-type MN 3 50 V179D 3 400
Wild-type RFII 3 50 Y181C 6 >3000.0
A98G 12 800 Y188L 1500 >3000.0
L100I 100 200 K101D+K103N 1500 >3000.0
K101E 25 800 K101D+L100I 1500 >3000.0
K103N 100 800 K103N+Y181C 400 >3000.0
V106A 12 100 L100I+K103N§ 25000 1500

*Comparative values are presented for efavirenz and the unrelated pyridinone L-697,661.
†Each mutant virus expressed the noted amino acid substitution at the indicated RT residue.
‡The EC95 was defined as the concentration of test compound that inhibited virus expression by at least 95% relative to virus expression in
untreated control cultures. Assays were performed in MT-4 human T-lymphoid cells.
§This variant was selected by passage of the HIV-1 IIIB strain in MT-4 cells in increasing concentrations of efavirenz.
Data from Young et al. (1995b).

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Table 9. Inhibition of HIV-1 replication in MT-4 cells by HEPT derivatives

R1
HN

O N R2

R3

Compound R1 R2 R3 EC50 (µM) CC50 (µM) SI

HEPT Me SPh HOCH2CH2OCH2 7.0* 740 106
E-HEPU-dM Et SPh(3,5-di-Me) HOCH2CH2OCH2 0.013* 149 11500
I-HEPU-dM i-Pr SPh(3,5-di-Me) HOCH2CH2OCH2 0.0027* 128 47400
E-HEBU-dM Et CH2Ph(3,5-di-Me) HOCH2CH2OCH2 0.013† 281 22000
I-HEBU-dM i-Pr CH2Ph(3,5-di-Me) HOCH2CH2OCH2 0.0027† 221 82000
E-BPU Et SPh PhCH2OCH2 0.0059‡ 34 5800
E-EBU-dM Et CH2Ph(3,5-di-Me) EtOCH2 0.0016† 207 130000
E-EBU Et CH2Ph EtOCH2 0.041† 245 6000
I-EBU-dM i-Pr CH2Ph(3,5-di-Me) EtOCH2 0.0006† 43 72000
MKC-442 i-Pr CH2Ph EtOCH2 0.0042† 186 44000
1 Et CH2Ph(3,5-di-Me) EtSCH2 0.004§ 68 17000
2 i-Pr CH2Ph EtSCH2 0.006§ 37 6200
3 Et CH2Ph MeSCH2 0.002§ 32 16000
4 i-Pr SePh(3-Me) EtOCH2 0.0081¶ 53 6540
5 i-Pr SePh(3,5-di-Me) EtOCH2 0.0047¶ >200 42600

Values may not be directly comparable due to differences in assay conditions.

Data from: *Tanaka et al. (1992a); †Tanaka et al. (1995); ‡Tanaka et al. (1991), two separate experiments.
The values was determined by the MTT method; §Danel et al. (1996).
EC50 was determined by the p24 antigen method and the MTT method was used for CC50.
The values are expressed as the mean of three independent determinations; ¶Kim et al. (1996).
The values were determined in CEM-SS cells and are the mean of two independent determinations in duplicate.

(phenylthio) moiety was investigated and substitution at the
2 or 4 position was ineffective, whereas substitution at the 3
position with methyl, ethyl or a fluoro substituent increased
the potency. Introduction of a methyl group or a chlorine at
both the 3 and 5 position was even more effective (Tanaka
et al., 1992a). Removal of the hydroxyl group in the (2-
hydroxyethoxy)methyl side chain also improved the poten-
cy (Tanaka et al., 1992b). Changing the phenylthio moiety
with benzyl analogues yielded even more potent inhibitors
of HIV-1 with selectivity indices of up to 130000 (Tanaka
et al., 1995). After studies on pharmacokinetics and follow-
ing toxicology tests, MKC-442 was selected as the candi-
date for clinical trials for AIDS chemotherapy (Tanaka et
al., 1995). The oral bioavailability of MKC-442 in rats was
18.4% and the 50% lethal dose in rats was >2000 mg/kg
(Tanaka et al., 1995). After molecular modelling studies on
HEPT derivatives (Hopkins et al., 1996), an analogue of
MKC-442 with naphtyl in place of phenyl was synthesized,
but it was 10-fold less active than MKC-442 and more toxic
(Danel et al., 1997). Many derivatives with variations in the
N-1 substituent have been synthesized. Among these are
some with more bulky groups, such as E-BPU (Tanaka et
al., 1991) (Table 9). Some have amines, amides and alkene
functionalities that are introduced into the N-1 linker
between the pyrimidyl moiety and different aromatic rings,
for example, phenyl, 2-furyl, 2-thienyl, 2-benzofuranyl and
so on (Pontikis et al., 1997). Some 1-substituted (ethyl-
thio)methyl and (methylthio)methyl analogues have shown
anti-HIV-1 activity comparable to MKC-442 and although
they have higher cytotoxicity, they still have high selectivity
indices (6200 to 17000) (Danel et al., 1996). Derivatives
with a selenyl in place of sulphur in the (phenylthio) moiety
have also been prepared (Kim et al., 1996) and some with
activities and selectivities that are comparable to those
obtained for MKC-442.
Some HEPT derivatives are highly bound to human
serum proteins and have been tested for antiviral activity in
the presence of varying percentages of human serum (HS)
in place of foetal bovine serum (FBS) (Baba et al., 1993).
MKC-442 (I-EBU) showed EC50 values of 0.014 µM (in
10% FBS), 0.018 µM (in 10% HS), 0.026 µM (in 30% HS)
and 0.063 µM (in 50% HS). Some 2-thio analogues of
HEPT have also been prepared and although the anti-HIV
activity has been good, they all bound with high affinity to
HS proteins, some with only 0.3 to 0.7% of the total com-
pound remaining unbound to proteins (Baba et al., 1993).

292 ©1999 International Medical Press

 The NNRTI boom

Figure 4. The basic structure of dihydroalkoxybenzyloxopyrimidines (DABOs) and

dihydrothioalkylbenzyloxopyrimidines (S-DABOs)

O O
5′ 5′
R1 R1
HN 3 4 5 4′
HN 3 4 5 4′
2 6 2
R2 1 3′ 6
R2 1 3′
O N 2′ S N 2′
DABOs S-DABOs

R1 : H, Me, Et or i-Pr

R2 : alkyl or cycloalkyl

Dihydroalkoxybenzyloxopyrimidines and thio
analogues
The dihydroalkoxybenzyloxopyrimidines (DABOs) and
their thio analogues (S-DABOs) are closely related to the
HEPT derivatives. DABO derivatives are characterized by
an alkoxy substituent, the S-DABOs by a thioalkyl group,
at C-2 in place of the N-1 substituent in the HEPT deriv-
atives (Figure 4).
Some 6-benzylpyrimidines were synthesized as dihy-
drofolate reductase inhibitors and because of their structur-
al similarities with HEPT they were tested, and some were
found to be active, against HIV-1 (Botta et al., 1992).
Unlike the HEPT derivatives, the DABOs are active with
hydrogen in the 5 position comparable with compounds
having a methyl group in the 5 position (Artico et al.,
1993). Substituting the 5 position with an ethyl or iso-
propyl does not increase the anti-HIV activity, however the
size of the C-2 alkoxy group seems to be important. The
best activities are achieved with bulky substituents for R2
(Figure 4), such as cyclohexyl, cyclopentyl or sec-butyl
(Artico et al., 1993). A methyl substituent in the 3′ position
increases the activity, whereas an additional methyl sub-
stituent in the 5′ position does not always increase the
potency. A compound with methyl in the 5 position, 3′,5′-
dimethyl substituted in the phenyl moiety and a sec-butyl
in the alkoxy group at C-2 had a selectivity of >416, and
has been one of the most active among the first DABO
compounds (Massa et al., 1995).
Replacing the side chain oxygen in the 2 position with
sulphur led to the S-DABO compounds, which showed
increased anti-HIV-1 activity (Mai et al., 1995). Alkylation
at N-3 and replacing C=O with C=S in the 4 position of the
pyrimidine ring led to compounds devoid of activity, where-
as substituting the 6-benzyl group with 1-naphtylmethyl
enhanced the activity of the S-DABO compounds (Mai et
al., 1997). Some highly active anti-HIV-1 compounds with

Table 10. Anti-HIV-1 activities of selected compounds of the S-DABO class

O

R1
HN

R3 R2
S N

R1 R2 R3 IC50 (µM)* ED50 (µM)† CD50 (µM)‡ SI§

Et phenyl allyl ND 1.5¶ >100 >67
H 1-naphtyl sec-butyl ND 0.33** >300 >909
Me phenyl MeSCH2 28.8±10.0†† 3.4±1.1 >100 32±10
Et phenyl MeSCH2 12.0±2.3†† 0.8±0.2 >100 146±38
i-Pr phenyl MeSCH2 5.6±2.4†† <0.001±0.000 >100 100000±0
H 2,6-di-F-phenyl sec-butyl 0.05‡‡ 0.04 >200 5000
Me 2,6-di-F-phenyl i-propyl 0.05‡‡ 0.05 >200 4000

*Concentration required to inhibit recombinant RT by 50%.

†Concentration to prevent the spread of HIV-1 in cell culture by 50%.
‡Concentration of compound that prevented proliferation of host cells by 50%.
§Selectivity index, CD50/ED50.
¶Danel et al. (1998).
**Mai et al. (1997).
††Sudbeck et al. (1998), (rA.dT template:primer).
‡‡Mai et al. (1999), (rC.dG template:primer).

Antiviral Chemistry & Chemotherapy 10:6 293

OS Pedersen & EB Pedersen
Figure 5. The structure of 2,3-dihydro-7H-thiazolo
[3,2-a]pyrimidin-7-ones, which can be considered a
hybrid between S-DABOs and HEPT
O Cl
2 R1
N c R1: Et, i-Pr
6
b
a 5 R2 : Ph, 3,5-Me2C6H3, 1-Naphtyl
R2
N4
S R3 : Me, Et, CH2CH2OH
1
OR3
a (methylthiomethyl)thio substituent at C-2 of the pyrimi-
dine ring (Table 10) have been designed based on the struc-
ture of the NNRTI binding pocket of RT (Sudbeck et al.,
1998). Molecular modelling supporting a hypothesis of
beneficial π-stacking interaction between Tyr-188 of the
NNRTI binding pocket in RT and the DABOs with 2,6-
dihalogenation in the benzyl group, has led to highly potent
inhibitors of HIV-1 (Mai et al., 1999). Some activities of S-
DABO compounds are presented in Table 10.
Bicyclic derivatives that can be considered as hybrids
between S-DABOs and HEPT analogues have also been
synthesized (Danel et al., 1998) (Figure 5).
These compounds showed only moderate anti-HIV
activity with the lowest EC50 value of 0.7 µM for the
compound with R1=ethyl, R2=3,5-Me2C6H3CH2 and
R3=ethyl. Some analogues with the thiazole ring fused to
the C-2 and N-3 bond of the S-DABO pyrimidine ring
was also synthesized, but these were either too toxic to the
host cells or devoid of antiviral activity (Danel et al.,
1998).
Imidazoles
In a screening programme seeking NNRTIs that would
inhibit HIV-1 strains that are resistant to known NNRTIs
or to zidovudine, AG 1549 (formerly S1153; Agouron
Pharmaceuticals and Shionogi Research Laboratories) was
Figure 7. The structures of some TIBO derivatives
S
HN
HN
N
H
CH3
N Cl
TIBO R82150
294
Figure 6. The structure of AG 1549, 5-(3,5-dichloro-
phenylthio)-4-isopropyl-1-(4-pyridyl)methyl-1H-
imidazol-2-yl-methyl carbamate
N
Cl
O
N
S
O
N NH2
selected from a set of derivatives of an initial lead com-
pound (Fujiwara et al., 1998). AG 1549 is a highly substi-
tuted imidazole (Figure 6), and had an IC50 value of 0.45
µM in a standard RT assay with poly(rA) and oligo(dT).
Some of the beneficial characteristics for AG 1549 are a
higher concentration in lymph nodes than in plasma after
oral administration to rats and an in vitro selectivity index
of 8000 (Fujiwara et al., 1998). The activities of AG 1549,
nevirapine, delavirdine and loviride were compared against
HIV-1 mutant clones (Table 11).
Mutant clones with single amino acid substitutions at
residues 100, 103, 106, 181, 188, 190, 227 and 236 showed
less than 10-fold reduced sensitivities compared to the
wild-type strain, whereas the clone with mutation L234I
was 22-fold less sensitive to AG 1549 (Fujiwara et al.,
1998) and was more sensitive to nevirapine and loviride
than the wild-type HIV strain. The double mutant strain
with the V106A plus Y181C mutation was still sensitive to
AG 1549, whereas the double mutant strain V106A plus
F227L was only somewhat sensitive.
AG 1549 was tested for in vitro selection of mutant
strains of HIV-1 and two clones were found and sequenced.
In both case more than one amino acid substitution muta-
tion was present. One strain contained the mutations V106A
plus F227L and the EC50 value for the clone was 740 ng/ml
S S
HN
N N
H H
CH3 CH3
N N
Cl
TIBO R82913 TIBO R86183
(9-Cl-TIBO) (8-Cl-TIBO)
©1999 International Medical Press
 The NNRTI boom

Table 11. Sensitivities of molecular clones of HIV with RT gene mutations to AG 1549 (S1153) and other
anti-HIV-agents

EC50 (µM)*
Virus mutation AG 1549 Nevirapine Delavirdine Loviride
Wild-type (strain NL342) 0.0069 0.025 0.011 0.018
L100I 0.0021 0.052 >0.905 0.015
K103N 0.0069 1.13 0.832 0.399
Y106A 0.0031 >1.88 0.271 0.285
Y181C 0.0093 >1.88 >0.905 >1.42
Y188C 0.0010 >1.88 0.058 0.655
G190A 0.0075 >1.88 0.0024 0.6712
F227C 0.0053 0.33 0.017 0.16
F227L 0.0010 0.11 0.0014 0.065
L234I 0.015 0.0013 0.024 0.0013
P236L 0.0024 0.079 >0.905 0.0080
V106A+Y181C 0.0055 >1.88 >0.905 >1.42
V106A+F227L 0.266 >1.88 0.067 >1.42

*Each value represents the mean of at least three experiments, each of which was performed in duplicate.
Data from Fujiwara et al. (1998).

(1.6 µM). Another clone containing K103T, V106A plus
L234I had an EC50 value of 37 ng/ml (0.08 µM) in cell cul-
ture using the MTT assay (Fujiwara et al., 1998).
Many NNRTIs bind to serum proteins, and AG 1549
has the greatest affinity for human albumin. In the presence
of 50 mg/ml of HS albumin and 1 mg/ml alpha-1-acid gly-
coprotein, AG 1549 showed a ninefold reduction in its activ-
ity compared with the activity without albumin. Taking this
into account, AG 1549 may still have a sixfold greater antivi-
ral activity than nevirapine in human plasma (Fujiwara et al.,
1998). AG 1549 is now undergoing clinical testing.
TIBO
Since the TIBO class ( Janssen Research Foundation) was
introduced as non-nucleoside inhibitors of HIV in vitro
(Pauwels et al., 1990), a lot of work concerning struc-
ture–activity relationships has been done using this class of
compounds (Figure 7).
In the early work of optimizing the TIBO class, it was
Figure 8. General structure of TIBO derivatives
X structure resulted in less active compounds or a total loss of
X = O, S or Se
HN 2
N 4
CH3
9
8
N early lead compounds, and 7-mono-methyl-substituted
7
found that a 3-methyl-2-butenyl substituent on N-6
(Kukla et al., 1991a), a methyl substituent at position 5 and
a thione in position 2, gave a very potent inhibitor of HIV-
1, particularly if the 5 position had the S-configuration
(R82150) (Pauwels et al., 1990) (Figure 8). Additionally, a
chloro substituent in position 9 gave a compound
(R82913) that had a 10-fold increase in activity, but also an
increase in cytotoxicity (Pauwels et al., 1990). Changing
the chloro substituent from position 9 to position 8 afford-
ed a compound (R86183) even more potent (Ho et al.,
1995). Compound R82913 has been subject to clinical
Phase I testing.
In the imidazole part of the structure it has been found
that replacement of the carbonyl oxygen with sulphur or
selenium causes an increase in the activity. A number of
variations in this position have been tested, including S-
phenylthiourea and O-methylated urea, and all have been
inactive. The proton on nitrogen in position 1 appeared to
be necessary, especially for the urea compounds, and this
group may be involved in direct hydrogen bonding to the
enzyme. Replacing the nitrogen in position 3 with a carbon
resulted in loss of activity. Most changes in the imidazole
activity (Kukla et al., 1991b).
Substitutions on the diazepine ring have also been inves-
tigated (Breslin et al., 1995). The 5-mono-methyl-substi-
tuted analogues, which were the original substitutions in the
analogues were comparable, being the most active in the
series. The 4,5,7-unsubstituted analogue and the 4-mono-
methyl-substituted analogues were less active. Substituting
larger and more bulky groups such as isopropyl and phenyl

Antiviral Chemistry & Chemotherapy 10:6 295

OS Pedersen & EB Pedersen

Table 12. Anti-HIV activities of some TIBO derivatives

HN
N

R1
N
R3 R2

Compound X R1 R2 R3 EC50(µM)* CC50(µM)† SI‡

R78305 O (+)-(S)CH3 allyl H 70§ 674 10
R82150 S (+)-(S)CH3 3,3-dimethylallyl H 0.028§ >870 >31071
R82913 S (+)-(S)CH3 3,3-dimethylallyl 9-Cl 0.0015§ 31 20667
1 S (±)-CH3 3,3-dimethylallyl H 0.097¶ ND** ND
2 Se (+)-(S)CH3 3,3-dimethylallyl 9-Cl 0.018¶ ND ND
3 S (+)-(S)CH3 3,3-dimethylallyl 8-SCH3 0.0050†† ND ND
4 S (+)-(S)CH3 3,3-dimethylallyl 8-F 0.0058†† ND ND
5 S (+)-(S)CH3 3,3-dimethylallyl 9-F 0.0250†† ND ND
R86775 S (+)-(S)CH3 3,3-dimethylallyl 8-Br 0.003‡‡ 53 18000
R84674 S (+)-(S)CH3 3,3-dimethylallyl 8-CH3 0.0014‡‡ 80 5700

*EC50 is the 50% inhibitory concentration for cytopathicity by HIV-1 in MT-4 cells.
†CC50 is the 50% cytotoxic dose in mock-infected MT-4 cells.
‡The ratio CC50/EC50 is the selectivity index (SI).
§Data from Pauwels et al. (1990).
¶Data from Kukla et al. (1991b).
**ND, not determined.
††Data from Ho et al. (1995).
‡‡Data from Pauwels et al. (1994).

produced no advantage except for compounds substituted
with isopropyl in position 4 and with an oxo group in posi-
tion 2, which were more active than the 4-methyl ana-
logues. Some (4 plus 5, 4 plus 7, 5 plus 6, 5 plus 7, 6 plus 7
and 7 plus 8) disubstituted or ring fused analogues were also
prepared (Breslin et al., 1995). The 5,7-di-Me (trans) ana-
logue was slightly better than the 5-mono substituted ana-
logue, being the most promising with an EC50 value of
0.042 µM in MT-4 cells. From this, the R,R (trans) and S,S
(trans) 5,7-dimethyl analogues were prepared for the 2-oxo
and 2-thio analogues. These compounds have a different
structure–activity relationship to the 5-methyl analogues.
The 2-oxo compounds were slightly more active than the
thio analogues and a chloro substituent at the 9 position
resulted in a significant loss in activity.
Substitution in the aromatic part of the TIBO structure
has also been investigated (Ho et al., 1995). Substituents in
the 8 position gave a large improvement in activity compared
with the parent compound, whereas substituents at the 9
position tended to have little effect on activity and 10 sub-
stituents decreased the activity (Ho et al., 1995) (Table 12).
PETT
The phenethylthiazolylthiourea (PETT) compounds were
derived from a systematic disassemblage of the molecular
structure of the known TIBO HIV-1 RT inhibitors
(Ahgren et al., 1995; Cantrell et al., 1996). The lead com-
pound of this series was LY73497 (Figure 9). Optimization
of this lead gave N-[2-(2-pyridyl)ethyl]-N-[2-(5-bro-
mopyridyl)]thiourea hydrochloride (LY300046:HCl) (tro-
virdine; Medivir), which has been selected for clinical trials.
Extensive structure–activity relationship studies of the
PETT compounds have been made. For this purpose the
structure of PETT is considered as a product of four parts
(Figure 10).
In part 1 of the structure, the phenethyl moiety, the sub-
stitution patterns have been investigated. Meta and partic-
ularly ortho substitution is preferred over para substitution
(Bell et al., 1995). Both mono substitution (Vig et al.,
1998), di and tri substitution (Bell et al., 1995) have given
very active compounds. The characteristics of the sub-
stituents have also been investigated (Bell et al., 1995).
Both electron donating and electron withdrawing of small
groups like fluoro, chloro, azido and methoxy substituents
were comparable with good activity. The chain length of an
alkoxy substituent was investigated, and the ethoxy sub-
stituent gave the maximum activity, whereas the more ster-
ically demanding propoxy and isopropoxy substituents
decreased the activity. Compounds where the phenyl group
was replaced with 2-pyridyl, as in trovirdine, gave the most
active compounds in a series with different heterocycles.
Active compounds have also been prepared with saturated

296 ©1999 International Medical Press

 The NNRTI boom

Figure 9. The structure of trovirdine and the lead Figure 10. Phenethylthiazolethiourea (PETT),
compound LY73497 separated into four parts for discussion of
structure–activity
S N

S S N
N N
H H
S
N N
LY 73497 H H

Br
S 1 2 3 4

N N N N
H H
.HCl
LY 300046 HCl
(trovirdine)
Trovirdine has an ED50 in HIV-1-infected MT-4 cells of 0.020 µM, and
an IC50 value against wild-type HIV-1 RT of 0.015 µM and IC50 values
against mutant HIV-1 RTs of 0.43 µM (Ile-100) and 2.50 µM (Cys-181)
(Cantrell et al., 1996).
heterocycles such as 1-piperidinyl and 1-piperazinyl (Mao
et al., 1998).
In part 2 of the molecule the ethyl linker was optimal for
activity. Methyl substitution in the benzylic position
enhanced activity, whereas a methyl in the phenylethyl
position diminished activity (Bell et al., 1995). A cyclo-
propyl linker with cis configuration, has been shown to be
an advantage for the urea-PETT analogues (Sahlberg et
al., 1998).
For part 3 of the molecule the N,N-unsubstituted-
thiourea was most active (Bell et al., 1995). Methyl substi-
tution on nitrogen adjacent to the phenethyl side chain
completely eliminated activity, whereas methyl substitution
on the nitrogen adjacent to the thiazole ring only decreased
the activity slightly. The reason for the difference in activi-
ty for N-methyl substitution may be owing to an internal
hydrogen bond (Figure 11).
Compounds with a urea part in place of the thiourea
have also been prepared. They give lower activity but may
possess better pharmacological properties than the thiourea
compounds (Sahlberg et al., 1998).
In part 4, the thiazole moiety, the most optimum com-
pounds have been achieved by replacing the thiazole with a
5-bromopyrid-2-yl. In the thiazole series several 4-substi-
tuted derivatives, including small alkyl, cyano, trifluo-
romethyl and ethoxycarbonyl substituted compounds were
quite potent inhibitors (Bell et al., 1995). In a series where
the thiazole was replaced with diazinyl it seemed that the
nitrogen in the 2 position was essential because the 4-pyri-
dazinyl derivate was devoid of activity (Heinisch et al.,
1997b). This seems to be in accordance with the proposed
internal hydrogen bond in anti-HIV active PETT com-
pounds (Figure 11).
The activity of new NNRTIs against strains of HIV
resistant to known NNRTIs is becoming more important,
and the PETT compounds show good activity against
some of the known resistant strains of HIV. Some of the
PETT derivatives showing good activity against single
mutations (Ile-100 and Cys-181) were tested in assays
against two double mutant HIV-1 strains. Five of the test-
ed compounds showed ED50 values below 10 µM against
one of the two double mutants (Ile-100 plus Asn-103 or
Ile-100 plus Cys-181) (Cantrell et al., 1996). These five
compounds are listed in Table 13.
The PETT compound trovirdine has shown to readily
penetrate the blood–brain barrier, as the concentration in
brain tissue parallelled those in plasma of male Fischer 344
rats (Ahgren et al., 1995). The in vitro protein binding of
trovirdine was 88.7% in rat plasma and 95.5% in human
Figure 11. The structure of PETT derivatives and
trovirdine with the proposed internal hydrogen
bond
S
(H,Me) R
N N
H
S N
PETT derivatives
S
HN N N
H
N
Br
Trovirdine

Antiviral Chemistry & Chemotherapy 10:6 297

OS Pedersen & EB Pedersen

Table 13. Five compounds tested with activity against double mutant HIV-1 RT in MT-4 cells

R3

R4 R2 R1
S

N N N
H H
R5

ED50 (µM)*
R1 R2 R3 R4 R5 WT† Ile-100 Cys-181 Ile-100/Asn-103 Ile-100/Cys-181
Cl F MeO H MeO 0.002 0.009 0.003 1.0 1.0
Br F H H EtO 0.013 0.09 0.007 1.6 1.0
Br F CN Me2N H 0.013 0.15 0.020 5.5 7.5
Br F EtO H F 0.006 0.10 0.006 10 1.2
Br CN EtO H F 0.004 0.04 0.005 >10 3.0

*Concentration of inhibitor that inhibited the infection of HIV-1IIIB in MT-4 cells, assayed with the XTT method after 5 or 6 days.
†Wild-type HIV-1 RT.
Data from Cantrell et al. (1996).

Table 14. Inhibition of HIV-1 by urea-PETT compounds

R1 R4
R2
O
R2 R4
O R1
N N N
H H
N N N
H H R3
R3

1–6 7–13

ED50 (µM)*
Compound R1 R2 R3 R4 WT WT† Clone 118‡ Clone 90§
1 H F F Cl 0.03 0.85 32 >32
2 NMe2 F F Br 0.5 NT¶ >25 >25
3 OMe F OMe Cl 0.011 0.09 17 3
4 OEt F OMe Cl 0.13 NT 14 >27
5 COMe F OMe Cl 0.2 NT >27 >27
6 OEt Cl F Br 0.07 NT 15 8
7 H F F Cl 0.01 0.01 NT NT
8 OEt Cl F Cl 0.016 0.06 0.1 NT
9 OEt Cl F CN 0.01 0.02 0.27 0.53
10 OEt F F Cl 0.01 0.03 0.75 0.27
11 OMe F OMe Cl 0.012 0.1 1.6 2.7
12 OEt F Cl Cl 0.01 0.1 0.1 0.1
13 OEt F OMe Br 0.025 0.4 NT NT
Trovirdine 0.02 5 0.8 >5
9-Chloro-TIBO 0.25 NT >22 124
Nevirapine 0.15 0.12 0.62 22
L-697,661 0.065 NT 0.85 >11

*Concentration of compound that reduced the CPE of HIV-1IIIB in MT-4 cells by 50% in an XTT assay.
†Tested in the presence of 15% human AB serum.
‡Clone 118 contains a L100I mutation.
§Clone 90 contains a Y181C mutation.
¶NT, Not tested.
Data from Sahlberg et al. (1998).

298 ©1999 International Medical Press

 The NNRTI boom

Table 15. The anti-HIV activity and inhibition of HIV-1 Table 16. Pyrimidine thioethers inhibition against
RT of selected alkenyldiarylmethanes (ADAM) HIV-1 wild-type and a delavirdine resistant strain
compared to delavirdine
H3COOC COOCH3 Cl

H3CO OCH3
N

X X H2N N S R

R EC90 (µM)*
Compound R HIV-1IIIB HIV-1MF†
R X IC50* EC50† CC50‡ TI§ 1 2-naphtyl 0.22 2.76
(CH2)4CH3 Br 0.38 9.2 138 15 2 CH=CHphenyl 0.15 5.05
CH2CH2N3 Br 94 1.1 >316 >278 3 CH=CHCONMe2 0.09 0.74
CH2CH2N3 Cl 2.0 0.27 41.8 155 4 CH=CHCONEt2 0.02 0.11
(CH2)3COOCH3 Cl 0.3 0.013 31.6 2430 5 3-methylphenyl 0.11 1.76
6 3-methoxyphenyl 0.27 3.21
*Inhibitory activity (µM) versus HIV-1 RT with rC.dG as the template 7 3-bromophenyl 0.35 4.52
primer. Delavirdine‡ 0.03 53.58
†50% inhibitory concentration (µM) for CPE of HIV-1RF in CEM-SS
cells.
‡Cytotoxic concentration (µM) for mock-infected CEM cells. *Concentration of drug that inhibited p24 production by 90% in
§Therapeutic index, CC50 divided by EC50. infected MT-4 cells.
Data from Cushman et al. (1998a). †Laboratory derived delavirdine-resistant variant of HIV-1.
‡Reference compound.
Data from Nugent et al. (1998).
plasma at a concentration of 2 µg/ml. Because of its simple
chemical synthesis, excellent antiviral activity, satisfactory potent compound of this class, with an EC50 value of 13
pharmacokinetic profile and acceptable toxicity, trovirdine nM and a selectivity index of 2430 (Cushman et al.,
entered Phase I clinical trials (Ahgren et al., 1995), but was 1998a,b).
later withdrawn. Bromo- and chloro substituents are preferred over iodo-
and unsubstituted derivatives (Table 15). The length of the
Urea-PETT alkenyl substituent is also important and it appears that a
The urea-PETT compounds may have better toxicological six atom chain is optimal for anti-HIV-1 activity
and phamacokinetic properties than the PETT com- (Cushman et al., 1998a).
pounds. It was found that the urea-PETT compounds
maintain their antiviral activity in cell culture in the pres- Pyrimidine thioethers
ence of added HS much better than the thiourea com- Pyrimidine thioethers (Pharmacia & Upjohn) as inhibitors
pounds (Sahlberg et al., 1998). This point urged the of HIV-1 RT were first reported by Althaus et al. (1996).
researchers at Medivir AB to make a structure–activity This class of RT inhibitors is primarily characterised by its
research (SAR) programme in which different urea-PETT potent activity against the P236L mutant, which renders
analogues were synthesized and evaluated (Table 14). This HIV-1 resistant to delavirdine (Nugent et al., 1998). The
gave ethyl linked (1–6) and conformational restricted lead compound of this class was 6-chloro-2-benzylthio-4-
cyclopropyl analogues (7–13). The cyclopropyl compounds pyrimidinamine, and several derivatives were investigated
were in general more potent than the ethyl linked com- by Nugent et al. (1998). Exchange of the chloro moiety in
pounds, especially against mutant HIV strains. the pyrimidine ring with trifluoromethyl gave a compound
only a little less potent, whereas exchange with other elec-
Alkenyldiarylmethanes tron-withdrawing groups was not so good. In the place of
Alkenyldiarylmethanes (ADAMs) were introduced as a R (Table 16) the enzyme can accommodate a large, but flat,
new class of NNRTIs in 1995 (Cushman et al., 1995, hydrophobic group. This could be an aryl group or an
1996). This afforded the first lead compound 3′,3′′-dibromo- alkenyl group. A secondary amide attached to an alkenyl
4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-1,1-diphenyl- has significantly less activity compared to a tertiary amide.
1-heptene, with an EC50 value of 9.2 µM and a selectivity This is thought to be caused by a hydrogen bonding pro-
index of 15. Further work has lead to methyl 3′,3′′- ton, or for steric reasons, in the lipophilic pocket of the
dichloro-4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-6,6- enzyme. Substitution of the sulphur with oxygen or nitro-
diphenylhexenoate (ADAM II) as the currently most gen decreased or removed the activity. Oxidation of the sul-

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OS Pedersen & EB Pedersen

Table 17. Antiviral activity of furo[2,3-c]pyridine pyrimidine thioethers against in vitro-selected NNRTI-resistant
HIV-1 variants

S N Cl
N

CH3 N

NH2

EC90 (µM)*
DLVR MF L-697,661R IIIB DLVR IIIB R88703R IIIB
Compound IIIB (WT) (P236L)† (Y181C)† (L100I)† (Y181C)†
(–)-(S)(PNU-142721) 0.001 0.008 1.1 0.07 0.17
(+)-(R) ND‡ >0.01 >3.0 ND ND
Racemate 0.002 0.01 2.4 0.06 0.17
Delavirdine 0.05 >10 5.2 >10 1.0
*EC90 concentration of drug that inhibited p24 antigen production by 90% in infected MT-4 cells.
†Primary resistance conferring mutation at the designated codon of HIV-1 RT.
‡ND, Not determined.
Data from Wishka et al. (1998a).

phur diminished the activity, and removal of the methylene
linker resulted in compounds devoid of activity. Table 16
shows some of the compounds with activity against wild-
type and the delavirdine-resistant HIV-1 (P236L) mutant
(Nugent et al., 1998).
Further study within the pyrimidine thioethers for com-
pounds with broad activity against several NNRTI-resistant
variants of HIV-1 have led to the furo[2,3-
c]pyridinethiopyrimidine class of compounds. These are
characterized by the aralkyl group and a methyl substituent
at the methylene linker. This methyl substitution introduces
a stereocentre at the carbon in the methylene linker (Table
17). Both the (R) and (S) enantiomers proved to be
Figure 12. Structure of other bicyclic TTD analogues
O O

Table 18. Antiviral activity of some TTDs S R1

N
O O
2′
7 S X S N O
1 N
2 3′
6 S (a)
R2
5 4N O
O O
R
N S R1
N
Compound X R EC50 (µM)* CC50 (µM)† H 3C N
QM96625 H 2-Cl-benzyl 0.1 >119 N O
QM96521 H CH2CN 0.9 502.7
R2 (b)
QM96537 H CH2CCH 1.0 376
QM96539 Cl CH2CN 0.09 340 O O
Br CH2CN 0.09 68.6
QM96639 F CH2CN 0.05 93.6 S S R1
N
Cl
*Compound concentration required to achieve 50% protection of
MT-4 cells from HIV-1IIIB induced cytopathogenecity, as determined N O
by the MTT method.
†Compound concentration dosage required to reduce the viability of R2 (c)
mock-infected cells by 50%, as determined by the MTT method. All
data represent mean values of at least two separate experiments. (a) Thieno[2,3-e][1,2,4]thiadiazine,(b) 6-methylpyrazolo[4,3-
Data from Arranz et al. (1998). c][1,2,4]thiadiazine, (c) 6-chlorothieno[3,2-e][1,2,4]thiadiazine.

300 ©1999 International Medical Press

 The NNRTI boom

Figure 13. Structure of carboxanilide UC84 with the
separation into four parts marked
O CH3
O CH3
H
N of HIV-1 resistant to known NNRTIs (Table 17).
S O
O methyl substituent in the furo[2,3-c]pyridine moiety has
Cl
a b c d
extremely potent inhibitors of wild-type HIV-1 RT with
IC50 values (rA.dT) from 20 to 85 nM, and of the mutant
RT P236L that is resistant to delavirdine, with IC50 values
from 22 to 25 nM (Wishka et al., 1998a). Interestingly,
activity against Y181C RT, which is observed to occur when
HIV-1 cultures are under pressure from many known
NNRTIs, was found to be dependent on the stereochem-
istry of these thiopyrimidines. PNU-142721, the (S)-enan-
tiomer, and the racemate were found to inhibit the enzyme
with IC50 values in the submicromolar range, whereas the
(R)-enantiomer was inactive. In cell culture PNU-142721
was very potent against HIV-1 wild-type and several strains
CH3 Another compound in this series, PNU-109886, with a
displayed increased potency against virus containing the
Y181C mutation. However, it is characterized by a less
favourable pharmacokinetic profile than PNU-142721
(Wishka et al., 1998b). PNU-142721 possess high antivi-
ral activity against a broad spectrum of HIV-1 variants and
a favourable pharmacokinetic profile, including penetra-
tion of the blood–brain barrier in the rat. The levels of
PNU-142721 found in the brain in an experiment with
rats was 75% of the simultaneous plasma concentrations
(Wishka et al., 1998a).

Figure 14. Structure of some active derivatives of UC 84

O CH3
O CH3
N
H
S O CH3

O
Cl
a b c d
H
H3C N
UC 38 O
H3C
S
H3C H O
N CH3
1 O
H3C
S
H3C H CH3
N CH2 N O
2 O CH3
H3C
S
H3C H O CH3
N
3 O
H3C
S
H3C H O
N
O
4
H3C O CH3
S
H3C H O
N
O
5
H3C O
S
CH3 H
N O CH3

6 H3C
O O CH3
S
CH3 H CH3
N O

7 H3C
O O CH3
S
CH3 H O
N CH3
8 H3C
O O CH3
S
CH3

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Table 19. Antiviral activity of oxathiin carboxanilide derivatives against wild-type and mutant HIV-1 strains in
CEM cells

EC50 (µM)*
Compound IIIB L100I V106A G138K Y181C CC50 (µM)†
UC 84 0.042 ≥112 >56 ≥56 42 25
UC 38 0.03 2.2 2.2 1.3 2.0 40
1 0.01 2 2 0.3 2.0 19
2 0.03 0.67 1.4 0.2 1.1 >317
3 0.1 1.3 1.7 0.33 1.8 20
4 0.1 1.8 2.1 1.7 1.8 36
5 0.6 2.2 1.6 1.8 1.6 14
6 0.6 0.91 1.2 0.2 1.8 30
7 0.9 2.1 1.2 2 2.0 30
8 0.9 1.9 1.0 0.35 1.5 2.3
Nevirapine 0.03 0.1 8.6 8.6 0.37 >75
TIBO R82913 0.03 0.9 6.2 2 5.3 >62

*Compound concentration required to reduce HIV-1-induced giant cell formation in CEM cell cultures by 50%.
†Compound concentration required to reduce viability of the host cells by 50%.
Data from Balzarini et al. (1995).

TTD resulted in less active compounds. Systems that have been

1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine (T-
TD) is a new class of NNRTI (Witvrouw et al., 1998). The
basic requirements for the structure of TTDs is N-4 alkyl
and N-2 benzyl groups (Table 18). Two compounds with a
2-picolyl in place of the N-2 benzyl were less active, where-
as a 3-picolyl derivative and a 2-picolyl derivative with a
benzyl group at N-4 was more potent than the benzyl ana-
logues (Arranz et al., 1998). Halogens have been substitut-
ed at the N-2 benzyl moiety, with optimum results
achieved by one ortho- or metha substituent because a 3-
fluorobenzyl derivative was more potent than the 3,5-
difluorobenzyl analogue (Witvrouw et al., 1998). The best
results concerning the N-4 alkyl substituent have so far
been with cyanomethyl, propargyl and benzyl. Substituents
of methyl, ethyl, propyl, allyl and cyanoethyl at N-4 pro-
duce less active compounds (Arranz et al., 1998; Witvrouw
et al., 1998).
Other bicyclic systems, where changes in the thiophene
ring of the thieno[3,4-e][1,2,4]thiadiazine have been tried,
investigated are thieno[2,3-e], 6-methylpyrazolo[3,4-e]
and 6-chlorothieno[3,2-e] fused TTD analogues (Arranz
et al., 1998) (Figure 12).
Carboxanilides and thiocarboxanilides
Oxathiin carboxanilide, UC 84 (NSC 615985), was origi-
nally synthesized as a potential fungicide by chemists at the
Uniroyal Chemical Company. In a screening programme
by the National Cancer Institute, UC 84 exhibited anti-
HIV activity. UC 84 completely protected CEM-SS cells
infected with HIV-1 from the cytopathic effect of HIV
with an EC50 value ranging from 0.1 µM to 1.0 µM,
depending on the infectivity condition (Bader et al., 1991).
UC 84 served as a lead (Balzarini et al., 1995) and consists
of an oxathiin moiety (part a), a carboxamide group (part b)
and a 2-chlorobenzoic acid (part c) that is esterified with
an isopropyl group (part d) (Figure 13).
A series of derivatives was synthesized (Balzarini et al.,
1995) with the following changes: part a, the oxathiin part,

Figure 15. Structure and substituents of UC 10, UC 82, UC 781 and UC 040

R= N and Z = O (UC 10)

O

Cl
S

N R R= and Z = S (UC 82)

H O
and Z = O (UC 781)
Z
CH3

R= and Z = S (UC 040)

O

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 The NNRTI boom

Table 20. Anti-HIV activities of UC 10, UC 82, UC 781
and UC 040
Compound EC50 (µM)* CC50 (µM)†
UC 10 0.008 20
UC 82 0.008 16
UC 781 0.008 >500 62500
UC 040 0.016 10
*Concentration required to inhibit the spread of HIV-1 by 50%
(XTT method), for paticular cell lines and virus isolates; see
Buckheit et al. (1997).
†50% cytotoxic concentration.
‡Therapeutic index.
Data from Buckheit et al. (1997).
was replaced by various alkoxy groups; part b was modified
from C=O to C=S, which in most cases increased the activ-
ity; part c was mostly unmodified; and part d was modified
with a variety of substituents. The eight most interesting
compounds in this series, UC 38 being the most potent, are
presented in Figure 14, and test results against HIV wild-
type and four mutant strains are presented in Table 19.
Further work with the thio analogues of this series have
led to three new highly active compounds related to UC 10
(Figure 15 and Table 20), with the compound UC 781 as a
very potent inhibitor (Buckheit et al., 1997).
UC 781 shows excellent inhibitory activity against sev-
eral mutant HIV-1 strains, including the L100I, V106A,
E138K and Y181C mutations (Table 21). In a test it has
selected for the mutations Y181C, V108I and K101E in
order of appearance (Buckheit et al., 1997). UC 781 was
shown to be a rapid tight-binding inhibitor of HIV-1 RT
(Barnard et al., 1997). In addition, UC 781 has been found
to readily penetrate isolated HIV-1 particles, and treatment
of isolated HIV-1 virions with UC 781 result in rapid inac-
tivation of the virus (Borkow et al., 1997). UC 781 may
thus be very interesting in a more protective manner as an
agent in retrovirucidal formulations.
TI‡
TDA (thiadiazole derivatives)
2500
The basic structure of the TDA derivatives is presented in
2000
Table 22. A derivative (RD3-2356) with a 2-chloro sub-
625
stituent in the phenyl moiety enhanced the activity com-
pared with a derivative containing an unsubstituted phenyl
moiety (RD3-2105) (Hanasaki et al., 1995). A 4-chloro
substituent has the opposite effect, producing compounds
with decreased or lacking activity (Ijichi et al., 1996).
Investigating the R2 and R3 alkyl substituents revealed
that the most potent congener of the TDA derivatives is 4-
(2,6-dichlorophenyl)-1,2,5-thiadiazol-3-yl N-methyl-N-
propylcarbamate (RD4-2024), whereas the
monoalkylcarbamate derivative, RD3-2380, was without
inhibitory effect (Ijichi et al., 1996). The easy synthesis of
TDA derivatives made them potential drug candidates for
HIV-1 infection (Hanasaki et al., 1995).
Sequence analysis of mutants resistant to TDA deriv-
atives has revealed a point mutation at position 181
(Tyr→ Cys) (Ijichi et al., 1996). When anti-HIV-1
assays were carried out in the presence of 50% HS to
evaluate TDA under more physiological conditions, the
inhibitory effects on HIV-1 replication showed a
10–200-fold decrease. The degree of reduction depends
on the lipophility, more lipophilic leading to less
inhibitory effect. The TDA derivatives were bound to
serum protein by more than 90% under these conditions
(Ijichi et al., 1996).
Diarylsulphones
The basic structure of diarylsulphones consists of two sub-
stituted phenyl groups linked by a sulphone group. In a
screening of 54 diarylsulphones and related derivatives, 2-

Table 21. Activities of UC compounds against viruses resistant to HIV-1-specific inhibition

EC50 (µM)*
Inhibitor to which isolate
is resistant (mutation) UC 10 UC 040 UC 781 UC 82 Nevirapine
HIV-1IIIB (control) 0.2 0.2 0.01 0.008 0.01
Oxathiin caboxanilide (L100I) 2.0 >2 0.5 0.3 0.1
UC 10-Costatolide (K103N) 7.3 >2 0.9 1.0 ND†
Thiazolobenzimidazole (V108I) 1.2 0.9 0.1 0.06 0.3
TIBO (A98G/V108I) 1.1 1.2 0.3 0.2 0.6
Calanolide A (T139I) 0.3 0.4 0.04 0.03 0.01
Diphenylsulphone (Y181C) 1.1 >2 0.9 0.2 5.9
Pyridionone (Y181C/L103N) >100 >2 >2 >2 >38
Costatolide (Y188H) 1.6 1.0 0.1 0.07 ND
HEPT (P236L) 0.2 0.4 0.02 0.02 0.02

*Concentration required to inhibit the spread of HIV-1IIIB in CEM-SS cells by 50% (XTT method).
†ND, Not determined.
Data from Buckheit et al. (1997).

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OS Pedersen & EB Pedersen

Table 22. Structure-activity relationsship of the TDA derivatives

R2

N R3
O
R1
O

N N
S

Compound R1 R2 R3 EC50 (µM)* CC50 (µM)†

RD3-2105 – Me Me 29 210
RD3-2356 2-Cl Me Me 0.44 162
RD3-2107 4-Cl Me Me 353 353
RD3-2236 2,3-dichloro Me Me 0.94 127
RD3-2219 2,4-dichloro Me Me 8.3 77
RD3-2218 3,4-dichloro Me Me 315 315
RD3-2233 2,5-dichloro Me Me 0.37 111
RD3-2220 2,6-dichloro Me Me 0.20 190
RD4-2025 2,6-dichloro Me Et 0.037 29
RD4-2024 2,6-dichloro Me Pr 0.013 28
RD3-2102 2,6-dichloro Me Bu 0.020 23
RD4-2031 2,6-dichloro Me Hex 0.12 19
RD3-2222 2,6-dichloro C5H10 0.96 221
RD3-2101 2,6-dichloro Et Et 0.25 314
RD4-2023 2,6-dichloro Et Bu 0.33 44
RD3-2380 2,6-dichloro H Bu 139 139

*50% Effective concentration, required to inhibit HIV-1-induced CPE by 50% in MT-4 cells (MTT method).
†50% Cytotoxic concentration, required to reduce cell viability by 50% in mock-infected MT-4 cells.
Data from Ijichi et al., (1996).

nitrophenyl phenyl sulphone (NPPS) was identified as a 1996). Several of the most active compounds in a series
RT inhibitor of the non-nucleoside class (McMahon et al., studied by Buckheit et al. (1996) had a chloro and a methy-
1993). The most active compounds are those with an lamine on the ring not containing the nitro group (Table
ortho-nitro group (McMahon et al., 1993; Buckheit et al., 23). Compounds where methyl replaced chloro were only

Figure 16. The structure of calanolide A and some anti-HIV active analogues

O O O O

O O O O O O O O O O O O

OH OH OH OAc

(+) Calanolide A (+) Calanolide B (–) Calanolide B 12-Acetoxycalanolide

ED50 0.1 µM ED50 0.4 µM (Costatolide) ED50 2.7 µM

IC50 20 µM IC50 15 µM ED50 0.3 µM IC50 13 µM

IC50 5.8 µM

EC50 is the concentration of inhibitor needed to prevent the spread of HIV by 50%. IC50 is the concentration of the inhibitor which reduce the
viability of host cells by 50%.

304 ©1999 International Medical Press

 The NNRTI boom

Table 23. Antiviral HIV-1 activity and RT inhibition of some diarylsulphones

R1 O O NO2

R2 S

R3

R4

Compound (NSC) R1 R2 R3 R4 EC50 (µM)* IC50 (µM)†

665527 -NH(CH2)3- Cl H 0.3 >200
667948 -NH(CH2)3- Me H 0.5 33
667951 NHMe H H Me 0.4 18.4
667952 NHMe H H Cl 0.08 61
671291 H Me NHMe H 0.2 32.7
671292 H Cl NHMe H 0.1 >200

*Concentration of compound required to inhibit the spread of HIV-1 in CEM-SS cells by 50% (XTT method).
†Concentration of compound required to inhibit HIV-1 RT by 50% using a rC.dG template primer.
Data from Buckheit et al. (1996).

slightly less active (Buckheit et al., 1996) and reduction of
the sulphone linker also reduces the antiviral activity
(McMahon et al., 1993). Compound NSC 667952 was the
most active in the series, retaining activity against the drug-
resistant virus isolate and having a sensitivity profile against
the L100I mutation (Buckheit et al., 1996). The diarylsul-
phones have recently been investigated as HIV-1 integrase
inhibitors. Some have been found to be interesting enough
for further investigation (Neamati et al., 1997).
Calanolide A
A 1:1 CH2Cl2:MeOH extract of fruits and twigs from
Callophyllum lanigerum var. austrocoriaceum, a rainforest tree
from Sarawak in Malaysia, showed anti-HIV activity in an
initial test (Kashman et al., 1992). From this extract some
coumarins were isolated and identified. The most active of
these compounds, in descending order, were (+)calanolide
A, (+)calanolide B and the ester derivative 12-acetoxy-
calanolide (Sarawak MediChem Pharmaceuticals) (Figure
16). In a search for calanolide A in other and more abun-
dant sources, several species of callophyllum were tested
(Fuller et al., 1994). In the latex from C. teysmannii miq.
var. inophylloide, a compound identified as the (–)calanolide
B or costatolide was isolated and tested. This costatolide,
though a known compound not previously identified as
having antiviral activity, showed anti-HIV activity compa-

Figure 17. The structure of the two pyridinones L-697,639 and L-697,661
Cl
H3 C

N
N H
H N
N O
O Cl
CH3
N O
N O H
H

L-697, 639 L-697, 661

HIV-1 RT HIV-1IIIB*

IC50† CIC95‡

L-697,639 20 nM 25–50 nM

L-697,661 19 nM 25–50 nM

*Assays using MT-4 cell culture preinfected with HIV-1IIIB at a low multiplicity.
†Concentration that caused 50% inhibition of HIV RT.
‡Concentration that inhibited the spread of HIV-1 infection by ≥95%.
Data from Goldman et al. (1991).

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Table 24. Anti-HIV-1 and anti-HIV-1 RT activity of Pyridinones

some pyridyl- and phenyl analogues of the 2-
The pyridinones L-697,639 and L-697,661 (Merck
pyridinone class
Research Laboratories; Figure 17) were reported in 1991
3′
MeO X (Goldman et al., 1991). Compound L-697,661, with 95%
4′
clearance concentration (ClC95) values in the nanomolar
H R
N 5′ range, has been clinically tested and good antiviral activity
Y was observed. However, antiviral activity was of short dura-
6′
tion owing to rapid onset of viral resistance (Hoffman et al.,
N O
H 1992). When new drug candidates are tested in HIV
antiviral and RT enzymatic assays they are often compared
X Y R IC50 (nM)* ClC95 (nM)† to L-697,661.
N CH 4′-Me, 5′-Et 19 13 Structural modifications on the 2-pyridone moiety have
CH CH 4′,5′-Me2 8 13 not been successful (Hoffman et al., 1992; Saari et al.,
N CH 4′,5′-Me2 9 50 1992). These include N-methylation, O-methylation, dele-
CH N 4′,5′-Me2 70 100
tion of one or both alkyl groups and substituting 5-ethyl
CH CH 265 400
with 5-methyl. Some structure–activity studies have also
N CH 680 800
been done replacing the benzoxazole by a pyridyl or a
*Concentration of compound that inhibit HIV-1 RT by 50% using phenyl (Wai et al., 1993) (Table 24). It was found that
rC.dG template primer.
†Concentration of compound that inhibits the spread of HIV-1 maximum enzyme inhibition was obtained with com-
infection in MT-4 cells, by ≥95% using a p24 core antigen ELISA pounds containing a 2′-methoxy group on either the
assay.
Data from Wai et al. (1993). phenyl or pyridyl ring. In the phenyl subclass several sub-
stituents were tried in the ortho position. Ethoxy- and
rable to (+)calanolide A (Fuller et al., 1994). nitro substituents were comparable with the methoxy sub-
A lot of structure–activity studies concerning (+)calano- stituent and some substituents (CN, F, Cl, MeS, Me) gave
lide A and (–)calanolide B have been performed (Galinis et only modestly active compounds. Substituents such as CF3,
al., 1996; Zembower et al., 1997) and despite increased NH2 and MeOCH2 were detrimental to activity. There is
knowledge of the structure–activity relationship for this no significant difference between the 2-methoxyphenyl
class of NNRTI, no new compounds more potent than the and 2-methoxy-3-pyridyl derivatives. In the pyridyl sub-
lead compounds have been found. Calanolide A is present- class the position of the pyridine nitrogen was found to be
ly in clinical testing. important, with the position of nitrogen at 3′ as the most

Table 25. Inhibition of HIV-1 RT and viral infection spread by selected 2-pyridinone analogues together with
the rates of acid hydrolysis
N
X
R

O
N O
H

Compound X R IC50 (nM)* ClC95 (nM) T1/2 (min)‡

L-697,661 NH 4,7-Cl2 20±4 50–100 17±4
1 CH2 H 23±1 50–100 218±18
2 CH2 4,7-Cl2 14±3 50 29±1
3 NH H 210±20 400–800 35±7
4 O H 191±30 ND¶ 12±0.2
5 O 4,7-Cl2 88±16 200 11±0.2
6 S 4,7-Cl2 11±1 25–50 34±7

*The concentration that produced 50% inhibition of RT using a rC.dG template primer, and stated as the mean of at least three determina-
tions ±SEM.
†The cell culture inhibitor concentration required to inhibit by > 95% the spread of HIV-1 in susceptible cell culture, stated as a range of
values if multiple determinations were made. An assay using MT-4 cells and HIV-1IIIB strain was used.
‡Determination were carried out in 90% ethanol, 10% 1 M HCl to ensure compound solubility and to maintain a final HCl concentration of
0.1 M.
¶ND, not determined.
Data from Hoffman et al. (1993).

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 The NNRTI boom

Table 26. Anti-HIV-1 RT activity and cytotoxicity of some α-APA analogues

R2

O NH2
Cl

N
H
R1
Cl

Compound Isomer R1 R2 EC50 (nM)* CC50 (µM)† SI‡

R 15345 (±) OCH3 H 610 15 25
R 18893 (±) NO2 H 88 80 909
R 87231 (+) NO2 H 1700 82 48
R 87232 (–) NO2 H 33 66 2000
R 88703 (±) C(O)CH3 H 26 130 5000
R 88976 (+) C(O)CH3 H 6500 120 18
R 88977 (–) C(O)CH3 H 19 52 2737
R 89439 (±) C(O)CH3 CH3 13 710 54615
R 90384 (+) C(O)CH3 CH3 2100 270 129
R 90385 (–) C(O)CH3 CH3 5 420 84000
L-697,661 22 320 14545
AZT 0.5 3.5 7000

*Concentration required for prevention of spread of HIV-1 in cell culture by 50% (MTT procedure).
†Fifty percent toxicity concentration in MT-4 cells (MTT procedure).
‡Selectivity index is the ratio of CC50 to EC50.
Data from Pauwels et al. (1993).

Figure 18. Other NNRTIs

H3C NH2
O
N N
N
O Cl S

Cl N O O
S O O
CH3 O
O O
1 2 3

NH2

H3C F

Cl N
S F
N N
O O N
N
O O
F F
F
S F
4 5 6

N
O
N N
H3C H
NH N
O
Cl S SiO
O O O
SiO N O
O
O
NH2
N NH2
H O OSi
NH2 S
O OSi
S
O O
O O
7 8 9

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OS Pedersen & EB Pedersen
Figure 19. Other NNRTIs
H H
N S
CH3
H3C
N CH3 O N
O O
H2C CH3
10 11
S-2720 HBY 097
MeO
MeO
N CN
O
MeO
Cl
13 14
U-78036
favourable. Small lipophilic groups at 4′- and 5′-positions
are required for optimum activity and analogues with larg-
er alkyl groups are less potent. Methyl substitution at the
3′- and 6′-positions was detrimental. In this series of com-
pounds 3-[[(5-ethyl-2-methoxy-6-methyl-3-pyridyl)-
methyl]amino]-5-ethyl-6-methylpyridin-2(1H)-one (first
entry in Table 24) was selected for clinical evaluation due
to the best oral availability in rats and monkeys.
A structure–activity relationship study of 2-pyridinones
with a hydrolytically more stable ethyl linker in place of the
amino-methylene linker was made (Hoffman et al., 1993)
although the original lead had shown less potential with an
ethyl linker. As observed in earlier studies, a change in the
length or a reduction in the flexibility decreased the
inhibitory potency. The effect of thiocarbonyl modification
of the pyridinones was minimal in enzyme inhibition, but
they were less effective in the prevention of virus spread in
cell culture, which could reflect poorer cell penetration of
these pyridinethione analogues. Many of the compounds
with a benzoxazole as in L-697,661 and an ethylene linker
were highly active, particularly those unsubstituted, substi-
tuted in the 4 or 7 position or disubstituted in the 4 and 7
position. The number of potent candidates was reduced by
investigating the susceptibility of hydrolysis in acidic envi-
ronments. This revealed one compound, the unsubstituted
analogue 1 in Table 25, 10-fold more stable to acid hydrol-
308
N S
CH3
S
H
O O S
N
H 3C CH3
O
12
Thiazoloisoindol-5-one, C10H7 derivative
MeO
OMe
OMe
ysis than the other derivatives. Compounds with an ether,
or a thioether linker were also prepared and tested (Table
25). The ether linker decreased the activity, whereas the
analogue of L-697,661 with a thioether linker was more
inhibitory to HIV-1 RT than L-697,661 and had an
improved stability in an acid environment. It was not as
stable as the unsubstituted counterpart with an ethyl link-
er (Compound 1 in Table 25).
The early candidate of the pyridinones, L-697,661, was
very tightly bound (99.6%) to human plasma and com-
pound 1 was found to be 4% unbound to human plasma
protein, which suggested a 10-fold higher free drug level in
vivo. Compound 1 has been studied clinically in HIV-pos-
itive patients. Resistance to compound 1 has been observed
in cell culture experiments with virus from clinical isolates
obtained from patients who developed resistance to L-
697,661 (Hoffman et al., 1993).
α-APA (α-anilinophenylacetamide)
A screening programme of 2000 compounds belonging to
different classes led to the discovery of the lead α-APA
derivative R 15345 with an EC50 of 0.6 µM in MT-4 cells
(Table 26). Through evaluation of structurally related
compounds, R 18893 with a nitro group in place of the
methoxy substituent in the ortho position of the aniline
moiety was identified as a more potent inhibitor, with an
©1999 International Medical Press

EC50 value of 88 nM in MT-4 cells (Pauwels et al., 1993).
At this stage it appeared as the antiviral activity was stere-
ospecific as the (–) isomer was 50-fold more potent (EC50
33 nM) compared with the (+) isomer (EC50 1700 nM).
Further optimization was made by replacing the nitro
substituent with an acetyl group, R88703 and by adding a
methyl substituent in the para position of the acetyl group
on the aniline moiety. This led to the most potent
inhibitor of this series, 90385, with a selectivity index of
80000 (Pauwels et al., 1993). The compound R 89439 (SI
54,615) was further evaluated against some mutant
strains of HIV-RT and RT mutants containing a Y181C
or Y188C mutation showed resistance to α-APA deriva-
tives, whereas RT containing a I100L mutation was still
sensitive to R 89439. A relatively easy chemical synthesis
of R 89439, good oral availability and favourable pharma-
cokinetics made R 89439 (loviride) a valid candidate
(Pauwels et al. 1993). The α-APA project and further
development of loviride has been stopped by Janssen
Pharmaceuticals.
Other compounds
A lot of compounds and classes of compounds have been
found to have activity against HIV-1 RT have been syn-
thesized. Some of these are presented in Figures 18 and 19.
Compound 1 was the most active of the 5-H-pyrrolo[1,2-
b][1,2,5]benzothiadiazepines (PBTDs) with an EC50 value
of 0.5 M and a selectivity index of >600 (Artico et al.,
1996). Compound 2, a pyrrolobenzoxazepinone with an
IC50 value in an enzymatic assay (rC.dG) of 250 nM com-
pared to nevirapine (IC50 500 nM), was the most potent
NNRTI in a series by Campiani et al. (1996). Further work
with sulphones and NPPS as a lead afforded the pyrryl aryl
sulphones (PAS). Two of these compounds, 3 and 4, had
similar anti-HIV-1 activities with an EC50 of 0.14 µM in
MT-4 cells and a selectivity index of >2140. This is a high-
er EC50 value and selectivity index than for zidovudine
(Silvestri et al., 1997).
With TBZ (5) (Chimirri et al., 1997) as the lead struc-
ture, a 2-aryl-substituted benzimidazole 6 with an EC50
value of 0.20 Μ in an antiviral assay was synthesized (Roth
et al., 1997).
A sulphone compound (7) was found to inhibit viral
spread in MT-4 cells with a ClC95 of 3 nM (Williams et al.,
1993).
Derivatives of TSAO-T (8) are also inhibitors of HIV-1
RT and are unique in that they interfere at the interface
between the p51 and p66 subunits of RT. One 1,2,3-triazole-
TSAO analogue, compound 9, is reported to have a selectiv-
ity index of 1470 in MT-4 cells (Velázquez et al., 1998).
Quinoxaline derivatives have also been an important
class of NNRTIs. S-2720 has shown activity in a cell
spread assay with a 50% effective concentration in the
Antiviral Chemistry & Chemotherapy 10:6
The NNRTI boom
nanomolar range and a selectivity index of 104 (Kleim et
al., 1993). HBY 097, another quinoxaline, was withdrawn
after finishing Phase IIa clinical testing. HBY 097 showed
activity against HIV-1 in PBL (mean of 41 clinical iso-
lates) with an EC50 of 0.002 µM and with a selectivity
index of 12500 (Kleim et al., 1995). Strains of HIV-1 gen-
erated under high selective pressure of HBY 097 revealed
a G190E mutation which is characteristic for the quinox-
alines (Kleim et al., 1995). RT with glutamic acid in posi-
tion 190 has shown a dramatic decrease in enzymatic
activity compared to the HIV-1MN RT (wild-type) (Kleim
et al., 1993). Compound 12 [(R)-9b-(1-naphtyl)-2,3-
dihydrothiazolo[2,3-a]isoindol-5(9bH)-one] is a member
of the thiazoloisoindol-5-ones, which has shown an EC50
value of 0.046 µM in MT-2 cells, but the compound was
only moderately orally available in rats (Mertens et al.,
1993). Also, the quinoline U-78036 (13) has shown activ-
ity against HIV-1 RT (Althaus et al., 1993). A tetrahy-
dronaphtalene lignan derivative (14) has shown a 50%
effective inhibition concentration in antiviral assays of
0.15 to 0.8 µM and a selectivity index of 70–400 (Hiroto
et al., 1997).
Future perspectives for NNRTIs
NNRTIs appear to be very promising therapies in the
treatment of HIV, when used in combination with other
anti-HIV drugs such as nucleoside RT inhibitors and pro-
tease inhibitors. NNRTIs have the advantage that they are
able to cross the blood–brain barrier and in this way can
have an antiviral effect against HIV-1 infections in reser-
voirs that are out of reach for many other anti-HIV drugs,
including most of the nucleoside RT inhibitors.
The first generation of NNRTIs, nevirapine and
delavirdine, have suffered from a rapid development of
resistance. To overcome this problem, the NNRTIs have
been used in high doses and in combination with two or
three other anti-HIV drugs in HAART. The problem of
resistant strains of HIV may be reduced with the second
generation of NNRTIs because RT will need two or more
mutations for HIV-1 to be resistant to these drugs. Also,
the uptake of the second generation of NNRTIs in the
blood and cells may be increased and thereby increase the
concentration that can effect the inhibition of RT. The per-
spectives of the new generation of NNRTI inhibitors are
thus promising with an expected slower development of
resistance combined with their ability to cross the
blood–brain barrier.
References
Ahgren C, Backro K, Bell FW, Cantrell AS, Clemens M, Colacino
JM, Deeter JB, Engelhardt JA, Hogberg M, Jaskunas SR, Johansson
309
OS Pedersen & EB Pedersen
NG, Jordan CL, Kasher JS, Kinnick MD, Lind P, Lopez C,
Morin JM Jr, Muesing MA, Noreen R, Oberg B, Paget CJ,
Palkowitz JA, Parrish CA, Pranc P, Rippy MK, Rydergard C,
Sahlberg C, Swanson S, Ternansky RJ, Unge T, Vasileff RT, Vrang
L, West SJ, Zhang H & Zhou X-X (1995) The PETT series, a
new class of potent nonnucleoside inhibitors of human immunod-
eficiency virus type 1 reverse transcriptase. Antimicrobial Agents and
Chemotherapy 39:1329–1335.
Althaus IW, Gonzales AJ, Chou JJ, Romero DL, Deibel MR, Chou
KC, Kezdy FJ, Resnick L, Busso ME & So AG (1993) The
quinoline U-78036 is a potent inhibitor of HIV-1 reverse tran-
scriptase. Journal of Biological Chemistry 268:14875–14880.
Althaus IW, Chou K-C, Lemay RJ, Franks KM, Deibel MR, Kezdy
FJ, Resnick L, Busso ME, So AG, Downey KM, Romero DL,
Thomas RC, Aristoff PA, Tarpley WG & Reusser F (1996) The
benzylthio-pyrimidine U-31,355, a potent inhibitor of HIV-1
reverse transcriptase. Biochemical Pharmacology 51:743–750.
Arranz E, Díaz JA, Ingate ST, Witrouw M, Pannecouque C,
Balzarini J, De Clercq E & Vega S (1998) Novel 1,1,3-trioxo-
2H,4H-thieno[3,4-e][1,2,4]thiadiazine derivatives as non-nucleo-
side reverse transcriptase inhibitors that inhibit human
immunodeficiency virus type 1 replication. Journal of Medicinal
Chemistry 41:4109–4117.
Artico M (1996) Non-nucleoside anti-HIV-1 reverse transcriptase
inhibitors (NNRTIs): a chemical survey from lead compounds to
selected drugs for clinical trials. Il Farmaco 51:305–331.
Artico M, Massa S, Mai A, Marongiu ME, Piras G, Tramontino E
& La Colla P (1993) 3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopy-
rimidines (DABOs): a new class of specific inhibitors of human
immunodeficiency virus Type 1. Antiviral Chemistry &
Chemotherapy 4:361–368.
Artico M, Silvestri R, Pagnozzi E, Stefancich G, Massa S, Loi AG,
Putzolu M, Corrias S, Spiga MG & La Colla P (1996) 5-H-
Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): a novel class
of non-nucleoside reverse transcriptase inhibitors. Bioorganic and
Medicinal Chemistry Letters 4:837–850.
Baba M, Yuasa S, Niwa T, Yamamoto M, Yabuuchi S, Takashima H,
Ubasawa M, Tanaka H, Miyasaka T, Walker RT, Balzarini J, De
Clercq E & Shigeta S (1993). Effect of human serum on the in
vitro anti-HIV-1 activity of 1-[(2Hydroxyethoxy)methyl]-6-
(phenylthio)thymine (HEPT) derivatives as related to their
lipophilicity and serum protein binding. Biochemical Pharmacology
45:2507–2512.
Bader JP, McMahon JB, Schultz RJ, Narayanan VL, Pierce JB,
Harrison WA, Weislow OS, Midelfort CF, Stinson SF & Boyd
MR (1991) Oxathiin carboxanilide, a potent inhibitor of human
immunodeficiency virus reproduction. Proceedings of the National
Academy of Sciences, USA 88:6740–6744.
Balzarini J, Brouwer WG, Felauer EE, De Clercq E & Karlsson A
(1995) Activity of various thiocarboxanilide derivatives against
wild-type and several mutant human immunodeficiency virus type
1 strains. Antiviral Research 27:219–236.
Barnard J, Borkow G & Parniak MA (1997) The thiocarboxanilide
nonnucleoside UC781 is a tight-binding inhibitor of HIV-1
reverse transcriptase. Biochemistry 36:7786–7792.
Barth B, Dierich M, Heinisch G, Jenny V, Matuszczak B, Mereiter
K, Planer R, Schöpf I, Stoiber H, Traugott T & Aufschnaiter PV
(1996) Pyridazino[3,4-b][1,5]benzoxazepin-5(6H)-ones: synthesis
and biological evaluation. Antiviral Chemistry & Chemotherapy
7:300–312.
Bell FW, Cantrell AS, Högberg M, Jaskunas SR, Johansson NG,
Jordan CL, Kinnick MD, Lind P, Morin JM Jr, Noréen R, Öberg
B, Palkowitz JA, Parrish CA, Pranc P, Sahlberg C, Ternansky RJ,
Vasileff RT, Vrang L, West SJ, Zhang H & Zhou X-X (1995)
Phenethylthiazolethiourea (PETT) compounds, a new class of
310
HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic
structure–activity relationship of PETT analogs. Journal of
Medicinal Chemistry 38:4929–4936.
Borkow G, Barnard J, Nguyen TM, Belmonte A, Wainberg MA &
Parniak MA (1997) Chemical barriers to human immunodeficien-
cy virus type 1 (HIV-1) infection: retrovirucidal activity of UC781,
a thiocarboxanilide nonnucleoside inhibitor for HIV-1 reverse
transcriptase. Journal of Virology 71:3023–3030.
Botta M, Artico M, Massa S, Gambacorta A, Marongiu ME, Pani
A & La Colla P (1992) Synthesis, antimicrobial and antiviral
activities of isotrimethoprim and some related derivatives.
European Journal of Medicinal Chemistry 27:251–257.
Breslin HJ, Kukla MJ, Ludovici DW, Mohrbacher R, Ho W,
Miranda M, Rodgers JD, Hitchens TK, Leo G, Gauthier DA, Ho
CY, Scott MK, De Clercq E, Pauwels R, Andries K, Janssen
MAC & Janssen PAJ (1995) Synthesis and anti-HIV-1 activity of
4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-
2(1H)-one (TIBO) derivatives. 3. Journal of Medicinal Chemistry
38:771–793.
Buckheit RW Jr, Fliakas-Boltz V, Russell JD, Snow M, Pallansch
LA, Yang SS, Bader JP, Khan TN & Zanger M (1996) A diaryl-
sulphone non-nucleoside reverse transcriptase inhibitor with a
unique sensitivity profile to drug resistant virus isolates. Antiviral
Chemistry & Chemotherapy 7:243–252.
Buckheit RW Jr, Snow MJ, Fliakas-Boltz V, Kinjerski TL, Russell
JD, Pallansch LA, Brouwer WG & Yang SS (1997) Highly potent
oxathiin carboxanilide derivatives with efficacy against nonnucleo-
side reverse transcriptase inhibitor-resistant human immunodefi-
ciency virus isolates. Antimicrobial Agents and Chemotherapy
41:831–837.
Campiani G, Nacci V, Fiorini I, De Filippis MP, Garofalo A, Greco
G, Novellino E, Altamura S & Di Renzo L (1996)
Pyrrolobenzothiazepinones and pyrrolobenzoxazepinones: novel
and specific non-nucleoside HIV-1 reverse transcriptase inhibitors
with antiviral activity. Journal of Medicinal Chemistry
39:2672–2680.
Cantrell AS, Engelhardt P, Högberg M, Jaskunas SR, Johansson
NG, Jordan CL, Kangasmetsä J, Kinnick MD, Lind P, Morin JM
Jr, Muesing MA, Noreén R, Öberg B, Pranc P, Sahlberg C,
Ternansky RJ, Vasileff RT, Vrang L, West SJ & Zhang H (1996)
Phenethylthiazolylthiourea (PETT) compounds as a new class of
HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further
structure-activity relationship studies of PETT analogs. Journal of
Medicinal Chemistry 39: 4261–4274.
Chimirri A, Grasso S, Molica C, Monforte A-M, Monforte P,
Zappala M, Bruno G, Nicolo F, Witvrouw M, Jonckeere H,
Balzarini J & De Clercq E (1997) Structural features and anti-
human immunodeficiency virus (HIV) activity of the isomers of 1-
(2′,6′-difluorophenyl)-1H,3H-thiazolo[3,4-a]benzimidazole, a
potent non-nucleoside HIV-1 reverse transcriptase inhibitor.
Antiviral Chemistry & Chemotherapy 8:363–370.
Cushman M, Golebiewski M, Buckheit RW Jr, Graham L & Rice
WG (1995) Synthesis and biological evaluation of an alkenyl-
diarylmethane (ADAM) which acts as a novel non-nucleoside
HIV-1 recerse transcriptase inhibitor. Bioorganic & Medicinal
Chemistry Letters 5:2713–2716.
Cushman M, Golebiewski WM, Graham L, Turpin JA, Rice WG,
Fliakas-Boltz V & Buckheit RW Jr (1996) Synthesis and biologi-
cal evaluation of certain alkenyldiarylmethanes as anti-HIV-1
agents which act as non-nucleoside reverse transcriptase inhibitors.
Journal of Medicinal Chemistry 39:3217–3227.
Cushman M, Casimiro-Garcia A, Hejchman E, Ruell JA, Huang
M, Schaeffer CA, Williamson K, Rice WG & Buckheit RW Jr
(1998a) New alkenyldiarylmethanes with enhanced potencies as
anti-HIV agents which act as non-nucleoside reverse transcriptase
inhibitors. Journal of Medicinal Chemistry 41:2076–2089.
©1999 International Medical Press

Cushman M, Casimiro-Garcia A, Williamson K & Rice WG
(1998b) Synthesis of a non-nucleoside reverse transcriptase
inhibitor in the alkenyldiarylmethane (ADAM) series with opti-
mized potency and therapeutic index. Bioorganic and Medicinal
Chemistry Letters 8:195–198.
Cywin CL, Klunder JM, Hoermann M, Brickwood JR, David E,
Grob PM, Schwartz R, Pauletti D, Barringer KJ, Shih C-K, Sorge
CL, Erickson DA, Joseph DP & Hattox SE (1998) Novel nonnu-
cleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-
Aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones.
Journal of Medicinal Chemistry 41:2972–2984.
Danel K, Larsen E, Pedersen EB, Vestergaard BF & Nielsen C
(1996) Synthesis and potent anti-HIV-1 activity of novel 6-benzy-
luracil analogs of 1-[(2-hydroxyethoxy)methyl]-6-
(phenylthio)thymine. Journal of Medicinal Chemistry
39:2427–2431.
Danel K, Nielsen C & Pedersen EB (1997) Anti-HIV active naphtyl
analogues of HEPT and DABO. Acta Chemica Scandinavica
51:426–430.
Danel K, Pedersen EB & Nielsen C (1998) Synthesis and anti-HIV-
1 activity of novel 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-
ones. Journal of Medicinal Chemistry 41:191–198.
De Clercq E (1998a) The role of non-nucleoside reverse transcrip-
tase inhibitors (NNRTIs) in the therapy of HIV-1 infection.
Antiviral Research 38:153–179.
De Clercq E (1998b) New perspectives for the treatment of HIV
infections. Collection of Czechoslovak Chemical Communications
63:449–479.
Ding J, Das K, Moereels H, Koymans L, Andries K, Janssen PAJ,
Hughes SH & Arnold E (1995) Structure of HIV-1 RT/TIBO R
86183 complex reveals similarity in the binding of diverse nonnu-
cleoside inhibitors. Nature Structural Biology 2:407–415.
Dueweke TJ, Poppe SM, Romero DL, Swaney SM, So AG,
Downey KM, Althaus IW, Reusser F, Busso M, Resnick L,
Mayers DL, Lane J, Aristoff PA, Thomas RC & Tarpley WG
(1993) U-90152, a potent inhibitor of human immunodeficiency
virus type 1 replication. Antimicrobial Agents and Chemotherapy
37:1127–1131.
Fujiwara T, Sato A, El-Farrash M, Miki S, Abe K, Isaka Y, Kodama
M, Wu Y, Chen BL, Harada H, Sugimoto H, Hatanaka M &
Hinuma Y (1998) S-1153 inhibits replication of known drug-
resistant strains of human immunodeficiency virus type 1.
Antimicrobial Agents and Chemotherapy 42:1340–1345.
Fuller RW, Bokesch HR, Gustafson KR, McKee TC, Cardellina JH
II, McMahon JB, Cragg GM, Soejarto DD & Boyd MR (1994)
HIV-inhibitory coumarins from latex of the tropical rainforest tree
Calophyllum teysmannii var. Inophylloide. Bioorganic & Medicinal
Chemistry Letters 4:1961–1964.
Galinis DL, Fuller WT, McKee TC, Cardellina JH II, Gulakowski
RJ, McMahon JB & Boyd MR (1996) Structure–activity modifi-
cations of the HIV-1 inhibitors (+)-calanolide A and (–)-calano-
lide B. Journal of Medicinal Chemistry 39:4507–4510.
Genin MJ, Poel TJ, Yagi Y, Biles C, Althaus I, Keiser BJ, Kopta LA,
Friis JM, Reusser F, Adams WJ, Olmsted RA, Voorman RL,
Thomas RC & Romero DL (1996) Synthesis and bioactivity of
novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase
inhibitors: structure–activity relationship and increased metabolic
stability of novel substituted pyridine analogs. Journal of Medicinal
Chemistry 39:5267–5275.
Glynn SL & Yazdanian M (1998) In vitro blood–brain barrier per-
meability of nevirapine compared to other HIV antiretroviral
agents. Journal of Pharmaceutical Sciences 87:306–310.
Goldman ME, Nunberg JH, O’Brien JA, Quintero JC, Schleif WA,
Freund KF, Gaul SL, Saari WS, Wai JS, Hoffman JM, Anderson
PS, Hupe DJ, Emini EA & Stern AM (1991) Pyridinone deriva-
Antiviral Chemistry & Chemotherapy 10:6
The NNRTI boom
tives: specifiic human immunodeficiency virus type 1 reverse tran-
scriptase inhibitors with antiviral activity. Proceedings of the
National Academy of Sciences, USA 88:6863–6867.
Hanasaki Y, Watanabe H, Katsuura K, Takayama H, Shirakawa S,
Yamaguchi K, Sakai S-I, Ijichi K, Fujiwara M, Konno K, Yokota
T, Shigeta S & Baba M (1995) Thiadiazole derivatives: highly
potent and specific HIV-1 reverse transcriptase inhibitors. Journal
of Medicinal Chemistry 38:2038–2040.
Hargrave KD, Proudfoot JR, Grozinger KG, Cullen E, Kapadia SR,
Patel UR, Fuchs VU, Mauldin SC, Vitous J, Behnke ML, Klunder
JM, Pal K, Skiles JW, McNeil DW, Rose JM, Chow GC, Skoog
MT, Wu JC, Schmidt G, Engel WW, Eberlein WG, Saboe TD,
Campbell SJ, Rosenthal AS & Adams J (1991) Novel non-nucleo-
side inhibitors of HIV-1 reverse transcriptase. 1. Tricyclic pyri-
dobenzo- and dipyridodiazepinones. Journal of Medicinal Chemistry
34:2231–2241.
Heinisch G, Huber E, Matuszczak B, Maurer A & Prillinger U
(1997a) Synthesis of pyridazino[3,4-b][1,5]benzodiazepin-5-ones
and their biological evaluation as non-nucleoside HIV reverse
transcriptase inhibitors. Archive der Pharmacie 330:29–34.
Heinisch G, Matuszczak B, Pachler S & Rakowitz D (1997b) The
inhibitory activity of diazinyl-substituted thiourea derivatives on
human immunodeficiency virus type 1 reverse transcriptase.
Antiviral Chemistry & Chemotherapy 8:443–446.
Hiroto H, Fujihashi T, Sakata T, Kaji A & Kaji H (1997)
Tetrahydronaphtalenelignan compounds as potent anti-HIV type
1 agents. AIDS Research and Human Retroviruses 13:695–705.
Ho W, Kukla MJ, Breslin HJ, Ludovici DW, Grous PP, Diamond
CJ, Miranda M, Rodgers JD, Ho CY, De Clercq E, Pauwels R,
Andries K, Janssen MAC & Janssen PAJ (1995) Synthesis and
anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-
jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 4. Journal of
Medicinal Chemistry 38:794–802.
Hoffman JM, Wai JS, Thomas CM, Levin RB, Goldman ME &
O’Brien JA (1992) Synthesis and evaluation of 2-pyridinone deriv-
atives as specific HIV-1 reverse transcriptase inhibitors. 1.
Phtalimidoalkyl and -alkylamino analogues. Journal of Medicinal
Chemistry 35:3784–3791.
Hoffman JM, Smith AM, Rooney CS, Fisher TE, Wai JS, Thomas
CM, Bamberger DL, Barnes JL, Williams TM, Jones JH, Olson
BD, O’Brien JA, Goldman ME, Nunberg JH, Quintero JC,
Schleif WA, Emini EA & Anderson PS (1993) Synthesis and
evaluation of 2-pyridinone derivatives as specific reverse transcrip-
tase inhibitors. 4. 3-[2-(Benzoxazol-2-yl)ethyl]-5-ethyl-6-
methylpyridin-2(1H)-one and analogues. Journal of Medicinal
Chemistry 36:953–966.
Hopkins AL, Ren J, Esnouf RM, Willcox BE, Jones EY, Ross C,
Miyasaka T, Walker RT, Tanaka H, Stammers DK & Stuart DI
(1996). Complexes of HIV-1 reverse transcriptase with inhibitors
of the HEPT series reveal conformational changes to the design of
potent non-nucleoside inhibitors. Journal of Medicinal Chemistry
39:1589–1600.
Ijichi K, Fujiwara M, Nagano H, Matsumoto Y, Hanasaki Y, Ide T,
Katsuura K, Takayama H, Shirakawa S, Aimi N, Shigeta S, Konno
K, Matsushima M, Yokota T & Baba M (1996) Anti-HIV-1
activity of thiadiazole derivatives: structure–activity relationship,
reverse transcriptase inhibition, and lipophilicity. Antiviral Research
31:87–94.
Kashman Y, Gustafson KR, Fuller RW, Cardellina II JH, McMahon
JB, Currens MJ, Buckheit RW Jr, Hughes SH, Cragg GM &
Boyd MR (1992) The calanolides, a novel HIV-inhibitory class of
coumarin derivatives from the tropical rainforest tree, Calophyllum
lanigerum. Journal of Medicinal Chemistry 35:2735–2743.
Kelly TA, Proudfoot JR, McNeil DW, Patel UR, David E, Hargrave
KD, Grob PM, Cardozo M, Agarwal A & Adams J (1995) Novel
non-nucleoside inhibitors of human immunodeficiency virus type
311
OS Pedersen & EB Pedersen
1 reverse transcriptase. 5. 4-Substituted and 2,4-disubstituted
analogs of nevirapine. Journal of Medicinal Chemistry
38:4839–4847.
Kelly TA, McNeil DW, Rose JM, David E, Shih C-K & Grob PM
(1997) Novel non-nucleoside inhibitors of human immunodefi-
ciency virus type 1 reverse transcriptase. 6. 2-Indol-3-yl- and 2-
azaindol-3-yl-dipyridodiazepinones. Journal of Medicinal Chemistry
40:2430–2433.
Kim D-K, Kim Y-W, Gam J, Kim G, Lim J, Lee N, Kim H-T &
Kim KH (1996) Synthesis and anti-HIV-1 activity of a series of
1-(alkoxymethyl)-5-alkyl-6-(arylselenyl)uracils and -2-thiouracils.
Journal of Heterocyclic Chemistry 33:1275–1283.
Kleim J-P, Bender R, Billhardt U-M, Meichsner C, Riess G, Rîsner
M, Winkler I & Paessens A (1993) Activity of a novel quinoxaline
derivative against human imunnodeficiency virus type 1 reverse
transcriptase and viral replication. Antimicrobial Agents and
Chemotherapy 37:1659–1664.
Kleim J-P, Bender R, Kirsch R, Meichsner C, Paessens A, Rösner
M, Rübsamen-Waigmann H, Kaiser R, Wichers M, Schneweis
KE, Winkler I & Reiss G (1995) Preclinical evaluation of HBY
097, a new nonnucleoside reverse transcriptase inhibitor of human
immunodeficiency virus type 1 replication. Antimicrobial Agents
and Chemotherapy 39:2253–2257.
Klunder JM, Hargrave KD, West M, Cullen E, Pal K, Behnke M,
Kapadia SR, McNeil DW, Wu JC, Chow GC & Adams J (1992)
Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 2.
Tricyclic pyridobenzoxazepinones and dibenzoxazepinones. Journal
of Medicinal Chemistry 35:1887–1897.
Klunder JM, Hoermann M, Cywin CL, David E, Brickwood JR,
Schwartz R, Barringer KJ, Pauletti D, Shih C-K, Erickson DA,
Sorge CL, Joseph DP, Hattox SE, Adams J & Grob PM (1998)
Novel nonnucleoside inhibitor of HIV-1 reverse transcriptase. 7.
8-Arylethyldipyridodiazepinones as potenet broad-spectrum
inhibitors of wild-type and mutant enzymes. Journal of Medicinal
Chemistry 41:2960–2971.
Kroeger MB, Rouzer CA, Taneyhill LA, Smith NA, Hughes SH,
Boyer PL, Janssen PAJ, Moereels H, Koymans L, Arnold E, Ding
J, Das K, Zhang W, Michejda CJ & Smith RH Jr (1995)
Molecular modelling studies of HIV-1 reverse transcriptase non-
nucleoside inhibitors: total energy of complexation as a predictor
of drug placement and activity. Protein Science 4:2203–2222.
Kukla MJ, Breslin HJ, Pauwels R, Fedde CL, Miranda M, Scott
MK, Sherrill RG, Raeymaekers A, Van Gelder J, Andries K,
Janssen MAC, De Clercq E & Janssen PAJ (1991a) Synthesis and
anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-
jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. Journal of
Medicinal Chemistry 34:746–751.
Kukla M J, Breslin HJ, Diamond CJ, Grous PP, Ho CY, Miranda
M, Rodgers JD, Sherrill RG, De Clercq E, Pauwels R, Andries K,
Moens LJ, Janssen MAC & Janssen PAJ (1991b) Synthesis and
anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-
jk][1,4]benzodiazepin-2(1H)-one (TIBO) derivatives. 2. Journal of
Medicinal Chemistry 34:3187–3197.
Larder BA, Purifoy DJM, Powell KL & Darby G (1987). Site-spe-
cific mutagenesis of AIDS virus reverse transcriptase. Nature
327:716–717.
McMahon JB, Gulakowski RJ, Weislow OS, Shultz RJ, Narayanan
VL, Clanton DJ, Pedemonte R, Wassmundt FW, Buckheit RW Jr,
Decker WD, White EL, Bader JP & Boyd MR (1993)
Diarylsulphones, a new chemical class of nonnucleoside antiviral
inhibitors of human immunodeficiency virus type 1 reverse tran-
scriptase. Antimicrobial Agents and Chemotherapy 37:754–760.
Mai A, Artico M, Sbardella G, Massa S, Loi AG, Tramontano E,
Scano P & La Colla P (1995) Synthesis and anti-HIV-1 activity
of thio analogues of dihydroalkoxybenzyloxopyrimidines. Journal of
Medicinal Chemistry 38:3258–3263.
312
Mai A, Artico M, Sbardella G, Quartarone S, Massa S, Loi AG, De
Montis A, Scintu F, Putzolu M & La Colla P (1997)
Dihydro(alkythio)(naphtylmethyl)oxopyrimidines: novel non-
nucleoside reverse transcriptase inhibitors of the S-DABO series.
Journal of Medicinal Chemistry 40:1447–1454.
Mai A, Artico M, Sbardella G, Massa S, Novellino E, Greco G, Loi
AG, Tramontano E, Marongiu ME & La Colla P (1999). 5-
Alkyl-2-(alkylthio)-6-(2,6-dihalophenylmethyl)-3,4-dihydropy-
rimidin-4(3H)-ones: novel potent and selective
dihydro-alkoxy-benzyl-oxopyrimidine derivatives. Journal of
Medicinal Chemistry 42:619–627.
Mao C, Vig R, Venkatachalam TK, Sudbeck EA & Uckun FM
(1998) Structure-based design of N-[2-(1-piperidinylethyl)]-N′-
[2-(5-bromopyridyl)]-thiourea and N-[2-(1-piperazinylethyl)]-N′-
[2-(5-bromopyridyl)]-thiourea as potent non-nucleoside inhibitors
of HIV-1 reverse transcriptase. Bioorganic & Medicinal Chemistry
Letters 8:2213–2218.
Massa S, Mai A, Artico M, Sbardella G, Tramontano E, Loi AG,
Scano P & La Colla P (1995) Synthesis and antiviral activity of
new 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs),
specific inhibitors of human immunodeficiency virus type 1.
Antiviral Chemistry & Chemotherapy 6:1–8.
Merluzzi VJ, Hargrave KD, Labadia M, Grozinger K, Skoog M, Wu
JC, Shih C-K, Eckner K, Hattox S, Adams J, Rosenthal AS,
Faanes R, Eckner RJ, Koup RA & Sullivan JL (1990) Inhibition
of HIV-1 replication by a nonnucleoside reverse transcriptase
inhibitor. Science 250:1411–1413.
Mertens A, Zilch H, König B, Schäfer W, Poll T, Kampe W, Seidel
H, Leiser U & Leinert H (1993) Selective non-nucleoside HIV-1
reverse transcriptase inhibitors. New 2,3-dihydrothiazolo[2,3-
a]isoindol-5(9bH)-ones and related compounds with anti-HIV-1
activity. Journal of Medicinal Chemistry 36:2526–2536.
Miller V, de Bethune M-P, Kober A, Stürmer M, Hertogs K,
Pauwels R, Stoffels P & Staszewski S (1998) Patterns of resistance
and cross-resistance to human immunodeficiency virus type 1
reverse transcriptase inhibitors in patients treated with the nonnu-
cleoside reverse transcriptase inhibitor loviride. Antimicrobial
Agents and Chemotherapy 42:3123–3129.
Miyasaka T, Tanaka H, Baba M, Hayakawa H, Walker RT, Balzarini
J & De Clercq E (1989) A novel lead for specific anti-HIV-1
agents: 1-[(2hydroxyethoxy)methyl]-6-(phenylthio)thymine.
Journal of Medicinal Chemistry 32:2507–2509.
Neamati N, Mazumder A, Zhao H, Sunder S, Burke TR Jr, Schultz
RJ & Pommier Y (1997) Diarylsulfones, a novel class of human
immunodeficiency virus type 1 integrase inhibitors. Antimicrobial
Agents and Chemotherapy 41:385–393.
Nugent AR, Schlachter ST, Murphy MJ, Cleek GJ, Poel TJ, Wishka
DG, Graber DR, Yagi Y, Keiser BJ, Olmsted RA, Kopta LA,
Swaney SM, Poppe SM, Morris J, Tarpley WG & Thomas RC
(1998) Pyrimidine thioethers: a novel class of HIV-1 reverse tran-
scriptase inhibitors with activity against BHAP-resistant HIV.
Journal of Medicinal Chemistry 41:3793–3803.
Nunberg JH, Schleif WA, Boots EJ, O’Brien JA, Quintero JC,
Hoffman JM, Emini EA & Goldman ME (1991) Viral resistance
to human immunodeficiency virus type 1-specific pyridinone
reverse transcriptase inhibitors. Journal of Virology 65:4887–4892.
Pauwels R, Andries K, Desmyter J, Schols D, Kukla MJ, Breslin HJ,
Raeymaeckers A, Van Gelder J, Woestenborghs R, Heykants J,
Schellekens K, Janssen ACM, De Clercq E & Janssen PAJ (1990)
Potent and selective inhibition of HIV-1 replication in vitro by a
novel series of TIBO derivatives. Nature 343:470–474.
Pauwels R, Andries K, Debyser Z, Van Daele P, Schols D, Stoffels P,
De Vreese K, Woestenborghs R, Vandamme A-M, Janssen CGM,
Anne J, Cauwenbergh G, Desmyter J, Heykants J, Janssen MAC,
De Clercq E & Janssen PAJ (1993) Potent and highly selective
human immunodeficiency virus type 1 (HIV-1) inhibition by a
©1999 International Medical Press

series of α-anilinophenylacetamide derivatives targeted at HIV-1
reverse transcriptase. Proceedings of the National Academy of Sciences,
USA 90:1711–1715.
Pauwels R, Andries K, Debyser Z, Kukla MJ, Schols D, Breslin HJ,
Woestenborghs R, Desmyter J, Janssen MAC, De Clercq E &
Janssen PAJ (1994) New tetrahydroimidazo[4,5,1-jk][1,4]-benzo-
diazepin-2(1H)-one and thione derivates are potent inhibitors of
human immunodeficiency virus type 1 replication and are syner-
gistic with 2′,3′-dideoxynucleoside analogs. Antimicrobial Agents
and Chemotherapy 38:2863–2870.
Pontikis R, Benhida R, Aubertin A-M, Grierson DS & Monneret C
(1997) Synthesis and anti-HIV activity of novel N-1 side chain-
modified analogs of 1-[(2-hydroxyethoxy)methyl]-6-
(phenylthio)thymine (HEPT). Journal of Medicinal Chemistry
40:1845–1854.
Proudfoot JR, Hargrave KD, Kapadia SR, Patel UR, Grozinger KG,
McNeil DW, Cullen E, Cardozo M, Tong L, Kelly TA, Rose J,
David E, Mauldin SC, Fuchs VU, Vitous J, Hoermann M,
Klunder JM, Raghaven P, Skiles JW, Mui P, Richman DD,
Sullivan JL, Shih C-K, Grob PM & Adams J (1995a) Novel non-
nucleoside inhibitors of human immunodeficiency virus type 1
(HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodi-
azepinones as potent inhibitors of both wild-type and cysteine-181
HIV-1 reverse transcriptase enzymes. Journal of Medicinal
Chemistry 38:4830–4838.
Proudfoot JR, Patel UR, Kapadia SR & Hargrave KD (1995b)
Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 3.
Dipyrido[2,3-b:2′,3′-e]diazepinones. Journal of Medicinal
Chemistry 38:1406–1410.
Ren J, Esnouf R, Hopkins A, Ross C, Jones Y, Stammers D &
Stuart D (1995) The structure of HIV-1 reverse transcriptase
complexed with 9-chloro-TIBO: lessons for inhibitor design.
Structure 3:915–926.
Romero DL, Busso M, Tan C-K, Reusser F, Palmer JR, Poppe SM,
Aristoff PA, Downey KM, So AG, Resnick L & Tarpley WG
(1991) Nonnucleoside reverse transcriptase inhibitors that potently
and specifically block human immunodeficiency virus type 1 repli-
cation. Proceedings of the National Academy of Sciences, USA
88:8806–8810.
Romero DL, Morge RA, Biles C, Berrios-Pena N, May PD, Palmer
JR, Johnson PD, Smith HW, Busso M, Tan C-K, Voorman RL,
Reusser F, Althaus IW, Downey KM, So AG, Resnick L, Tarpley
WG & Aristoff PA (1994) Discovery, synthesis, and bioactivity of
bis(heteroaryl)piperazines. 1. A novel class of non-nucleoside
HIV-1 reverse transcriptase inhibitors. Journal of Medicinal
Chemistry 37:999–1014.
Romero DL, Olmsted RA, Poel TJ, Morge RA, Biles C, Keiser BJ,
Kopta LA, Friis JM, Hosley JD, Stefanski KJ, Wishka DG, Evans
DB, Morris J, Stehle RG, Sharma SK, Yagi Y, Voorman RL,
Adams WJ, Tarpley WG & Thomas RC (1996) Targeting delavir-
dine/atevirdine resistant HIV-1: identification of
(alkylamino)piperidine-containing bis(heteroaryl)piperazines as
broad spectrum HIV-1 reverse transcriptase inhibitors. Journal of
Medicinal Chemistry 39:3769–3789.
Roth T, Morningstar ML, Boyer PL, Hughes SH, Buckheit RW Jr
& Michejda CJ (1997) Synthesis and biological activity of novel
nonnucleoside inhibitors of HIV-1 reverse transcriptase. 2-Aryl-
substituted benzimidazoles. Journal of Medicinal Chemistry
40:4199–4207.
Saari WS, Wai JS, Fisher TE, Thomas CM, Hoffman JM, Rooney
CS, Smith AM, Jones JH, Bamberger DL, Goldman ME,
O’Brien JA, Nunberg JH, Quintero JC, Schleif WA, Emini EA &
Anderson PS (1992) Synthesis and evaluation of 2-pyridinone
derivatives as specific HIV-1-reverse transcriptase inhibitors. 2.
Analogs of 3-aminopyridin-2(1H)-one. Journal of Medicinal
Chemistry 35:3792–3802.
Antiviral Chemistry & Chemotherapy 10:6
The NNRTI boom
Sahlberg C, Noreen R, Engelhardt P, Högberg M, Kangasmetsä J,
Vrang L & Zhang H (1998) Synthesis and anti-HIV activities of
urea-PETT analogs belonging to a new class of potent non-nucle-
oside HIV-1 reverse transcriptase inhibitors. Bioorganic and
Medicinal Chemistry Letters 8:1511–1516.
Silvestri R, Artico M, Massa S, Stefancich G, Congeddu E, Putzolu
M & La Colla P (1997). Sulfone derivatives with anti-HIV activi-
ty. Il Farmaco 52:323–329.
Sudbeck EA, Mao C, Vig R, Venkatachalam TK, Tuel-Ahlgren L &
Uckun FM (1998) Structure-based design of novel dihydroalkoxy-
benzyloxopyrimidine derivatives as potent nonnucleoside
inhibitors of the human immunodeficiency virus reverse transcrip-
tase. Antimicrobial Agents and Chemotherapy 42: 3225–3233.
Tanaka H, Baba M, Saito S, Miyasaka T, Takashima H, Sekiya K,
Ubasawa M, Nitta I, Walker RT, Nakashima H & De Clercq E
(1991) Specific anti-HIV-1 ‘acyclonucleosides’ which cannot be
phosphorylated: synthesis of some deoxy analogues of 1-[(2-
hydroxyethoxy)methyl]-6-(phenylthio)thymine. Journal of
Medicinal Chemistry 34:1508–1511.
Tanaka H, Takashima H, Ubasawa M, Sekiya K, Nitta I, Baba M,
Shigeta S, Walker RT, De Clercq E & Miyasaka T (1992a)
Structure–activity relationships of 1-[(2-hydroxyethoxy)methyl]-6-
(phenylthio)thymine analogues: effect of substitutions at the C-6
phenyl ring and at the C-5 position on anti-HIV-1 activity.
Journal of Medicinal Chemistry 35:337–345.
Tanaka H, Takashima H, Ubasawa H, Sekiya K, Nitta I, Baba M,
Shigeta S, Walker RT, De Clercq E & Miyasaka T (1992b)
Synthesis and antiviral activity of deoxy analogs of 1-[(2-hydrox-
yethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and
selective anti-HIV-1 agents. Journal of Medicinal Chemistry
35:4713–4719.
Tanaka H, Takashima H, Ubasawa M, Sekiya K, Inouye N, Baba M,
Shigeta S, Walker RT, De Clercq E & Miyasaka T (1995)
Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-
hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent
and selective anti-HIV-1 agents. Journal of Medicinal Chemistry
38:2860–2865.
Tantillo C, Ding J, Jacobo-Molina A, Nanni RG, Boyer PL, Hughes
SH, Pauwels R, Andries K, Janssen PAJ & Arnold E (1994)
Locations of anti-AIDS drug binding sites and resistance muta-
tions in the three-dimensional structure of HIV-1 reverse tran-
scriptase. Journal of Molecular Biology 243:369–387.
Tucker TJ, Lumma WC & Culberson JC (1996) Development of
nonnucleoside HIV reverse transcriptase inhibitors. Methods in
Enzymology 275:440–472.
Velázquez S, Alvarez R, Perez C, Gago F, De Clercq E, Balzarini J
& Camarasa M-J (1998) Regiospecific synthesis and anti-human
immunodeficiency virus activity of novel 5-substituted N-alkylcar-
bamoyl and N,N-dialkyl carbamoyl 1,2,3-triazole-TSAO ana-
logues. Antiviral Chemistry & Chemotherapy 9:481–489.
Vig R, Mao C, Venkatachalam TK, Tuel-Ahlgren L, Sudbeck EA &
Uckun FM (1998) Rational design and synthesis of phenethyl-5-
bromopyridyl thiourea derivatives as potent non-nucleoside
inhibitors of HIV reverse transcriptase. Bioorganic & Medicinal
Chemistry 6:1789–1797.
Wai JS, Williams TM, Bamberger DL, Fisher TE, Hoffman JM,
Hudcosky RJ, MacTough SC, Rooney CS, Saari WS, Thomas
CM, Goldman ME, O’Brien JA, Emini EA, Nunberg JH,
Quintero JC, Schleif WA & Anderson PS (1993) Synthesis and
evaluation of 2-pyridinone derivatives as specific HIV-1 reverse
transcriptase Inhibitors. 3. Pyridyl and phenyl analogs of 3-
aminopyridin-2(1H)-one. Journal of Medicinal Chemistry
36:249–255.
Williams TM, Ciccarone TM, MacTough SC, Rooney CS, Balani
SK, Condra JH, Emini EA, Goldman ME, Greenlee WJ,
Kauffman LR, O’Brien JA, Sardana VV, Schleif WA, Theoharides
313
OS Pedersen & EB Pedersen
AD & Anderson PS (1993) 5-Chloro-3-(phenylsulfonyl)indole-2-
carboxamide: a novel, non-nucleoside inhibitor of HIV-1 reverse
transcriptase. Journal of Medicinal Chemistry 36:1291–1294.
Wishka DG, Graber DR, Kopta LA, Olmsted RA, Friis JM, Hosley
JD, Adams WJ, Seest EP, Castle TM, Dolak LA, Keiser BJ, Yagi
Y, Jeganathan A, Schlachter ST, Murphy MJ, Cleek GJ, Nugent
RA, Poppe SM, Swaney SM, Han F, Watt W, White WL, Poel T-
J, Thomas RC, Voorman RL, Stefanski KJ, Stehle RG, Tarpley
WG & Morris J (1998a) (–)-6-Chloro-2-[(1-furo[2,3-c]pyridin-
5-yl-ethyl)thio]-4-pyrimidinamine, PNU-142721, a new broad
spectrum HIV-1 non-nucleoside reverse transcriptase inhibitor.
Journal of Medicinal Chemistry 41:1357–1360.
Wishka DG, Graber DR, Seest EP, Dolak AD, Han F, Watt W &
Morris J (1998b) Stereoselective synthesis of furo[2,3-c]pyridine
pyrimidine thioethers, a new class of potent HIV-1 non-nucleo-
side reverse transcriptase inhibitors. Journal of Organic Chemistry
63:7851–7859.
Witvrouw M, Arranz ME, Pannecouque C, Declerq R, Jonckheere
H, Schmit J-C, Vandamme A-M, Diaz JA, Ingate ST, Desmyter J,
Esnouf R, Van Meervelt L, Vega S, Balzarini J & De Clercq E
Received 26 March 1999; accepted 20 July 1999
314
(1998) 1,1,3-Trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazine
(TTD) derivatives: a new class of nonnucleoside human immun-
odeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors
with anti-HIV-1 activity. Antimicrobial Agents and Chemotherapy
42:618–623.
Young SD, Britcher SF, Tran LO, Payne LS, Lumma WC, Lyle TA,
Huff JR, Anderson PS, Olsen DB, Carroll SS, Pettibone DJ,
O’Brien JA, Ball RG, Balani SK, Lin JH, Chen I-W, Schleif WA,
Sardana VV, Long WJ, Byrnes VW & Emini EA (1995a) L-
743,726 (DMP-266): a novel, highly potent nonnucleoside
inhibitor of the human immunodeficiency virus type 1 reverse
transcriptase. Antimicrobial Agents and Chemotherapy
39:2602–2605.
Young SD, Britcher SF, Payne LS, Tran LO & Lumma WC (1995b)
WO95/20389.
Zembower DE, Liao S, Flavin MT, Xu Z-Q, Stup TL, Buckheit
RW Jr, Khilevich A, Mar AA & Sheinkman AK (1997) Structural
analogues of the calanolide anti-HIV agents. Modification of the
trans-10,11-dimethyldihydropyran-12-ol ring (ring C). Journal of
Medicinal Chemistry 40:1005–1017.
©1999 International Medical Press