Received: 9 February 2019 | Revised: 28 April 2019 | Accepted: 1 May 2019

DOI: 10.1002/ardp.201900045

REVIEW ARTICLE

Quinolone derivatives: Potential anti‐HIV

agent—development and application

Ruo Wang | Kai Xu | Weixiong Shi

College of Chemistry, Fuzhou University,

Fuzhou, Fujian, People’s Republic of China
Correspondence
Dr. Ruo Wang, College of Chemistry, Fuzhou
University, Fuzhou, Fujian 350116, People’s
Republic of China.
Email: wangruo1201@gmail.com
Abstract
Acquired immune deficiency syndrome (AIDS)/human immunodeficiency virus (HIV)
is one of the largest and most devastating public health pandemics throughout the
world. The global pandemic of drug‐sensitive HIV and the increasing threat from
drug‐resistant HIV result in an urgent need to develop more effective anti‐HIV
candidates. Quinolone represents a significant class of privileged heterocycles, and its
derivatives possess promising in vitro and in vivo anti‐HIV properties. The 4‐
quinolone elvitegravir has already been approved for the treatment of HIV; thus,
quinolone derivatives might be promising candidates with anti‐HIV activity. This
review emphasizes quinolone derivatives with potential anti‐HIV activity, covering
articles published between 1992 and 2019. The structure‒activity relationship is also
discussed to provide insights for further development of more active quinolone
derivatives.

KEYWORDS
AIDS, HIV, hybrid compounds, quinolone, structure‒activity relationship

1 | INTRODUCTION
Acquired immune deficiency syndrome (AIDS), caused by human
immunodeficiency virus (HIV), is one of the largest and most
devastating public health pandemics.[1,2] HIV interferes with the
immune system and increases the risk of opportunistic infections
such as tuberculosis, and tumors that rarely affect people who
have working immune systems. Two types of HIV viruses (HIV‐1 and
HIV‐2) have been characterized, and they are closely related
retroviruses that share 30‒60% overall genetic homology and similar
[3]
structural and genomic organization. HIV‐1, which is more virulent
and more infective, is the predominant cause of HIV infections
globally, while HIV‐2 has relatively poor transmission.[4]
It has been estimated by the World Health Organization (WHO)
that approximately 36.9 million people (35.1 million adults and 1.8
million children) are living with HIV in 2017 worldwide, with above
1.5 million new cases and around 1 million deaths annually.[5,6] The
highly active antiretroviral therapy (HAART), which is crucial for
HIV/AIDS treatment, has significantly reduced AIDS‐related death
cases.[7,8] Around 21.7 million people with HIV received anti‐
retroviral treatment by the end of 2017, but it only accounted for
59% of HIV‐infected patients.[9] The emergence of multidrug‐
resistant HIV and the inability of the HAART to eradicate HIV from
infected patients make a great need to develop new agents.
Quinolones (including 2‐quinolones and 4‐quinolones) possess
diverse pharmacological properties, such as antibacterial,[10,11]
antimalarial,[12,13] antitubercular,[14,15] anticancer,[16,17] anti‐Alzhei-
mer’s disease,[18,19] antifungal,[20,21] anti‐HCV,[22,23] and anti‐
HIV[24,25] activities, playing an intriguing role in the development of
new drugs. Elvitegravir (Figure 1), the first quinolone integrase
inhibitor, has already been approved by the U.S. Food and Drug
Administration for the treatment of HIV infection, demonstrating
that quinolone derivatives might have potential anti‐HIV activ-
ity.[26,27]
In the last three decades, numerous quinolone derivatives have
been screened for their anti‐HIV activities, and some of them
exhibited promising potency. In this review, the recent advances of
quinolone derivatives as potential anti‐HIV agents are highlighted,

Arch Pharm Chem Life Sci. 2019;e1900045. wileyonlinelibrary.com/journal/ardp © 2019 Deutsche Pharmazeutische Gesellschaft | 1 of 17
https://doi.org/10.1002/ardp.201900045
2 of 17 | WANG
FIGURE 1 Chemical structure of elvitegravir
and the structure–activity relationship (SAR) is also discussed to
provide an insight to develop quinolone derivatives with higher anti‐
HIV activity.
2 | 2‐Q U I N O L O N E D E RI V A T I V E S
2‐Quinolone derivatives represent a significant class of privileged
heterocycles with a variety of biological activities. Some of them such
as viridicatin, viridicatol, and tipifarnib (Figure 2) are being under
clinical trials for the treatment of various diseases.[28] Accordingly, 2‐
quinolone motif is a useful pharmacophore to develop new drugs.
The HIV‐1 capsid plays an important role in HIV‐1 assembly and
maturation, and it has been identified as a potential target for the
development of new anti‐HIV agents.[29] The capsid protein consists
of two domains (the N‐terminal domain [NTD], and the C‐terminal
domain [CTD]), and mutations in both the NTD and CTD lead to
[30]
defects in viral assembly and release. Several HIV‐1 inhibitors
targeting NTD have been identified, but small molecules targeting
CTD of HIV‐1 capsid are rarely reported. To fill this gap and identify
new classes of anti‐HIV‐1 agents, a series of 2‐quinolone derivatives
1 (IC50: 1.06 to >38.9 µM against HIV‐1IIIB in MT‐2 cells) were
screened for their potential CTD and HIV‐1 inhibitory activities by
Curreli et al.[31] The results indicated that these derivatives were
highly effective in preventing mature like particles by binding to the
hydrophobic cavity of the CTD of the capsid. The SAR indicated that
2‐quinolone moiety was essential for anti‐HIV‐1 activity since lactam
fragment could form a hydrogen bond with Asn183 located at the
hydrophobic cavity of CTD. R1 and R2 positions required hydrophobic
moieties, and furan was more favorable than thiophene. Substituted
phenyl groups were also tolerated at R1 and R2 positions. For R1
position, the introduction of the methyl group at the phenyl ring
showed a detrimental effect on the anti‐HIV‐1 activity. For R2
position, incorporation of chloro, bromo, and methyl at para‐position
of phenyl group could improve the activity, while a bulkier group
such as isopropyl and methoxy led to the loss of the activity. Methyl
at R3 position could boost up the activity, while methoxy and ethyl
reduced the activity. The most active compound 1a (Figure 3) with
IC50 of 1.06 µM against HIV‐1IIIB (in MT‐2 cells) was also found with
low cytotoxicity towards MT‐2 and PBMC cells (CC50: >61.45 µM).
Further study revealed that compound 1a possessed broad‐spectrum
antiviral activity against a wide variety of laboratory‐adapted (IIIB,
MN, SF2, RF, AZT‐R and HIV‐1RF/L‐323‐12‐3 in MT‐2 cells; Bal and 89.6
in PBMC cells) and primary HIV‐1 isolates (94UG103, 92UG037,
ET AL.
92US657, 93IN101, 92UG024, 93BR020, RU570, and BCF02 in
PBMC cells) with IC50 in the range of 1.06–6.17 µM. Overall,
compound 1a has broad anti‐HIV‐1 activity and excellent safety
profile, and it could act as a lead for further optimization.
Integrase (IN) represents a clinically validated target for the
development of anti‐HIV agents, so it is worth to search for new
lead compounds with HIV‐1 IN inhibition potential. A series of
3‐[(N‐cycloalkylamino)methyl]‐2‐quinolones (2 and 3) were screened
as potential HIV‐1 IN inhibitors by Sekgota et al,[32] and nearly all the
compounds exhibited a measure of HIV‐1 IN inhibition at 20 µM.
None of the compounds showed significant inhibition to either HIV‐1
protease (PR) or reverse transcriptase (RT), suggesting that these
derivatives could selectively inhibit HIV‐1 IN. The SAR revealed that
methoxy at the C‐8 position of 2‐quinolone moiety reduced the
activity, while methoxy at C‐6 position could enhance the activity to
some extent. Among them, compound 2e inhibited 60.1% of HIV‐1 IN
at 20 µM, and it has no cytotoxicity towards human embryonic
kidney HEK 293 cells at the same concentration.
The 2‐quinolones 4 and 2‐naphthyridinones 5 (Figure 3) displayed
considerable inhibitory activity against HIV‐1 vectors containing
wild‐type (wt, EC50: 4–62 nM) or mutant IN (Y143R, N155H, G140S/
Q148H, G118R, and E138K/Q148K, EC50: 4.9–2,200 nM).[33] The
SAR indicated that 2‐naphthyridinones 5 were more potent than 2‐
quinolones 4. For 2‐quinolones 4, hydroxyl at the C‐8 position (R2) of
the 2‐quinolone core was crucial for the high activity and chloro at
phenyl ring (R1) was better than fluoro. For 2‐naphthyridinones 5,
hydroxyl at N‐1 position (R1) was indispensable for the high activity,
while attachment of hydroxyl at C‐4 position (R3) could not enhance
the activity. Among them, compounds 5c (EC50: 4.9‐438 nM) and 5f
(EC50: 11–308 nM) have better antiviral efficacies than raltegravir
(EC50: 154–1900 nM) against a panel of IN mutants (Y143R, N155H,
and G118R), and the double mutants (G140S/Q148H and E138K/
Q148K). Both compounds 5c and 5f (EC50: 5.1 and 6.2 nM) had
comparable activity to raltegravir (EC50: 4 nM) against wt IN. Further
investigations indicated that incorporation of free amine and
alkylamines at the C‐4 position of 2‐naphthyridinone fragment was
favorable to the activity, while arylamines were disfavored. The
relative contribution order was free amine > alkylamines > aryla-
mines.[34] In particular, compound 6o (EC50: 1.1–35 nM) (Figure 3)
was highly active against IN wt and mutants (Y143R, N155H, R263K,
G118R, and G140S/Q148H), and it was 1.4‐64.8 folds more potent
than the reference raltegravir against all tested HIV‐1 IN. Moreover,
compound 6o (CC50: >250 µM) was intoxic against human
FIGURE 2 Chemical structures of viridicatin, viridicatol, and
tipifarnib
WANG ET AL.
FIGURE 3 Chemical structures of 2‐quinolone derivatives 1–6
osteosarcoma cells. Thus, compound 6o represents an attractive
platform to develop next‐generation HIV‐1 IN strand transfer
inhibitors .
Besides IN, RT, and PR are also essential for HIV replication.
Therefore, RT and PR have also been used as targets by anti‐HIV
therapeutics.[34] 2‐Quinolone derivatives 7 (Figure 4) exhibited
promising inhibitory activity against wt (IC50: 0.24–0.71 µM) and
mutant HIV‐1 RT (Cys181 and Il100, IC50: 0.86–2.50 µM), which
were comparable to nevirapin (IC50: 0.30 µM) against wt RT, but >40‐
fold more active than nevirapin (IC50: > 100 µM) against mutant HIV‐
1 Cys181 and Il100 RT.[35,36] All derivatives also demonstrated
excellent antiviral activity against HIV‐1IIIB and nevirapin‐resistant
HIV‐1 with IC50 values of 0.035–0.242 µM and 0.368‐2.210 µM,
respectively. The SAR indicated that oxidization of sulfur (7c, IC50:
0.100 and 0.368 µM against HIV‐1IIIB and nevirapin‐resistant HIV‐1,
respectively) to sulfoxide (7c, IC50: 0.242 and 2.210 µM against HIV‐
1IIIB and nevirapin‐resistant HIV‐1, respectively) resulted in great
loss of activity especially against nevirapin‐resistant HIV‐1. Similar
[37]
results were also observed by Cheng et al. Replacement of sulfur
with oxygen (7a, IC50: 0.035 and 0.607 µM) could improve the
activity against HIV‐1IIIB, but reduced the activity against nevirapin‐
resistant HIV‐1. In addition, compound with n‐propyl at C‐3 position
hold higher activity than that with isopropyl.
| 3 of 17
2‐Quinolone derivatives 8 with cyclopropyl tethered C‐3 and C‐4
positions displayed great potency against wt HIV‐1 virus with EC50
ranging from 1 to 221 nM.[38,39] The SAR revealed that R group
preferred straight aliphatic chains, and n‐butyl (8d, EC50: 3 nM),
n‐4‐pentenyl (8e, EC50: 1 nM), as well as n‐pentyl (8f, EC50: 1 nM)
were optimal. Either longer or shorter aliphatic chains led to reduced
activity, and derivatives with branched alkyl, phenyl alkyl or phenyl
groups showed poor antiviral activity. These data were consistent
with the modeling studies, which suggested a narrow hydrophobic
pocket in the enzyme. Expansion of the cyclopropyl to cyclobutyl
(9a), or replacement of ethyl ester by cyano (9b), ketone (9c), and
amides, or without cyclopropyl (9d and 9e) was detrimental to the
activity. Reduction of ester to alcohol (10a, EC50: 743 nM) also
resulted in the loss of activity, but the ether analogs 10b–d (EC50: 45,
65, and 37 nM, respectively) showed considerable activity (Figure 4).
Replacement of ethyl ester by methyl ester (11a, EC50: 1 nM) or allyl
ester (11b, EC50: 1 nM) had no influence on the activity, while
aromatic esters decreased the activity. Twelve derivatives with
EC50 < 100 nM were further evaluated for their potency against a
panel of non‐nucleoside reverse transcriptase inhibitors (NNRTI)
resistant mutants (E138K, F227L, I135V, K103N, L100I, L106A,
Y181C, Y188L, V179E, Y181H, and Y181S), and all compounds
exhibited low single‐digit nanomolar potency against E138K, F227L,
4 of 17 | WANG
FIGURE 4 Chemical structures of 2‐quinolone derivatives 7–15
I135V, L100I, and Y181H. Amongst them, the most active compound
8f (EC50: 1–238 nM) was 2–50 times more potent than the reference
nevirapine against the majority of the tested HIV‐1 wt and NNRTI‐
resistant mutants, and it could serve as an advanced lead for further
optimization.
All 2‐quinolone derivatives 12 except 12f displayed potential
antiviral activities against HIV‐1 with IC50 of 14–917 nM, but all of
them were less active than efavirenz (IC50: 2 nM).[40] Compared with
the unsubstituted compound 12a (R = H, IC50: 14 nM), installation of
amines, amides, and ethers at R position was disfavorable to the
activity. In general, derivatives with ethers at R position were more
potent than the corresponding amine and amide analogs. The
position of substituents at phenyl ring also had a great influence on
the activity, and para‐position was optimal. Compounds 12a, 12o, and
12r showed considerable activity against NNRTI‐resistant mutants
K103N, L100I, and K103N/L100I with IC90 in the range of
23–4830 nM. The most active compound 12o (IC90: 50, 23, and
ET AL.
4830 nM) was more potent than the reference efavirenz (IC90: 64,
77, and 7300 nM) against all tested NNRTI‐resistant mutants
(K103N, L100I, and K103N/L100I).
Calanolide A is under clinical trial for the treatment of AIDS, but
the instability and poor bioavailability in physiological medium are
the limitations.[41] The EC50 value of (±)‐aza‐calanolide A 13
(0.12 µM) was much lower than that of the natural product calanolide
A (0.27 µM), indicating that compound 13 is worth to be further
investigated. The 2‐quinolone derivatives 14a,b exhibited excellent
anti‐HIV activity with EC50 of 0.24 and 4.6 nM respectively, and they
were 187.5 and 9.7 folds more potent than azidothymidine (EC50:
45 nM).[42] The most active compound 14a showed low cytotoxicity
towards H9 cells with IC50 of 28 µM, and the therapeutic index (TI,
IC50/EC50) was as high as 119,333.
The SAR of 2‐naphthyridinones 15 (Figure 4) revealed that
incorporation of phenyl (15b–e) or benzyl (15f,g) at C‐4 position
could enhance the activity against HIV‐1 ribonuclease H (RT‐RNH)
WANG ET AL.
when compared with unsubstituted 15a.[43] Compound 15 g which
was found to be most active against RT‐RNH (IC50: 45 nM) was highly
active in the inhibition of HIV‐1 replication (HeLa P4‐2 cells) with
IC50 of 190 nM.
The 2‐quinolone derivatives 16 (Figure 5) showed potential
cytotoxicity against KB, A549, HCT‐8, CAKI‐1, MCF‐7, HOS, IA9, and
U‐87‐MG human cancer cell lines, but none of them showed any anti‐
HIV activity.[44] 2‐Quinolone‐thiazole hybrids 17 which could inhibit
0‐95% MTB H37Rv at 12.5 µg/ml were also found inactive against
[45]
HIV. 2‐Quinolone derivatives 18 and 19 (Figure 5) displayed
promising antibacterial, antifungal, antitubercular, and anticancer
activities, but they were devoid of activity against HIV‐1IIIB and
HIV‐2ROD in MT‐4 cells.[46,47]
3 | 4‐Q U I N O L O N E D E RI V A T I V E S
All the marketed quinolone drugs are 4‐quinolone derivatives, so
4‐quinolone moiety plays an intriguing role in the development of
new drugs.[48,49] Numerous chemical modifications can be made on
the N‐1, C‐5, C‐6, C‐7, and C‐8 positions to obtain compounds with
different physical, chemical, pharmacokinetic, and antimicrobial
properties. [50]
3.1 | N‐1 and C‐8 modifications
Substituents at N‐1 position of 4‐quinolone could influence on the
overall potency, microbiological and pharmacokinetic properties
significantly,[51] while substituents at C‐8 position have a great
influence on oral pharmacokinetics, spectrum, and mutants.[52] Some
of the clinically used quinolones such as ofloxacin and levofloxacin
bear a six‐membered ring connecting the N‐1 to C‐8 position, so the
modifications on both N‐1 and C‐8 positions will be discussed in this
section.
Various alkyl, cycloalkyl, alkenyl, alcohols, amines, and aromatic
ring were introduced into N‐1 position of 4‐quinolone moiety, and
the results indicated that the substitution pattern on this position
had great influence on their anti‐HIV potency. A series of new
5‐hydroxylquinolone‐3‐carboxylic acids with various aryl (20) or
benzyl (21) substituents on N‐1 position were screened for their in
FIGURE 5 Chemical structures of 2‐quinolone derivatives 16–19
| 5 of 17
vitro anti‐HIV activities against wt HIV‐1 and HIV‐1 mutant virus
A17 in C8166 cells by He et al.[53,54] All derivatives displayed
considerable activity against wt HIV‐1 and HIV‐1 mutant virus A17
with EC50 in the range of 3.17 to 307.57 µM. The biological results
and the docking study revealed that the substitution pattern on the
N‐1 position of the quinolone core might contribute to physicochem-
ical properties of the derivatives and has a great influence on their
antiviral potency. The SAR indicated that the derivatives with
(substituted) benzyl group at N‐1 position were more potent than
the corresponding phenyl analogs. Compared with the unsubstituted
compound 20a, derivatives 20b–e with either electron‐donating
methyl or electron‐withdrawing bromo at phenyl ring showed higher
anti‐HIV activity (Figure 6). For derivatives 21, the introduction of
electron‐donating methyl or electron‐withdrawing fluoro at benzyl
group (R1 position) led to the loss of activity, while chloro at R2
position was favorable to the activity. The most active compound 21a
exhibited potential activity against wt HIV‐1 and HIV‐1 mutant virus
A17 with EC50 values of 3.17 and 17.88 µM, respectively, but it was
far less potent than elvitegravir (EC50: 0.00021 and 0.0010 µM). For
4‐quinolone‐pyrazole hybrids 22, the esters 22a,b and acids 22c,d
(IC50: >100 µM) were inactive against HIV‐1 IN, while the phenol‐
containing hybrids 22e,f (IC50: 21.16 and 2.60 µM) showed consider-
able activity.[55,56] The 4‐quinolone‐metronidazole hybrids 23 (Figure
6) displayed promising antifungal activities against C. tropicalis,
C. albicans and G. intestinals, but they were devoid of activity against
HIV‐1IIIB and HIV‐2ROD (EC50: >19.22 µM).[57]
All N‐fluorobenzyl 4‐quinolone derivatives 24b–d (inhibition
rate: <10% at 100 µM) had a significant negative effect on inhibition
of HIV IN in contrast to the corresponding unsubstituted 24a
(inhibition rate: 70% at 100 µM), indicating that fluorobenzyl group in
compounds might lead to unfavorable physicochemical properties
and poor anti‐HIV‐1 activity.[58]
Bifunctional quinolinonyl diketo acid derivatives are potential
inhibitors of 3′‐processing (3′‐P) and strand transfer (ST) functions of
HIV‐1 IN and ribonuclease H (RNase H).[59] Based on these facts, the
N‐benzyl quinolinonyl diketo acid derivatives 25 and 26 (Figure 6)
were evaluated for their activities against HIV IN ST and RNase H
function of RT by Pescatori et al.[60] In general, the activity of
derivatives 25 and 26 against RNase H and HIV IN 3′‐P was
negligible, with only a few compounds active at concentrations higher
6 of 17 | WANG ET AL.

FIGURE 6 Chemical structures of 4‐quinolone derivatives 20–27 with aromatic ring at the N‐1 position

than 10 µM. However, the majority of the derivatives showed anti‐HIV‐1IIIB activity of ethyl esters 25 was higher than acids 26.
considerable activity against IN ST. All quinolinonyl diketo acids 26 Replacement of phenyl with pyridinyl, quinolinyl and naphthyl (27)
showed excellent activity against IN ST with IC50 in nanomolar level, was detrimental to the anti‐HIV‐1IIIB activity. Among them, the ester
with higher potency than the corresponding ethyl esters 25, but the derivatives 25j, 25l and acid 26f were active against HIV‐1IIIB with

FIGURE 7 Chemical structures of 4‐quinolone derivatives 28–33 with alkyl or cycloalkyl at N‐1 position
WANG ET AL.
EC50 values in the submicromolar range (EC50: 0.58, <0.2, and
0.87 µM, respectively), and no cytotoxicity against the same HeLa‐
CD4‐LTR‐β‐gal cells was found (CC50: >50 µM).
All nitrogen‐tethered diarylpyrimidine‐quinolone hybrids 29
(Figure 7) were devoid of antiviral activity against HIV‐1IIIB and
NNRTI‐resistant double mutant strain K103N/Y181C in MT‐4 cells,
regardless of the substituent on N‐1 position.[61] Nevertheless,
several oxygen‐tethered diarylpyrimidine‐quinolone hybrids 28
showed moderate inhibitory activity against wt HIV‐1 replication
[61]
with EC50 values ranging from 0.28 to 1.16 µM. The most active
hybrid 28a displayed an EC50 value of 0.28 µM against HIV‐1IIIB, and
a couple of enzyme‐based assays clearly pinpointed an RT‐targeted
mechanism of action. Interestingly, the introduction of a halogen
atom bromine (30) or iodine (31) to the C‐6 position of 4‐quinolone
motif could improve the antiviral activity against HIV‐1IIIB and
NNRTI‐resistant double mutant strain K103N/Y181C signifi-
cantly.[62] All iodine diarylpyrimidine‐quinolone hybrids 31 (EC50:
9.6–570 nM and 0.77–4.73 µM against HIV‐1IIIB and NNRTI‐resistant
double mutant strain K103N/Y181C; IC50: 0.37–6.30 µM against HIV
RT) were more potent than the corresponding bromine analogs
(EC50: 18–1570 nM and 0.90 to >32.58 µM; IC50: 0.41–10.05 µM).
For hybrids 31, linear alkyl groups such as ethyl, n‐propyl, and n‐butyl
were more favorable than the branched alkyl groups (sec‐butyl and
tert‐butyl) at N‐1 position. The positive correlation between the
activity and the length of the alkyl group at the N‐1 position was
observed for hybrids 31. In particular, hybrid 31c (EC50: 9.6 nM and
0.98 µM; IC50: 0.51 µM) had comparable activity to azidothymidine,
efavirenz, and entecavir (EC50: 5.6, 5.4, and 1.9 nM, respectively)
against HIV‐1IIIB, and it was ≥11.2‐fold more potent than nevirapine
(EC50: 244 nM and ≥11 µM) against HIV‐1IIIB and NNRTI‐resistant
double mutant strain K103N/Y181C. Thus, compound 31c could act
FIGURE 8 Chemical structures of 4‐quinolone derivatives 34–38
| 7 of 17
as an ideal starting point to develop next‐generation NNRTIs with
improved antiviral efficacy and resistance profile.
4‐Quinolone derivatives 32 (EC50: 1.83–23.54 µM, respectively;
Figure 7) showed moderate antiviral activities against HIV‐1, and
all of them were far less potent than the reference elvitegravir
(EC50: 0.00021 µM). These might be attributed to the introduction of
the C‐5 hydroxyl group resulted in an unfavorable physicochemical
property. The lack of the influence of C‐7 methoxy group which
together with N‐1 hydroxyalkyl moiety could lead to a synergistic
improvement of antiviral activity.[63] The SAR revealed that the
branched alkyl and cycloalkyl were more favorable than the linear
alkyl. Further docking study revealed that the anti‐HIV activity of
these compounds could be explained with two‐metal chelating
mechanism.
Compared with unsubstituted and monosubstituted (R2 posi-
tion) 4‐quinolones 33a–h (IC50: 0.410–2.300 µM) (Figure 7), the bis‐
substituted analogs 33i–q (IC50: 0.026–0.370 µM) displayed higher
inhibitory activity against IN ST.[64] In general, the derivatives 33l–q
(EC50: 0.290–2.340 µM and IC50: 0.026–0.083 µM) with alkyl at N‐1
position were more potent than the unsubstituted 33k (EC50:
3.400 µM and IC50: 0.026–0.070 µM) against HIV‐1 and IN ST,
suggesting the substituents at N‐1 position had great influence on
the activity[64,65]. Further study indicated that incorporation of
acids (34a,b) or amides (34c,d) or aminoethylene (34e) could not
improve the activity, while hydroxyalkyl (34f,g) was favorable to the
activity (Figure 8).[64,66] Esterification of hydroxyl group was
detrimental to the activity.[67] For the N‐hydroxylethylene
4‐quinolone derivatives 35, the introduction of fluoro at R1, R2, or
R3 position reduced the activity. Electron‐donating methoxy at
R2 position could enhance the activity, whereas electron‐with-
drawing groups such as trifluoromethyl, chloro, and cyano
8 of 17 | WANG
decreased the activity.[64,68] All 4‐quinolone derivatives 36 demon-
strated great potency against HIV‐1 and IN ST with EC50 and IC50
values of 1–52 nM and 6–15 nM, respectively. The SAR revealed
that linear and branched alkyl groups at R1 position were better
than the cycloalkyl, and iso‐butyl was optimal[64,69,70]. Methoxy was
essential for the high anti‐HIV‐1 activity as evidenced by that the
anti‐HIV‐1 activity of all methoxy‐containing compounds 36h–j
(IC50: 1 nM) was extremely high, and thus all of them warrant
further investigations.
Some of 4‐quinolone‐sugar hybrids were screened for their
antiviral activities against HIV‐1IIIB and HIV‐2ROD, as well as
inhibitory potency against HIV IN, but none of them were active
against the tested HIV‐1IIIB and HIV‐2ROD strains.[71,72] The N‐amino
and N‐acetamidyl 4‐quinolones 37 with different substituents at C‐6
position of quinolone motif showed low antiviral activities against
HIV‐1IIIB and HIV‐2ROD, while their analogs 38 (Figure 8) with vinyl at
N‐1 position demonstrated the excellent anti‐HIV‐1IIIB activity with
EC50 of 5−190 nM.[73] Among them, compounds 38c (EC50: 5 nM
against HIV‐1IIIB) and 38b (EC50: 550 nM against HIV‐2ROD) with
selectivity index (SI) ≥ 10 were worth to be further optimized.
R‐71762 (39) (Figure 9), a derivative of ofloxacin, not only
exhibited potential antibacterial activities against a panel of patho-
gens (MIC: 0.25–64 µg/ml) but also showed considerable antiviral
activity against HIV‐1 with IC50 of 1.7 µM.[74,75] Further study
revealed that R‐71762 could inhibit virus replication in both acutely
and in chronically HIV‐1‐infected cells, suggesting that R‐71762 is a
novel inhibitor of HIV‐1 replication and effective even in HIV‐1
[74]
chronically infected cells. The SAR indicated that removal of
fluoro at the six‐membered ring linked N‐1 and C‐8 positions led to
[75]
the loss of activity. For 4‐quinolone derivatives 40, the anti‐HIV
activity was influenced greatly by the substituents at C‐8 position,
and the order was difluoromethoxy (40c, IC50: 0.25 µM) > methoxy
(40b, IC50: 1.8 µM) >> fluoro (40a, IC50: 50 µM) (Figure 9).[75] Further
modification yielded 8‐difluoromethoxy‐4‐quinolone derivatives 41,
and the SAR demonstrated that the substituents at piperazinyl
[75]
played a pivotal role in the anti‐HIV activity. The relative
contribution order of substituents at piperazinyl to the activity was
phenyl (41c, IC50: 0.063 µM) > pyridin‐2‐yl > pyrimidin‐2‐yl >> hydro-
gen, methyl, and benzyl. Introduction of electron‐donating group
methoxy or electron‐withdrawing chloro group on the phenyl ring
FIGURE 9 Chemical structures of 4‐quinolone derivatives 39–41 with different substituents at C‐8 position
ET AL.
reduced the activity, while 4‐fluoro (41c, IC50: 0.059 µM) could
enhance the activity slightly.
3.2 | C‐2 modifications
Substituents at the C‐2 position of 4‐quinolone moiety neighbor to
the DNA‐gyrase binding site and substituents with big size at this
position were usually harmful to the biological activity. Therefore,
few modifications have been made at the C‐2 position.[76,77] The
natural product 2‐undecyl‐4‐quinolone 42 (Figure 10) isolated from
the marine sponge Homophymia sp. had an IC50 value of 3 nM in vitro
activity against HIV‐1, suggesting that it can act as a lead for further
optimization.[78,79]
Transactivator of transcription (Tat), a small HIV protein, is rich in
arginines and it interacts with transactivation responsive region
(TAR). Tat‐TAR interaction is essential for viral gene expression,
replication, and pathogenesis.[80] 2‐Phenylquinolones 43 have the
capacity to efficiently interfere with Tat/TAR complex in vitro, and
they may act as potential anti‐HIV candidates.[80,81] Both compounds
44a (IC50: 35 µg/ml) and 44b (IC50: 35 µg/ml; Figure 10) exhibited
moderate activity against HIV in acutely infected H9 lymphocytes,
and they had a therapeutic index of 2.9 and 5.4, respectively.[82]
3.3 | C‐3 and C‐4 modifications
4‐Oxo‐3‐carboxylic acid fragment is indispensable for hydrogen
bonding interactions with DNA bases.[51] and substitution of the
carboxylic acid at C‐3 is generally detrimental to the biological
activity of 4‐quinolones.[83] However, the precursors of carboxylic
acid which can convert to carboxylic acid in vivo are tolerated at the
C‐3 position.[84]
Three quinolone‐acylhydrazones 45 (Figure 11) were evaluated
for their antiviral activities against HIV‐1 (PBMC cells) and herpes
simplex virus (HSV), and all hybrids showed potential anti‐HIV
activity with EC50 of 3.4, 100, and 56 µM[85]. The anti‐HIV SAR of 4‐
quinolone‐1,3,4‐oxadiazole hybrids 46 showed that conjugates
bearing small alkyl groups, such as methyl, ethyl, and propyl, were
inactive in anti‐HIV‐1 assay, whereas hybrids possessing benzyl or
substituted benzyl at the same position showed potential anti‐HIV
activity with the range of 20–57% at 100 µM[86]. The substituents at
- -
WANG ET AL.
F I G U R E 1 0 Chemical structures of 4‐
quinolone derivatives 42–44
FIGURE 11 Chemical structures of 4‐quinolone derivatives 45–52
the benzyl group influenced the activity remarkedly, and the order
was methyl > fluoro > chloro. Among them, hybrid 46e showed
reasonable cell‐based anti‐HIV activity (EC50: 50 µM) without
considerable cytotoxicity (CC50: >100 µM) in the cell viability assay,
making it a lead for further optimization.
Lomefloxacin‐/ofloxacin‐zidovudine conjugates 47a and 47b
could inhibit syncytium formation and protected HIV‐1 induced
MT24 cell lytic effects and showed obviously inhibitory effect on the
HIV‐1IIIB (C1866 cells) and HIV‐1KM018 (PBMC cells) clinical isolate
[87]
with EC50 values of 6.5, 3.1, and 1.9, 36 nM. Both of them were
3.8–157.3 folds more active than zidovudine (EC50: 25 nM and
299 nM) against HIV‐1IIIB and HIV‐1KM018 clinical isolate, and they
also showed significant inhibition effect on the Staphylococcus aureus,
which was comparable with lomefloxacin and ofloxacin. Obviously,
both of them were potential anti‐HIV‐1 and antibacterial agents, and
worth to be further investigated.
Incorporation of metal ions into drugs usually has profound
effects on their biological activities, and some metal chelating agents,
| 9 of 17
such as ferroquine, are potential drugs or have already been used in
clinics.[88] Complexation of the metal ion into the quinolone is an
essential step for the exertion of biological activities,[89,90] and
4‐quinolone metal chelating agents are potential anti‐HIV agents.
Ruthenium(II) arenes displayed considerable anti‐HIV activity,[91,92]
and the 4‐quinolone‐ruthenium(II) arene 48 and its ligand showed
inhibitory activity in the micromolar concentration range in anti‐HIV‐
1 integrase enzymatic assays, with selectivity towards ST catalytic
process.[93] The IC50 of complex 48 against HIV IN ST was 17 µM,
which was higher than that of the ligand (IC50: 3.1 µM). The
quinolone‐magnesium (49a) and ‐manganese (49b) complexes
(Figure 11) also showed promising activity against HIV IN ST with
IC50 values of 4 and 2 µM, suggesting the metal ion had a great
influence on the activity.[91]
All 4‐quinolones 50 with hydrogen, acetyl, carboxylic acid and
methyl ester at C‐3 position were inactive in inhibition of IN‐LEDGF/
p75 protein‐protein interaction.[94] However, the hydroxyl‐contain-
ing derivatives 51a,b (Figure 11) displayed potential activity against
10 of 17 | WANG
HIV‐1 RT, HIV‐2 RT, and MuLV RT with IC50 ranging from 0.31 to
>225 µM. Further study indicated that the hydroxyl group at C‐3
position was the key fragment for the inhibitory activity since the
hydroxyl group of the derivatives could interact with the enzyme and
form the hydrogen bond.[95,96]
The majority of quinolinonyl diketo acid derivatives 52 were
devoid of activity against HIV‐1, while compounds 52a–c with EC50
values of 4.1, 3.2, and 0.17 µM, respectively, showed activity against
HIV‐1, indicating that they could be amenable to further develop-
[97]
ment to identify new anti‐HIV‐1 agents.
3.4 | C‐5 and C‐6 modifications
Manipulation of the substituent at C‐5 position of 4‐quinolones has
moderate influence on the antibacterial potency. Hydrogen, amino,
fluoro, hydroxyl, and methyl are tolerated at this position [98]
. Up to
date, hydrogen is optimal for the antiviral activity[51,99,100]. Several
substituents such as fluoro, amino, and various substituted benzyl
have been introduced into C‐6 position of 4‐quinolone core, and
fluoro is the most common substituent for the antibacterial agents
since fluoro facilitates the penetration of 4‐quinolone into the
microbial [101,102]
. development of a new class of HIV‐1 transcription inhibitors[106]. The
Three 4‐quinolone alkaloids 53a–c (Figure 12) isolated from
Melochia odorata were screened for their in vitro anti‐HIV activities.
The results showed that compounds 53a,b displayed potential anti‐
HIV activity, while 53c was inactive[103]. Among them, the most
active compound 53a exhibited significant activities in vitro anti‐HIV
FIGURE 12 Chemical structures of 4‐quinolone derivatives 53–60
ET AL.
cytoprotection assay at concentrations of 0.84 µM and inhibition of
HIV P24 formation of more than 50% at 0.95 µM.
Some of 4‐quinolone derivatives 54 and 55 (Figure 12) with
hydrogen, fluoro, trifluoromethyl, methoxy, amino and hydroxyl at
the C‐6 position of quinolone fragment showed remarked antiviral
activities against HIV‐1IIIB and HIV‐2ROD with EC50 values lower than
1 µg/ml.[104–108] The SAR revealed that trifluoromethyl group was
not suitable for C‐6 position, while the coupling of methoxy and
hydroxyl with an appropriate 4‐arylpiperazine at the neighboring C‐7
position was tolerated, suggesting a strict interdependency between
the C‐6 and C‐7 substituents in modulating the anti‐HIV property.
Compound 55k with hydroxyl was found to be highly active against
HIV‐1IIIB and HIV‐2ROD (MT‐4 cells) with EC50 values of 80 and
33 nM, and it was comparable to or better than nevirapine (EC50: 23
and >4000 nM, respectively)[104]. The amino‐containing compound
55l (MW5) showed excellent anti‐HIVIIIB activity in de novo‐infected
human lymphoblastoid cells with EC50 of 100 nM[105], and further
study indicated that MW5 could inhibit HIV‐1 replication in acutely
infected cells as well as in chronically infected cells with EC50 values
of 600 and 850 nM, respectively[106]. Notably, MW5 was found to
efficiently complex TAR RNA, with a dissociation constant of 19 nM,
suggesting that MW5 was a promising lead compound for the
derivatives 55m (HM‐12) and 55n (HM‐13) showed high activity on
acutely and chronically HIV‐1‐infected human M/M cells with EC50
values of 50, 25, and 50, 11 nM, respectively[107]. In an artificial hu‐
SCID mouse model for HIV‐1 latency based on SCID mice engrafted
with latently HIV‐1‐infected promyelocytic OM‐10.1 cells in which
WANG ET AL.
FIGURE 13 Chemical structures of fluoroquinolone‐isatin hybrids 61–69
HIV‐1 can be reactivated in vivo by the administration of human
tumor necrosis factor alpha (hTNF‐α), HM‐12, and HM‐13 could
generate a pronounced suppressive effect on viral reactivation.
Introduction of cyclopropyl (56) instead of methyl at N‐1 position
also demonstrated excellent anti‐HIV activity, and the most active
compound 56b (WC‐13) could inhibit HIV production in OM‐10.1
cells by EC50 of 5.6 ng/ml[108].
The 6‐aminoquinolone derivatives 57 with various substituents at
N‐1 and C‐7 positions also proved to be highly effective in inhibiting
HIV replication, and compounds 57a–d (Figure 12) were tested with
EC50 values in the range of 0.0087–0.7 µg/ml against HIV‐1IIIB and
| 11 of 17
HIV‐2ROD in MT‐4, PBMCs and CEM cell lines[109–112]. The SAR
revealed that the antiviral activity was fundamentally sensitive to
substitution at the C‐7 position where the 4‐(2‐pyridinyl)‐1‐piper-
azinyl substituent was shown to be the best, and the opening of the
piperazine ring was detrimental for activity[112]. Methyl at N‐1
position could be replaced by cyclopropyl, but bulky groups such as
tert‐butyl led to a great loss of activity[109]. The carboxylic acid
moiety at C‐3 position was indispensable for the anti‐HIV activity,
and replacement with an amide, ketone or oxime resulted in
completely devoid of anti‐HIV properties[112]. This may be attributed
to a 4‐oxo‐3‐carboxylic fragment which was crucial for target
12 of 17 | WANG
recognition through an Mg2+ bridge[112]. Time‐of‐addition experi-
ments clearly confirmed that the 6‐aminoquinolones could interact at
a post‐integration step in the replication cycle of HIV. Amongst them,
the most potent compound 57d with EC50 values ranging from
8.7–43 nM against HIV‐1IIIB and HIV‐2ROD in MT‐4, PBMCs and CEM
cell lines demonstrated the potency in the treatment of patients
infected with HIV‐1 or HIV‐2.
The 6‐iminequinolone 58 (EC50: >100 µM) was inactive against
[113]
HIV‐1, suggesting that imine at C‐6 position reduced the activity
Incorporation of ether (59) or alkenyl (60) at C‐6 position was
tolerated, and the acids 59b and 60b (EC50: 1 and 5 µM) were more
potent than the ethyl esters 59a and 60a (EC50: 13 and >140 µM)
against HIV‐1, and ether was more favorable than alkenyl (Figure
12)[114].
3.5 | C‐7 modifications
The substituents at the C‐7 position of 4‐quinolone play a pivotal in
the biological potency, bioavailability and safety profiles, and the C‐7
position is deemed as the most adaptable site for chemical
[115]
modifications. It is worth to note that the introduction of bulky
substituent at C‐7 position of quinolone motif is not a barrier to cell
membrane penetration, and various pharmacophores can be installed
into this position.[52,116]
Isatin derivatives possess a variety of biological activities,[117,118]
and 4‐quinolone‐isatin hybrids exhibited promising antibacter-
[119,120] [121,122] [123,124]
ial, antitubercular, anticancer, and anti‐HIV
properties. Some fluoroquinolone‐isatin hybrids were designed,
synthesized and screened for their antibacterial, antitubercular,
anti‐HCV, and anti‐HIV activities by Sriram et al., and the majority of
the hybrids displayed considerable in vitro anti‐HIV activities. The
SAR indicated that the substituents at C‐3 and C‐5 positions of isatin
motif and fluoroquinolone core have a great influence on the anti‐
HIV activity. For fluoroquinolone‐isatin‐trimethoprim hybrids 61
(Figure 13), the relative contribution order of fluoroquinolone core
was norfloxacin (61a and 61k, EC50: 12.1 and 11.3 µM) > ciproflox-
acin (61b, 61e, and 61g, EC50: 17.9, 9.4, and 11.6 µM) > gatifloxacin
(61c and 61i, EC50: 25.2 and 21.2 µM) > lomefloxacin (61d, 61f and
61h, EC50: 57.1, 17.2, and 28.4 µM), and chloro > bromo > fluoro
> methyl > hydrogen for substituents at C‐5 position of isatin
moiety.[125–129] The norfloxacin‐/ciprofloxacin‐/gatifloxacin‐/lome-
floxacin‐isatin‐sulfadiazines 62 (EC50 >48 µM, in CEM cells) and
norfloxacin‐isatin‐sulfadoxine 63 (EC50 >34 µM) were inactive
against HIV‐1, demonstrating the substituents at the C‐3 position
of isatin motif were crucial for the activity.[129,130]
Incorporation of semicarbazide or thiosemicarbazide (64,
EC50: >12 µM, in CEM cells) at C‐3 position of isatin motif was
detrimental to the anti‐HIV activity, [131,132]
but introduction of
hydroxyl (65, EC50: 4.18–33.38 µM, in MT‐4 cells) and methoxy (66,
EC50: 1.86–19.15 µM, in MT‐4 cells) could enhance the activity
(Figure 13).[133] The SAR revealed that fluoroquinolone‐isatin‐
thiosemicarbazide hybrids 66 were more active than the correspond-
ing analogs 65, indicating methyl at thiosemicarbazide fragment was
ET AL.
essential for the high activity. The relative contribution order of
fluoroquinolone core and substituent at the C‐5 position of isatin
moiety was gatifloxacin > lomefloxacin > ciprofloxacin ≈ norfloxacin,
and fluoro ≈ methyl > chloro, respectively. The most active hybrids
66k,l (EC50: 1.88 and 1.86 µM) also exhibited promising antituber-
cular activity (MIC: 0.15 and 0.31 µM against MTB H37Rv) and low
cytotoxicity (CC50: 170.51 and 154.06 µM), and they had the
potential to treat HIV caused opportunistic infections.[133] The
. norfloxacin‐isatin‐thiosemicarbazone 67 also exhibited significant
anti‐HIV activity with EC50 of 3.12 µM, but it was less active than
efavirenz (EC50: 0.78 µM).[132]
The norfloxacin‐isatin‐aminopyrimidinimino hybrids 68 (EC50:
11.2, 9.4, and 14.9 µg/ml, in MT‐4 cells) showed potential anti‐HIV
activity, and hybrid 68b emerged as the most potent broad‐spectrum
chemotherapeutic agent active against HIV‐1 replication (EC50:
9.4 µg/ml), MTB H37Rv (MIC: 3.13 µg/ml), and various pathogenic
bacteria (MIC: 0.009–4.88 µg/ml).[134] Three fluoroquinolone‐isatin‐
lamivudine hybrids 69a–c (EC50: 1.11, 49.0, and 1.16 µM in CEM
cells; Figure 13) displayed promising activity against HIV‐1, but all of
them were less active than lamivudine (EC50: 0.1 µM).[135]
The norfloxacin‐/ciprofloxacin‐/gatifloxacin‐/lomefloxacin‐tetra-
cycline hybrids 70 (Figure 14) were evaluated for their anti‐HIV‐
1IIIB, HIV‐1 IN and anti‐mycobacterial activities, and the results
indicated that hybrids 70a–d (EC50: 7.58–20.2 µM in CEM cells)
derived from tetracycline showed potential activity against HIV‐1
replication, while the majority of the hybrids derived from
[8]
oxytetracycline did not show any activity against HIV‐1 replication
at a concentration below their toxicity threshold.[136] All hybrids
(IC50: 12–65 µM) showed moderate inhibition of both 3′‐P and ST
steps of HIV‐1 IN and they were more active than tetracycline (IC50:
204 and 188 µM). Conjugate 70i was found to be the most promising
compound against HIV‐1 replication with EC50 of 5.2 µM and was
nontoxic towards the CEM cells (CC50: 200 µM), and MIC of 0.2 µg/
ml against MTB H37Rv, with moderate inhibition of both 3′‐P and ST
steps of HIV‐1 IN (IC50: 20 and 18 µM). The norfloxacin‐/ciproflox-
acin‐stavudine hybrids 71a,b (EC50: 100.0 and 61.8 µM in CEM cells)
showed moderate anti‐HIV activity, but they were far less than the
reference stavudine (EC50: 0.09 µM)[137]. The SAR of fluoroquino-
lone‐zidovudine hybrids revealed that the link pattern was closely
related to the activity, and the hybrids 73 (EC50: 1.2–33 nM in MT‐4
cells) tethered through C‐3 carboxylic acid were far more potent
than the analogs 72 (EC50: 3.87–9.31 µM in MT‐4 cells) linked via C‐7
piperazine ring.[138] In particular, hybrids 73c,e (EC50: 1.8 and 1.2 nM)
were highly active against HIV‐1IIIB, and they were 15‐ and 22.5‐fold
more potent than the reference azidothymidine (EC50: 27 nM).
Moreover, both of them showed low cytotoxicity towards MT‐4
(CC50: 45.04 and 34.05 µM) and C8166 (CC50: >272.22 and
>219.81 µM) cells, and the SI were as high as ≥25,022 and
≥28,375. The excellent anti‐HIV activity together with the favorable
safety profile made the hybrids 73c,e ideal leads for further
investigation (Figure 14).
The naphthyridine‐pyridine/benzothiazole hybrids 74 (Figure 14)
showed submicromolar activity against HIV‐1IIIB, and the SAR
WANG ET AL.
FIGURE 14 Chemical structures of 4‐quinolone hybrids 70–74
suggested that hybrid 74b (EC50: 0.05 µM in MT‐4 cells) with
benzothiazole moiety at the C‐7 position of naphthyridine was more
potent than the corresponding pyridine analog 74a (EC50:
[139]
>8.32 µM). Further study indicated that substituents at N‐1
[140–142]
position also influenced the antiviral activity of hybrids 74.
Hybrids 74c,d (EC50: 0.16 and 0.02 µM) with vinyl were more active
than the cyclopropyl analogs 74a,b against HIV‐1IIIB, and they (EC50:
0.21 and 0.025 µM) were also highly active against HIV‐2ROD.
Obviously, conjugate 74c represents a promising lead molecule for
further anti‐HIV drug design.
A series of 4‐quinolone and naphthyridine derivatives bearing
oxygen‐containing substituents at C‐7 position were screened for
their inhibitory potency against HIV IN[143,144]. The results indicated
that for 4‐quinolone derivatives, methoxy group at C‐7 was crucial
for the high inhibitory activity, and compound 75 (IC50: 8 nM) (Figure
FIGURE 15 Chemical structures of 4‐quinolone hybrids 75–78
| 13 of 17
15) was highly active in the inhibition of HIV‐1 IN ST[143]. All
naphthyridine derivatives 76 possessed great potency against HIV‐1
IN with EC50 of 0.9–16 nM, and the SAR indicated that the existence
of hydrogen bond donor hydroxyl was favorable to the activity[144]. In
particular, compound 76e (EC50: 0.9 nM) was found to be the most
active, and it could act as a lead compound for further study.
Introduction of phenyl ring into heterocycle at C‐7 position was
also tolerated[145,146], and the representative compound 77 (K‐12,
EC50: 0.2‐0.6 µM) was active against different strains of HIV‐1
(including azidothymidine and ritonavir‐resistant HIV‐1 strains), HIV‐
2 and simian immunodeficiency virus in MT‐4, CEM, C8166, and
peripheral blood mononuclear cells (Figure 15). K‐12 could also
inhibit Moloney murine sarcoma virus‐induced transformation of
C3H/3T3 cells with an EC50 of 6.9 µM, and it proved inhibitory to
herpesvirus saimiri, human cytomegalovirus, varicella‐zoster virus,
14 of 17 | WANG
and herpes simplex virus types 1 and 2[145]. Further study indicated
that K‐12 was an interesting new anti‐HIV agent that could target
the Tat transactivation process, and it was worth to be further
investigated.
The quinolinonyl diketo acid derivatives 78 (Figure 15) with
various nitrogen‐containing heterocycles, such as piperazine, mor-
pholine, and pyrrolidine at the C‐7 position of quinolone moiety were
evaluated as potential HIV‐1 IN and RNase H inhibitors[147]. The anti‐
HIV‐1 SAR revealed that the substituents at C‐7 position have great
influence on the activity, and the relative contribution order was
pyrrolidine > morpholine > piperazine. Interestingly, the ethyl esters
were more potent than the corresponding acids. All compounds (IC50:
0.028–28.7 µM) showed great potency against HIV‐1 IN and RNase
H. Two of them 78j and 78k inhibited HIV‐1 IN with IC50 values
below 100 nM for HIV‐1 IN ST and showed a two order of magnitude
selectivity over 3′‐P. These ST selective inhibitors also inhibited HIV‐
1 RNase H with low micromolar potencies. Molecular modeling
studies based on HIV‐1 IN and RNase H catalytic core domains
provided new structural insights for the future development of the
compounds as dual HIV‐1 IN and RNase H inhibitors.
4 | CONC LU SION
AIDS/HIV, one of the largest and most devastating public health
pandemics, results in more than 1.5 million new cases and around 1
million deaths annually. The emergence of multidrug‐resistant HIV
virus and the inability of the HAART to eradicate HIV virus from
infected patients have further aggravated the situation, making a
great need to develop new anti‐HIV agents.
Quinolones, one of the most common drugs in anti‐infective
chemotherapy, possess various atypical biological properties including
anti‐HIV activity. Elvitegravir, the first quinolone integrase inhibitor, has
ET AL.
F I G U R E 1 6 The SAR of 4‐quinolone
derivatives. SAR, structure–activity
relationship
already been approved for the treatment of HIV infection, demonstrat-
ing quinolone derivatives are potential anti‐HIV agents.
This review covers the recent advances in the search for
quinolone derivatives as potential anti‐HIV agents, and some of
them that are exemplified by 2‐quinolones 6o, 7c, and 18f and
4‐quinolones 31c, 55k, MW5, HM‐12, and HM‐13 are highly active
against HIV‐1, mutant HIV‐1, and HIV‐2 strains with EC50 values in
nanomolar level, while compounds 66k, 66l, and 68b have the
potential to treat HIV‐induced opportunistic infections, such as
bacterial infections, tuberculosis, and tumors. The SAR is also
discussed, and the modifications of different positions of the
4‐quinolone nucleus are depicted in Figure 16.
The enriched SAR may pave the way to the further rational
development of quinolones that not only hold high efficiency against
both drug‐sensitive and drug‐resistant HIV infections but also
possess a broad spectrum of chemotherapeutic properties to treat
HIV‐induced opportunistic infections.
ORCI D
Ruo Wang http://orcid.org/0000-0002-8151-8025
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How to cite this article: Wang R, Xu K, Shi W. Quinolone
derivatives: Potential anti‐HIV agent—development and
application. Arch Pharm Chem Life Sci. 2019;e1900045.
https://doi.org/10.1002/ardp.201900045