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Paullones 4
Paullones 4
0 Elsevier, Paris
5 6 7 P
8 10
0 0
Cl
15 R = -N”-y--J-C”, Cl N Cl m N
0 Cl N 11 II
ml
12 3 tiJ\ 13
2 4
Scheme 1.
Table I. Interatomic distances (A) of basic nitrogen atoms in amodiaquine, 2bbd, 3b-d, 4b-d, 15, 1, chloroquine, mefloquine
and quinine at their minimum energy conformations computed from an MkIX force field with TCroutines.
Compound Conformationa Min energy (kcal mol-11 Nl.. .N3+b N,. . .N4+b NJ. . .N5+b
Amodiaquine A 17.85 10.09
B 17.52 8.30
2b - - 8.72
2c - - 8.80 12.05
2d - - 8.74 13.52
3b A 20.80 10.09
20.45 8.29
3c i 85.03 10.09 13.31
B 84.54 8.24 11.00
3d A 73.12 10.02 14.15
B 72.67 8.54 13.18
4b - - 9.54
4c - - 9.51 12.31
4d - - 9.58 13.23
15 - 14.24
1 8.71 11.14
Chloroquine 8.38
Mefloquine 6.52~
Quinine 6.55~
aAmodiaquine and the anilinoquinolines 3b-d have 2 stable conformations A and B. In conformer A, the basic ammo side
chain is orientated away from the quinoline ring. In conformer B, the side chain is orientated towards the quinoline ring (fig 2);
bsee figure 1 for numbering on N atoms; cN1.. .N,+ refers to the distance between the quinoline ring N and the protonated side-
chain ring N.
quinoline series [3] and gives support to our proposed The indolo[3,2-clquinolines 2 and anilinoquino-
mode of interaction involving the ring nitrogen of lines 3 are found to be active against sensitive and
quinoline (or its isostere) and the side-chain nitrogen. resistant isolates of P falciparum. It would appear that
The tetrahydroindolo[3,2-dlbenzazepines (4) are the conformational characteristics and overall plana-
generally less active than the other 2 ring systems. rity of these 2 ring systems are not critical to activity.
This may be attributed to the non-aromatic ring B of 4 However, these factors may be important insofar as
in which being non-planar would weaken hydropho- they result in an optimum N.. .N+ distance for effec-
tive interaction with the receptor. As seen from table I,
bic bonding involving this moiety and the flat area at the N,. . .N,+ distances of these compounds do not
the proposed receptor site. deviate by more than 0.5 A from those of amodia-
quine and chloroquine. In contrast, the less active
Table II. Degree of planarity for compounds 2b, 3b, and tetrahydroindolo[3,2-d]benzazepines 4, which are
4b. conformationally intermediate between the indolo-
[3,2-c]quinolinesO and anilinoquinolines, have N,. . .N,+
Compound distances (9.5 A) which are longer than those of
amodiaquine and chloroquine.
2b -0.06” It is interesting to note that although the indolo-
[3,2-clquinolines have N,. . .N,+ distances comparable
3bb 41.31”
to that of amodiaquine (conformer B), they are in fact
4b 22.36” structural analogues of conformer A of amodiaquine.
The nature of the side chain exerts a subtle effect
%4n appropriate torsion angle is chosen to best indicate the on antimalarial activity. The monobasic diethylamino-
angle of twist for each molecule; bconformer B. methyl side chain, present in amodiaquine, appears to
111
Table III. In vitro antimalarial activity of 2a-b, 3a-b, 4a-b, chloroquine (CQ) and mefloquine (MF) against different isolates
of P falciparum.
Concentration (picomoles) of drug in well (50 ~1) required to inhibit schizonts
Category 1 isolatesa CQ MT 2a 2b 2c 2d 3a 3b 3c 3d 4a 4b 4c 4d
Sensitive to CQ and MF
1 2 157 <28 <26 48 39 < 28 26 < 24 2000 476 320 300
2 4” 8 250 28 < 26 24 312 28 52 < 24 597 - - -
3 2 1000 <28 < 26 96 156 ~28 26 < 24 1200 - - -
4 : 0.5 1300 < 28 <26 48 78 28 207 < 24 -
2 02532 05 - - - - - - - - - 476
238 1300
84 2400
373
Category 2 isolate&
Resistant to CQ and MF
8 128 2000 < 28 415 192 500 28 < 26 200 1000 - - -
9 6”: 128 2000 < 28 26 192 312 28 170 48 1200 - - -
10 64 128 1000 <28 <26 96 623 < 28 < 26 24 120 - - -
11 z: 128 500 28 104 48
12 128 1000 114 52 96 628 226 827 2500 960 238 101 746
Resistant to CQ sensitive
to MF
13 16 0.5 - - - - - - - - - 59 50 187
14 i; 8 - - - - - - 119 101 <23
15 32 < 28 170 24 1 190 320 373
16 “6: 2 2000 28 - 192 312 <;S <26 -24 500 - - -
17 2 2000 < 28 - 96 623 ~28 < 26 24 120 - - -
acategory 1 isolates (l-7) were freshly obtained from venous blood of infected patients and tested immediately. Category 2
isolates (8-14) were established in the laboratory by continuous in vitro culture. bIf schizonts survived in 8 picomoles or more
of chloroquine per test well (50 pl), the isolate is said to be resistant to chloroquine. The same threshold value for mefloquine is
64 picomoles per well.
be optimum for both indolo[3,2-clquinolines and tural modification of existing antimalarials may still
anilinoquinolines. Dibasic side chains such as c and d be a viable approach to the design of new compounds
did not give rise to improved efficacy as originally against drug-resistant plasmodia.
intended.
An interesting compound to take note of is 3d,
which has a dibasic side-chain and is active against Conclusion
several isolates. Compound 3d, in conformer A, is the
only compound in the present study which has a4basic Using amodiaquine as a lead compound, a series of
nitrogen (NJ whose N,. . .N,+ distance at 14.15 A is indolo[3,2-clquinolines, anilinoquinolines and tetra-
close to the N,. . .N,+ distance (14.24 A) of 15. Com- hydroindolo[3,2-d]benzazepines have been designed
pound 15, an active antimalarial [ 131, has only one as potential antimalarial agents. These compounds
side-chain nitrogen (N5) of sufficient basicity to be differ in the conformational planarity of the key nuclei
protonated at physiological pH, unlike 3d which has 2 as well as the distance between the side-chain nitro-
(N3 and N4). One wonders which of the 2 nitrogens of gen and ring nitrogen functions. The latter (N...N+)
3d is active, since N, (conformer B) is analogous to distance have been proposed to be an important deter-
the side-chain nitrogen of amodiaquine (conformer B) minant of activity in amodiaquine. In vitro evaluation
whereas N, (conformer A) is analogous to N5 of 15. of these compounds against various isolates of
The overall significance of this work is the obser- P falciparum showed that conformational planarity
vation that there are a number of compounds (for per se was not an important determinant of activity. It
example 2b, 2c, 3b, and 3c) which are more effective was, however, important in determining the distance
than chloroquine or mefloquine when tested against between the 2 key nitrogen atoms of the side-chain
isolates resistant to these drugs. It indicates that struc- and the ring. Where the distance was greater than that
112
observed in amodiaquine, as observed in the tetra- General procedure for the preparation of hydrazines 10~ and 1Od
hydroindolo[3,2-dbenzazepines, antimalarial activity
was low. Hydrazines 1Oc and 10d were prepared from arylamines SC and
Sd according to the standard procedure [4]. They were unstable
in air and were always freshly prepared before use.
Experimental protocols
l-(5’-Hydrazino-2-methoxybenzyl)-3-dimethylaminopyrrolidine
Unless otherwise stated, materials were obtained from com- 1oc
mercial suppliers and used without further purification. Melting IR (neat): 3325, 3200, 1620 cm-r. NMR (CDCl,) 6: 1.02-2.83
points were determined with a Gallemkamp melting point (m, pyrrolidinyl H, N(CH,),), 3.18 (s, NH), 3.52 (s, Ar-CH3),
apparatus and were uncorrected. IR spectra were obtained in 3.67 (s, OCH,), 6.32-7.17 (m, aryl H).
pressed KBr discs on a Jasco IR-810 spectrophotometer. rH-
NMR spectra were recorded on a FT Jeol FX 90Q (90 MHz)
instrument and chemical shifts were reported as 6 relative to 5-Hydrazino-2-metho~-[N-(3’-dimethylaminopropyl)-N-methyl]-
tetramethylsilane when taken in deuterated organic solvents, or benzylamine 1 Od
sodium 3-(trimethylsilyl)propanesulfonate in the case of D,O IR (neat): 3350, 3225, 1635 cm-l. NMR (CDCl,) F 1.43-2.53
solutions. Mass spectra were determined on a Micromass 7035 (m, N-CH,, N-(CH,),-N), 3.37 (s, Ar-CH,), 3.65 (s, OCH,),
E double focussing mass spectrometer. Thin-layer chromato- 6.50-7.18 (m, aryl H).
graphy (TLC) was carried out on 5 x 20 cm Kieselgel G type
60 (Merck) plates. Elemental analyses (C, H, N, Cl) were 7-Chloro-4-[4f-methoxy-3~-(3”-dimethylaminopyrrolidin-I”-yl)-
performed on a Perkin-Elmer Auto-Analyser 240. methylJanilinoquinoline 3c
General method for the preparation of nitro amines 7c and 7d To a solution of SC trihydrochloride (1.26 g, 0.0035 mol) in
50 ml H,O was added 0.7 g (0.0035 mol) 4,7-dichloroquinoline
2-Chloromethyl-4-nitroanisole 6 [7] (5g, 0.026 mol) and an 12. The pH was adjusted to 3-4 using concentrated HCl and
excess (0.135 mol) of the appropriate amine (dimethylamino- the mixture heated on a water bath for 2 h, stirred at room
pyrrolidine for 7c and N,Wfl-trimethylpropanediamine for 7d) temperature overnight, and filtered. The precipitate was stirred
were retluxed for 18 h in methanol, after which the solvent was with excess concentrated ammonia, filtered and dried, yielding
removed by evaporation under reduced pressure. The residue 1.24 g of 3c (86% yield). Recrystallization from benzene gave
was dissolved in ether and washed with water until neutral. On 0.7 g of white solid (48% yield), mp 150-151.5”C. IR: 3400,
drying over anhydrous Na,S04, and removal of the solvent 1610 cm-l; NMR (CDC&) 1.28-2.92 (m, pyrrolidinyl H, N-
under reduced pressure, an oil was obtained. It was dissolved in CH,), 3.58 (s, Ar-CH,), 3.75 (s, OCH,), 6.50-8.23 (m, aryl H);
dry ether and acidified by dropwise addition of freshly pre- MS m/z 410.1869 (talc for C,,H&lN,O 410.1873). Anal talc
pared ethanolic HCl which precipitated the product as the HCl for C,3H,CIN40: C, 67.22, H, 6.62; N, 13.63; Found: C, 67.23;
salt. H, 6.58; N, 13.77.
2-[(3’-Dimethylaminopyrrolidin-l’-yl)methyl]-4-nitroanisole 7c
The HCl salt was obtained in 51% (4 g) yield, mp 192- 7-Chloro-4-14’-methoxy-3’-[N-(3”-dimethylaminopropyl)-N-
193.5”C, after recrystallization from ethanol/ether. IR: 2450, methylaminomethylJ}anilinoquinoline 3d
1650, 1590, 1510, 1335 cm-i; NMR (CD,OD) 6: 2.83 (s,
N(CH,),), 2.82 (s, Ar-CH,), 3.99 (s, OCH,), 2.08-3.01 (m, A mixture of Sd trihydrochloride (2.04 g, 0.0056 mol) and 12
pyrrolidinyl H, N-CH3), 7.12-8.27 (m, aryl H). MS m/z (1.12 g, 0.0056 mol)-was reacted together as described for the
279.1578 (talc for C,,H,,N303 279.1582). Anal talc for svnthesis of 3c: 2.12 e crude 3d was obtained (91% vield)
C4HZ1N303: C, 60.20; H, 7.58; N, 15.04. Found: C, 60.03; H, Which was recrystallizevd from benzene to give white feathery
7.61; N, 14.96. crystals mp 154.6-155°C. IR 3400, 1610 cm-l; NMR (CDCl,)
6: 1.42-3.42 (m, N(CH,), N-(CH,),-N), 3.45 (s, Ar-CH,), 3.77
2-[N-(3’-Dimethylaminopropyl)-N-methylamino]methy1-4-nitro- (s, OCH,), 6.50-8.33 (m, aryl H). MS m/z 412.2039 (talc for
anisole 7d C,,H,,ClN,O 412.2030). Anal talc for C2,H,,CIN,0: C, 66.90;
The HCl salt (3.4 g, 38.7%) was obtained after recrystallization H, 7.08; N, 13.57. Found: C, 66.62; H, 7.07; N, 13.42.
from ethanol/dry ether giving mp 219-220°C. IR: 2650, 2460,
1608, 1590, 1510, 1340 cm-i; NMR (CD,OD) 6: 2.85 (s, N- 3-Chloro-8-methoxy-9-[3 ‘-dimethylaminopyrrolidin-I ‘-yl]-
CH3), 2.92 (s, N(CH,),), 4.03 (s, OCH,), 4.47 (s, Ar-CH,),
7.15-8.37 (m, aryl H). MS m/z 281.1740 (talc for C1,HZsN30, methyl-IlH-indolo[3,2-clquinoline 2c
281.1740). Anal talc for C,,H2,N,03.2HCl: C, 47.46; H, 7.11;
N, 11.86. Found: C, 47.35; H, 7.10; N, 11.95. To a solution of 2.29 g (0.0126 mol) 4-keto-7-chloro-1,2,3,4-
tetrahydroquinoline 1118j and 3.71 g. (0.0141 mol) 1Oc in 13.4
General procedure for the preparation of arylamines SC and 8d ml absolute ethanol was added 2.9 ml concentrated HCl. The
mixture was refluxed for 18 h. On cooling, 2.31 g of crude 2c
Each nitro amine (7c, 7d) (0.0098 mol) was dissolved in etha- hydrochloride was obtained (34.4% yield). The HCl salt had
nol (100 ml) and hydrogenated at 50 psi, 29°C in a Parr hydro- mp 225-228°C after recrystallization from ethanol. The free
genator using PtO, (10% by weight) as a catalyst. When the base was recrvstallized from benzene giving mn 253°C. IR
uptake of hydrogen had ceased, the catalyst was filtered and the (base): 3425, j620 cm-i; NMR (HCl sait in D,Oj 6: 2.84 (m,
filtrate acidified with ethanolic HCl. Removal of solvent under N-CH2-CH,), 3.13 (s, N-CH& 4.0 (s, OCH,), 4.65 (s, AI-CHJ,
reduced pressure gave the arylamine as the HCl salt which 7.11-8.90 (m, aryl H). MS m/z. 408.1715 (talc for
was used without further purification for the next stage of C,,H2,C1N40 408.1717). Anal talc for C23H,,C1N40: C, 67.56;
reaction. H, 6.16. Found: C, 67.25; H, 6.20.
113