Syntheses and antifilarial profile of 7-chloro-4(substituted amino) quinolines: A new class of antifilarial agents

Article abstract of DOI:10.1016/S0960-894X(00)00255-9

The syntheses of 7-chloro-4-(substituted amino) quinolines (2-22) and their antifilarial activities are delineated. Some of the screened compounds have shown promising filarial response and sterilization effect on female Acanthocheilonema viteae in rodents. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00255-9

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1409±1412
Syntheses and Anti®larial Pro®le of 7-Chloro-4-(substituted
Amino) Quinolines: a New Class of Anti®larial Agentsy
Swati Tewari, a P. M. S. Chauhan, a,* A. P. Bhaduri, Nigar Fatima a
and R. K. Chatterjee b
aDivision of Medicinal Chemistry, Central Drug Research Institute, Lucknow 226 001, India
bParasitology, Central Drug Research Institute, Lucknow 226 001, India
Received 31 January 2000; accepted 12 April 2000
AbstractÐThe syntheses of 7-chloro-4-(substituted amino) quinolines (2±22) and their anti®larial activities are delineated. Some of
the screened compounds have shown promising ®larial response and sterilization e€ect on female Acanthocheilonema viteae in
rodents. # 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Amodiaquine exhibits strong therapeutic e€ect against
adult forms of L. carinii in Mongolian gerbils11,12 and
other 4-aminoquinolines also exhibited anti®larial activity
in vivo.13 The details of the synthesis and anti®larial
potential in vivo of adult A. viteae are reported here.
Problem associated with the chemotherapy of ®lariasis
is the non-availability of non-toxic macro®laricide or at
least an agent which can sterilize ®lariae permanently
and thus blocking the further transmission of infec-
tion.1,2 Associated with this problem is the kinetics of
the death of micro®lariae (mf) which must not allow
anaphylactic or side reactions. The candidate drug Die-
thylcarbamazine (DEC) which kills mf but has no e€ect
on most of the adult ®larial species and causes side
e€ects.3 No drug yet has been found to be e€ective
against adult worms.4,5 Therefore, R&D activities are
involved for the search of a new molecular structure as
macro®laricidal or at least an sterilizing agent. In our
earlier e€orts in search for macro®laricidal agent, we
have explored 2,4,6-substituted triazines,4 5-amino and
5,8-diaminoisoquinolines,6 aplysinopsin derivatives,7
1,1-dicyano-2-substituted-ethylenes,8 1,3-disubstituted
pyrido indoles,9 and quinolones.10 Extensive work has
been done on 4-aminoquinolines as antimalarials but no
sincere e€orts have been carried out in exploring this
pharmacophore as anti®larial.
Chemistry
The synthetic strategy to obtain the molecular frame
work of 7-chloro-4-(substituted amino) quinolines 2±22
can be divided into two (Schemes 1 and 2). Compounds
2, 3 and 6 were prepared by reacting 4,7-dichloro-
quinoline 1 with appropriate amines in dry methanol.
Nitration of compound 6 with fuming HNO3 produced
the nitro derivative 7. The compound 6 was reacted at
0 ꢀC with SOCl2 in dry benzene to furnish compound 8.
This could be made to react with excess anhydrous
piperazine in dry methanol to furnish mono-substituted
derivative 11. Compounds 9, 10 and 12 were obtained by
re¯uxing the mixture of 8 with para-substituted phenols
and substituted piperazine respectively, in dry DMF:
K2CO3 in a ratio 1:1. Elaboration of compound 11 was
carried out by coupling with N-Boc aminoacids in pre-
sence of HOBT and DCC to yield compound 13±17 and
their deprotection by 50% tri¯uoroacetic acid in meth-
ylene chloride gave compounds 18±22. Bisquinolines 4
and 5 were obtained by re¯uxing compound 1 with 1,4-
diaminobutane and l-Lysine hydrochloride in presence
of triethylamine and N-methyl pryrrolidene-2 as solvent
in a ratio of 2:1:2 respectively. All the compounds were
characterized by spectroscopic analysis.14
In this present work, we have explored, 4-aminoquinoline
derivatives (2±22) as a new lead compounds in anti®larial
chemotherapy. The design of these 7-chloro-4-(substituted
amino) quinolines (2±22) is based on the observation that
*Corresponding author. Tel.: +91-522-212411, ext. 4332; fax: +91-
522-223405; e-mail: root@csdri.ren.nic.in
yCDRI Communications No.6015.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00255-9

1410
S. Tewari et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1409±1412
Scheme 1. Reagents and conditions: (i) Primary amines, dry methanol, re¯ux; (ii) Ethanolamine, re¯ux, NaOH; (iii) Concd H2SO4, fuming HNO3,
stirring at 0 ꢀC, liquid. Ammonia; (iv) SOCl2, stirring at 0 ꢀC, Dry benzene, NH4OH; (v) Dry DMF, K2CO3, substituted phenol, re¯ux; (vi) Dry
Methanol/Dry DMF, K2CO3, substituted Piperazine; (vii) Diamines, N-methylpyrrolidone, Et3N, re¯ux.
Scheme 2. Reagents and conditions: (i) Dry DMF, DCC, HOBT, N-Boc (Gly, Ala, Phe, Ile, Pro), Stirring at 0 ꢀC; (ii) CF3CO2H, CH2Cl2, ether,
stirring at room temperature.
Compound 2 having nitrophenyl hydrazine group at
position 4 of quinoline ring has maximum 78% adulticidal
activity along with 50% sterilization of female worms.
Material and methods
The micro- and macro®lariacidal activities of the syn-
thesised compounds were evaluated in vivo against A.
viteae infection in Mastomys natalensis.15 Compounds
being insoluble in water were made ®ne suspension with
1% Tween 80. Two of the three animals were used for
each dose level studied and at least two replicates were
used for con®rmation of activity.
Compound 19 has shown maximum sterilization (100%)
of female worms. Compound 5 having aminoacid l-
Lysine has 85% micro®laricidal and compound 6 having
ethanolamine has 86% micro®laricidal activity along
with 22% adulticidal activity, respectively. Whereas
incorporation of NO2 group in compound 6 enhanced its
adulticidal activity (7, 58%). Compound 9 having p-
cyano phenoxy group has 56% adulticidal activity while
compound 10 having p-nitro phenoxy group is inactive.
Compound 4 (bisquinoline) having simple 1,4 diamino
butane is 47% adulticidal, while compound 5 (bisquino-
line) having aminoacid l-Lysine is 85% micro®laricidal.
Compound 11 and 12 are inactive, while exploring com-
pound 11 to furnish Boc-protected glycine, i.e., 13 has
shown 63% sterilization whereas 15 and 19 has shown
Results and Discussion
All the synthesised compounds (2±7, 9±22) were exam-
ined in vivo against A. viteae but only nine compounds
2, 4, 5, 6, 7, 9, 13, 15 and 19 were found active (Tables 1
and 2).

S. Tewari et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1409±1412
1411
Table 1.
Compound
2
Acknowledgements
R
Compound
R
One of us (Swati Tewari) is indebted to CSIR for the
award of Senior Research Fellowship and NF is grateful
to CSIR for the award of Research Associateship. We
are also indebted to RSIC, Lucknow, for providing
spectroscopic data.
12
3
13, 18
CH2ÐNH
References and Notes
4
5
(CH2)4
14, 19
15, 20
1. Ottesen, E. A.; Ramchandran, C. P. Parasitol. Today 1995,
2, 129.
2. Coa, W.; Ploeg, C. P. B.; Ren, Z.; Habbema, J. D. F. WHO
1997, 18, 17±20.
3. Chauhan, P. M. S.; Singh, S. N.; Chatterjee, R. K. Ind. J.
Chem. 1993, 32B, 858.
4. Chauhan, P. M. S.; Chatterjee, R. K. Ind. J. Chem. 1994,
33B, 32.
X
9
16, 21
17, 22
CN
5. Campbell, W. C. Parasitol. Today 1985, 1, 10.
6. Srivastava, S. K.; Chauhan, P. M. S.; Agarwal, S. K.;
Bhaduri, A. P.; Singh, S. N.; Fatma, N.; Chatterjee, R. K.;
Bose, C.; Srivastava, V. M. L. Bioorg. Med. Chem. Lett. 1996,
6, 2623.
7. Singh, S. N.; Bhatnagar, S.; Fatma, N.; Chauhan, P. M. S.;
Chatterjee, R. K. Trop. Med. Int. Health 1997, 2, 535.
8. Tewari, S.; Chauhan, P. M. S.; Bhaduri, A. P.; Singh, S. N.;
Fatma, N.; Chatterjee, R. K.; Srivastava, V. M. L. Bioorg.
Med. Chem. Lett. 1997, 7, 1891.
9. Srivastava, S. K.; Agarwal, A.; Chauhan, P. M. S.; Agar-
wal, S. K.; Bhaduri, A. P.; Singh, S. N.; Fatma, N.; Chatterjee,
R. K. J. Med. Chem. 1999, 42, 1667.
10. Srivastava, S. K.; Haq, W.; Murthy, P. K.; Chauhan, P.
M. S. Bioorg. Med. Chem. Lett. 1999, 9, 1885.
11. Thompson, P. E.; Boche, L.; Blair, L. S. J. Parasitol. 1968,
54, 834.
10
11
NO2
H
Table 2. Anti®larial in vivo activity of 7-chloro-4-substituted ami-
noquinolines (2±22) against A. viteae at 200 mg/kgÂ5 days (po)
Compounda
Anti®larial activity (% reduction in parasite load)
Mif.
Maf.
Sterl. of ,
2
4
5
6
7
9
13
15
19
41
0
85
86
0
0
0
0
0
90
78
47
0
22
58
56
0
0
0
0
50
0
0
0
0
12. Burckhalter, J. H.; Tendick, F. H.; Jones, E. M.; Jones, P.
A.; Holcomb, W. F.; Rawlins, A. L. J. Am. Chem. Soc. 1948,
17, 1363.
0
63
50
100
0
13. Elslager, E. F.; Perricone, S. C.; Tendick, F. H. J. Med.
Chem. 1969, 12, 965.
14. Spectroscopic data for representative compounds 2: yield
DECb citrate
63%; mp 215ꢀC (dec.); MS: m/z (M++2, 316,Cl37), (M+ 314,
1
Cl35) ; IR (KBr): 3442, 3151, 2750, 1510, 1332, 1109, 839 cm
;
aInactive compounds are not listed here; mif=micro®lariae; maf.=
macro®lariae; sterl.=sterilization; ,=female worms; O=inactive.
bDEC=Diethylcarbamazine (Standard Anti®larial Drug).
1H NMR (200 MHz, DMSO-d6): d 9.80 (bs, 1H, NH), 8.71
(d,1H, J=8Hz). 8.50 (d, 1H, J=8Hz), 8.19 (d, 1H, J=10Hz),
7.95 (bs, 1H, NH), 7.68 (d, 1H, J=10 Hz), 7.04±6.93 (m, 4H). 5:
yield 46%, mp 262ꢀ (dec), FAB MS: m/z 492 [M+Na+], 470
[M+H]+; IR (KBr): 3370, 3228, 3060, 1635, 1609, 1455, 1205,
50% and 100% sterilization, respectively. One interest-
ing observation is that among the modi®ed peptide
derivatives of quinoline 13±22 only three compounds
i.e., 13, 15 and 19 were found active and that also in
sterilization only. From the SAR of the 4-(substituted
amino) analogues, we can conclude that nitrophenyl
hyrazaine at position 4 of quinoline ring plays an
important role in eliciting biological response against A.
viteae and the compound 2, 4, 5, 9, 13±22 having bulky
substitution at 4th position of quinoline ring were found
active as anti®larials. The novel modi®ed peptide deri-
vative of quinoline having Boc-protected glycine 13, Boc-
protected phenylalanine 15 and Boc-free alanine 19
showed good sterilization of female worms which pro-
vides useful lead to conduct further modi®cation to gen-
erate sterilizing agent to combat ®larial infection.
Therefore, there is need of reevaluation of 7-chloro-4-
(substituted amino) quinolines as well as bisquinolines
as anti®larials.
1
1
858 cm ; H NMR (300 MHz, DMSO-d6): d 8.56 (bs, 1H,
NH), 8.44±8.36 (m, 4H), 7.83±7.80 (m, 2H), 7.55±7.45 (m,
2H), 6.63 (d, 1H, J=6.6 Hz), 6.44 (d, 1H, J=6Hz), 4.25±4.23
(m, 1H, NH), 2.49±2.47 (m, 1H, CH), 2.49±2.47 (m, 2H), 2.08±
2.97 (m, 2H), 1.77±1.49 (m, 4H); 9: yield 83%; mp 178 ꢀC; MS:
m/z (M++2, 325, Cl37), (M+ 323, Cl35); IR (KBr): 3840, 3269,
1
3068, 2925, 2360, 2225,1579, 1506,1452, 1253, 1051, 837 cm
;
1H NMR (200 MHz, CDCl3); d 8.80 (d, 1H, J=6Hz), 8.17 (d,
1H, J=4.8 Hz), 8.07 (d, 1H, J=1.2 Hz), 7.60 (t, 2H, J=2.8
Hz), 7.26 (t, 1H, J=8Hz), 7.19±6.89 (m, 2H), 6.74 (d, 1H, J=6
Hz), 4.85 (bs, 1H, NH), 4.53 (t, 2H, J=4Hz, OCH2), 4.07 (t,
2H, J=4Hz, NCH2), 13: yield 76%, mp 201 ꢀC, FAB MS: m/z
448 [M+H] +; IR (KBr): 3754, 3340, 2290, 2877, 1706, 1620,
1456, 1166, 1020 cm 1; 1H NMR (200 MHz,CDCl3): d 8.53 (d,
1H, J=6Hz), 7.97 (d, 1H, J=2Hz), 7.75 (d, 1H, J=10 Hz),
7.66 (d, 1H, J=8 Hz), 6.39 (d, 1H, J=4 Hz), 5.84 (bs, 1H, NH),
5.50 (bs, 1H, NH), 3.86 (dd, 2H, J=6, 12 Hz, CH2), 3.35 (t, 4H,
J=6 Hz, NCH2), 2.81 (t, 2H, J=6 Hz, CH2), 2.55 (d, 4H,
J=4.4 Hz, NCH2), 1.45 [s, 9H, O-C(CH3)3], 1.12 (t, 2H,
J=6Hz, COCH2), 19: Yield 47%, mp 115 ꢀC (dec); FABMS:

1412
S. Tewari et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1409±1412
m/z 362 [M+H]+; IR (KBr): 3816, 3759, 3149, 1631, 1406,
1074, 1029 cm
J=7.2 Hz), 8.25 (d, 1H, J=10 Hz), 7.73 (d, 1H, J=2Hz),
7.59±7.49 (m, 1H), 6.73 (d, 1H, J=7.2 Hz), 4.44±4.37 (m, 1H,
COCH), 3.96 (t, 2H, J=9Hz, NCH2), 3.79±3.27 (m, 10H,
NCH2, NHCH2), 1.43±1.18 (m, 3H, CH3).
15. Worms, M. J.; Terry, R. J.; Terry, R. J. J. Parasitol. 1961,
47, 963.
1
;
1H NMR (200 MHz, D2O): 8.26 (d, 1H,