Bioorganic & Medicinal Chemistry Letters 15 (2005) 73–76
Design, synthesis and evaluation of 5-substituted
amino-2,4-diamino-8-chloropyrimido-[4,5-b]quinolines
as novel antimalarials
Advait A. Joshi, Sachin S. Narkhede and C. L. Viswanathan*
Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai 400 098, India
Received 7 August 2004; accepted 12 October 2004
Available online 2 November 2004
Abstract—Novel 5-substituted amino-2,4-diamino-8-chloropyrimido-[4,5-b]quinolines were designed based on a pharmacophore
developed for potent antimalarial activity using Chem-X and MOE softwares. The designed molecules were synthesized by follow-
ing a novel route and were evaluated by RaneÕs test for blood schizonticidal activity in mice infected by Plasmodium berghei. Based
on the Mean Survival Time (MST) data, of the nine compounds evaluated, three had curative potential when compared with
chloroquine.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Malaria is a serious health problem and as per the recent
report of WHO, there are 300 million new cases of ma-
laria every year and about a million children die each
year of the disease.1 Moreover, drug resistance is a seri-
ous problem in malaria and it can be attributed to the
use of single drug (monotherapy) for treatment and to
the adaptation of the malarial parasite by developing
alternate pathways for survival. Hence, the present
strategy for new drug development is directed towards
identifying the essential enzyme systems in the parasite
and developing molecules to inhibit them. With this in
view, the inactivation of potent drugs like chloroquine
by malarial parasites has been studied in depth.2
schizonticide), quinacrine (gametocidal activity against
P. vivax and P. malariae), sulfadoxine (long duration
of action against blood schizonts) and pyronaridine
(inhibits P. falciparum topoisomerase II).3 The study
was carried out using Chem-X4 and Molecular Operat-
ing Environment (MOE)5 softwares on Pentium IV
1.6GHz computer. The conformers of each molecule
were generated by using dynamic simulations at the tem-
perature of 310ꢁC and the sampling time was taken as
5 · 10À4 s. The lowest energy conformations were identi-
fied for each molecule and were then used for arriving at
a three-point pharmacophore. The basic nucleus, 2,4,5-
triamino-8-chloropyrimido-[4,5-b]quinoline, was built
using the features of the pharmacophore.
The present work is aimed towards developing novel
molecules with improved potential for treating malaria
and with decreased probability for developing drug
resistance. It is proposed to achieve this by generating
a common pharmacophore from the structures of potent
antimalarials belonging to different classes, by designing
novel molecules, synthesizing and evaluating them.
Synthesis of the basic nucleus is outlined in Scheme 1.
Reaction of guanidine nitrate 1 with malononitrile 2 in
the presence of sodium alkoxide in dry ethanol or meth-
anol yielded 2,4,6-triaminopyrimidine 3 (mp 249ꢁC).
This was condensed with 2,4-dichlorobenzoic acid 4, in
the presence of activated copper bronze powder at
180–190ꢁC to yield N-(2,4-diamino-6-pyrimidino)-4-
chloroanthranilic acid 5 (mp 181ꢁC) which on cycliza-
tion using concentrated sulfuric acid yielded 5-oxo-
(10H)-2,4-diamino-8-chloropyrimido-[4,5-b]quinoline 6
(mp 160ꢁC). This was reacted with phosphorous oxy-
chloride to get 2,4-diamino-5,8-dichloropyrimido-[4,5-
b]quinoline 7 (mp 151ꢁC) which on stirring with liquor
ammonia at room temperature gave 2,4,5-triamino-8-
chloropyrimido-[4,5-b]quinoline 8 (mp 200ꢁC, dec.).
A three-point pharmacophore was developed by using
structures of potent antimalarials like chloroquine
(blood schizonticidal activity), pyrimethamine (tissue
Keywords: Malaria; Pyrimido-[4,5-b]quinolines; Antimalarials.
*
Corresponding author. Tel.: +91 22 26670871; fax: +91 22
0960-894X/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.10.037