Bioorganic & Medicinal Chemistry Letters
Structure–activity relationship studies of antiplasmodial
aminomethylthiazoles
Peter Mubanga Cheuka a, Diego Gonzalez Cabrera a, Tanya Paquet a, Kelly Chibale a,b,c,
⇑
a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa
b Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
c South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Structure–activity relationship (SAR) studies around a previously reported antimalarial aminomethylthi-
azole pyrazole carboxamide 1 are reported. Several analogues were synthesised and profiled for in vitro
antiplasmodial activity against the drug-sensitive Plasmodium falciparum malaria parasite strain, NF54.
Although all the reported analogues exhibited inferior in vitro antiplasmodial activity (IC50 = 0.125–
Received 25 August 2014
Revised 22 September 2014
Accepted 24 September 2014
Available online xxxx
173
lM) relative to compound 1 (IC50 = 0.0203
l
M), one analogue, compound 5a, retained submicromo-
lar activity (IC50 = 0.125
l
M).
Keywords:
Ó 2014 Elsevier Ltd. All rights reserved.
Thiazoles
Aminomethylthiazoles
Antiplasmodial activity
Structure–activity relationship
Antimalarial drug
Endemic mainly in tropical and subtropical regions of the
world, malaria closely rivals human immunodeficiency virus
(HIV) and tuberculosis (TB) infections in being a devastating and
lead killer disease.1 According to the World Health Organization’s
latest estimates released in 2013, about 207 million malaria cases
and 627,000 deaths were reported in 2012 especially among chil-
dren in Africa.2 There are four species of malaria parasites of the
genus Plasmodium implicated in human malaria infection and
these include; falciparum, vivax, malariae, and ovale with Plasmo-
dium falciparum being the most deadly. In addition, Plasmodium
knowlesi, a strain responsible for infections in monkeys has been
recently reported in humans.2
The efficacy of most marketed and commonly used antimalarial
drugs has been seriously compromised due to the emergence of
resistance.3–5 Thus, there is a critical need to intensify research
efforts aimed at developing effective and affordable drugs against
this parasitic disease.
mouse model showing 99.5% reduction in parasitemia at an oral
dose of 4 Â 50 mg/kg. Preliminary SAR studies to establish the min-
imum structural requirements for in vitro antiplasmodial activity
revealed that the unsubstituted aminomethyl group was critical
for potent activity. Furthermore, the activity was significantly
reduced in derivatives lacking the pyrazole moiety. However, in
the aforementioned studies, replacements or modifications of the
thiazole and pyrazole motifs, as well as other portions of compound
1 were not comprehensively studied. We, therefore, set to expand
SAR studies focusing on these aspects.
In the hope of uncovering other aromatic/heteroaromatic
groups that might be tolerated in place of the thiazole and pyrazole
cores, analogues 5a, 5c and 11e–k were synthesised. In addition,
analogue 5b was designed to investigate how tolerable an alterna-
tive position for the aminomethyl side chain on the thiazole ring is.
Within the context of replacements for the pyrazole core,
analogues 15a–e and 11a were synthesised in which substituents
on the benzyl moiety were introduced or the benzyl moiety
Aminomethylthiazoles have recently been recognised as poten-
tial antimalarial agents.6a Lead compound 1 (Fig. 1) was character-
ised by good in vitro antiplasmodial activity against drug
sensitive, NF54, (IC50 = 0.07
lM) and multi-drug resistant, K1,
H
(IC50 = 0.08 M) strains of P. falciparum. In addition, compound 1
l
N
N
N
H2N
N
demonstrated promising in vivo efficacy in the Plasmodium berghei
S
O
1
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Corresponding author. Tel.: +27 21 6502553; fax: +27 21 6505195.
Figure 1. Chemical structure of lead compound 1.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.