Bioorganic & Medicinal Chemistry Letters
Synthesis and in vitro evaluation of novel 8-aminoquinoline–
pyrazolopyrimidine hybrids as potent antimalarial agents
Kannan Murugan , Anandkumar V. Raichurkar , Fazlur Rahman Nawaz Khan , Pravin S. Iyer a,
a,b
a
b,
⇑
⇑
a
Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India
Organic and Medicinal Chemistry Research Laboratory, Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore 632014, Tamil Nadu, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
In the search of novel chemotherapeutic agents for emerging drug resistant parasites, the hybridization
approaches have successfully emerged as an efficient tool in malarial chemotherapy. Herein, a rational
design and synthesis of novel 8-aminoquinoline and pyrazolopyrimidine hybrids and their antimalarial
activity against wild type Plasmodium falciparum (Pf_NF54) and resistant strain (Pf_K1) is reported. The
medicinal chemistry approach to expand the scope of this series resulted in an identification of potent
compounds with nanomolar potency (best IC50 5–10 nM). Systematic structure activity relationship
Received 13 August 2014
Revised 1 January 2015
Accepted 5 January 2015
Available online 9 January 2015
Keywords:
(SAR) studies revealed that pyrazolopyrimidine and 8-aminoquinoline ring are essential for achieving
8
-Aminoquinoline
good P. falciparum potency. The docking study revealed that the compound 6 can retain some of the
critical interactions within pfDHODH drug target.
Pyrazolopyrimidine
Plasmodium falciparum
Structure activity relationship
Hybridization
Ó 2015 Elsevier Ltd. All rights reserved.
8
The last decade has witnessed the world’s need of novel drugs
to fight malaria. According to the World Health Organization, there
were an estimated 207 million cases of malaria resulting in
attempted to improve tissue and blood schizonticidal activity. The
triazolopyrimidine core (DSM1) has been reported as a potent
inhibitor of pfDHODH and is active against P. falciparum.9 Lead
6
2
27,000 deaths and 482,000 children under five years of age in
012. The vast majority of deaths are caused by Plasmodium
optimization identified
pfDHODH (DSM265) that successfully translated into efficacy
a metabolically stable inhibitor of
1
1
0
falciparum and Plasmodium vivax infections. Artemisinin-based
combination therapy is the most effective in treating patients with
P. falciparum infection. The rapid emergence of malarial parasite
resistance to currently available antimalarial drugs, including
artemisinin derivatives, pose a threat to derail the global efforts
against P. falciparum both in vitro and in vivo. Recognizing the
importance of these two bioactive cores, we were interested in
hybridization of the pharmacophoric features of them into a single
molecule to explore potential synergies. Herein, we report a
rational design, synthesis and SAR relationship of aminoquinoline
with ring bioisosteres of triazolopyrimidine.
2
3
to cure malaria. With the onset of drug-resistant Plasmodium
parasites, new approaches are being developed to combat the
widespread disease. The hybridization strategy involves an incor-
The target compounds, 1–9 have been achieved as outlined in
Schemes 1 and 2. The aromatic nucleophilic substitution, S Ar of
N
4
poration of key pharmacophoric features from existing drugs to
design a novel molecule with a different efficacy and resistance
profile. This approach has seen some success in recent times in
chloro-containing heterocycles with 8-aminoquinoline in the pres-
ence of NaH, DMF yielded the desired aminoquinolines, 1, 4 and 6
1
0b,11
as depicted in Scheme 1.
To synthesize the aminoquinolines 2,
5
delivering novel chemical entities against protozoan parasites.
5 and 7, initially a S Ar reaction was carried out to afford the inter-
N
Primaquine, an 8-aminoquinoline moiety is the only drug avail-
able to eliminate exoerythrocytic infection, and provide a radical
cure for vivax malaria (Fig. 1). A primaquine analog, tafenoquine
mediates 2a, 5a and 7a which undergo further hydrogenation–
dechlorination reaction in the presence of Pd/C in triethylamine
under ambient hydrogen pressure resulting in desired products
6
1
2
with a long half-life (2–3 weeks) is currently in clinical trials for
in good yields.
7
the prophylactic treatment of malaria. A recent literature report
Synthesis of aminoquinolines 3, 8 and 9 is achieved as outlined
in scheme 2. Commercially available amino pyrazoles treated with
N,N-dimethylformamide dimethyl acetal, followed by cyclization
with malononitrile in pyridine under microwave conditions affor-
ded the corresponding intermediates, 19, 20. Subsequently, they
were converted to the desired aminoquinolines, 8, 9 under
revealed that modifications of 8-aminoquinoline moiety have been
⇑
(
F.R.N. Khan).
960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
0