Issue 36, 2015

Highly active 4-aminoquinoline–pyrimidine based molecular hybrids as potential next generation antimalarial agents

Abstract

In order to overcome the problem of emerging drug resistance in malarial chemotherapy, a series of highly active 4-aminoquinoline–pyrimidine hybrids were synthesized and evaluated for their antimalarial activity against CQ-sensitive (NF54) and CQ-resistant (Dd2) strains of P. falciparum in an in vitro assay. The most active hybrid 19f exhibited 74-fold better potency than chloroquine and 4-fold better potency than artesunate against the drug-resistant strain of P. falciparum. Compound 19e, when evaluated for in vivo activity in the P. berghei-mouse malaria model showed 93.9% parasite suppression at 30 mg kg−1 dose on Day 4 with a mean survival time of 11 days. To gain insights towards the mechanism of action of these hybrids, heme binding and molecular modelling studies were performed on the most active hybrids. It was observed that inhibition of formation of β-hematin and dihydrofolate reductase-thymidylate synthase Pf-DHFR-TS enzyme could be associated with the observed antimalarial activity of these compounds.

Graphical abstract: Highly active 4-aminoquinoline–pyrimidine based molecular hybrids as potential next generation antimalarial agents

Supplementary files

Article information

Article type
Paper
Submitted
09 Dec 2014
Accepted
13 Mar 2015
First published
16 Mar 2015

RSC Adv., 2015,5, 28171-28186

Author version available

Highly active 4-aminoquinoline–pyrimidine based molecular hybrids as potential next generation antimalarial agents

S. Manohar, V. Satya Pavan, D. Taylor, D. Kumar, P. Ponnan, L. Wiesner and D. S. Rawat, RSC Adv., 2015, 5, 28171 DOI: 10.1039/C4RA16032K

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