Chloroquine analogs as antimalarial candidates with potent in vitro and in vivo activity

Abstract

In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and were also active against P. berghei infected mice. Among the compounds tested, DAQ, a chloroquine analog with a more linear side chain, was shown to be the most active in vitro and in vivo, with low cytotoxicity, and therefore may serve as the basis for the development of more effective chloroquine analogs to aid malaria eradication.

Keywords: Chloroquine; Drug design; Malaria; Resistance.

Graphical abstract

Fig. 1

Molecular structure of the CQ derivatives.

Fig. 2

Microscopy of synchronized parasites continuously treated with CQ and DAQ at concentration of 10-fold the IC₅₀ values and DMSO (control). Representative images of three independent experiments. (A) P. falciparum 3D7 CQ-sensitive parasite; (B) P. falciparum K1 CQ-resistant parasite. (C) Quantification of viable parasites by optical microscopy.

Fig. 3

Docking results for CQ and its analogs DAQ, GIQ, CEQ and PCQ (top) to dimeric heme (bottom). At the bottom of the Figure, on the right, superimposed poses of DAQ (red) and CQ (blue) to the NADH (green) binding site in PfLDH. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)