Antimalarial activity and mechanisms of action of two novel 4-aminoquinolines against chloroquine-resistant parasites

Abstract

Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.

Figure 1. Inhibition of hemozoin formation by the CQ analogs BAQ and MAQ (mean ± SD from triplicates), in two different experiments.

Statistical differences as compared to drug-free controls are indicated in each graph by an asterisk (p<0.05). The p and r values represent the statistical correlation analyses.

Figure 2. Chemical structures of the protonated forms of the CQ analogs BAQ and MAQ.

Figure 3. Compounds docked in dimeric hematin.

(A) Protonated CQ, (B) MAQ-1, (C) MAQ-2, (D) MAQ-3, (E) BAQ-1, (F) BAQ-2.

Figure 4. Best conformations of the protonated forms of chloroquine, MAQ and BAQ (in green) in the binding pocket of NADH (in CPK) as generated by the MVD® software.

(A) Protonated chloroquine, (B) MAQ-1, (C) MAQ-2, (D) MAQ-3, (E) BAQ-1, (F) BAQ-2.