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.

New approaches in antimalarial drug discovery and development: a review

“…The results, which are measured using enzyme-independent reactions (Dorn et al 1995, Parapini et al 2000, Ncokazi & Egan 2005, are rapidly obtained (a 60-min incubation is used) and were shown to agree across four different laboratories (Ncokazi & Egan 2005). We have successfully used this test after many attempts to establish a protocol to evaluate the activity of two CQ analogues [monoquinoline (MAQ) and bisquinoline (BAQ)]; both analogues inhibited Hz formation in vitro, a result that was further supported by docking tests; the interactions with dimeric haematin and the inhibition of haeme polymerisation were dose-dependent (Aguiar et al 2012). Several in vivo tests that use animal models are available; all require the approval of protocols regarding the ethical issues for animal use ).…”

“…and dialkynes, 12 compounds have demonstrated activity against P. berghei in mice, especially those with methylene groups in the sidechain (de Souza et al 2011). Two new CQ analogues, MAQ and BAQ, in which the 4-aminoquinoline pharmacophore group and protonaccepting sites are maintained to increase the bioavailability of the compound in the digestive vacuole of the parasite, were active in vitro against P. falciparum at nanomolar concentrations and exhibited a therapeutic index similar to that of CQ (Aguiar et al 2012).…”

Synthesis and evaluation of the anti-nociceptive and anti-inflammatory activity of 4-aminoquinoline derivatives

“…The aminoquinoline derivatives 7-Cl-MAQ and BAQ were prepared as reported in Ref. 5, with slight modifications. The IR spectra were recorded on a Varian 640-IR instrument with an ATR device.…”

“…5 For 2-CF3-MAQ, the 1 H NMR spectrum displayed five signals (two triplets, two doublets and one singlet) for the aromatic hydrogen atoms that were observed between 8.16 and 6.79 ppm, as well as an additional four triplets related to the methylenic groups between 3.53 and 2.73 ppm. The hydrogen signals of the amino groups were either not observed or had integration values lower than those predicted, owing to fast H/D exchange with the deuterated solvent.…”

“…1), with slight modifications. 5 The mechanisms of all of the synthetic reactions operate via a S N Ar route. All compounds were isolated as white or slightly yellow solids and were fully characterised by NMR, MS, and IR spectroscopy.…”