The effect of novel Quinoxaline derivatives on the life cycle of malaria parasite and vector

Abstract

Malaria is one of the major global health problems especially in the sub-Saharan Africa. While the current treatments are effective, there is a growing concern about the emergence of resistant strains of Plasmodium to antimalarial drugs and the Anopheles vector to insecticides. Therefore, there is a need to develop novel compounds. As such, thirty-five novel quinoxaline-based hybrid compounds consisting of quinoxaline-chalcone-phenyl (QCP), quinoxaline-pyrazoline-phenyl(QPP), quinoxaline-chalcone-quinoline(QCQ) and quinoxaline-pyrazoline-quinoline (QPQ) compounds were synthesized with the aim to evaluate their effect on the life cycle of Plasmodium and Anopheles. Twenty-four compounds exhibited antimalarial activity against the asexual stages of the NF54 strain of P. falciparum using the parasite lactate dehydrogenase (pLDH) assay; with eleven compounds displaying promising activity with IC50 values less than 10 μM. Compound QCQ3 was the most active (IC50 value: 4.19 ± 0.52 μM); but was less active than dihydroartemisinin (DHA) (IC50 value: 0.006 ± 0.01 μM) and quinine (IC50 value: 0.11 ± 0.01 μM). Two of the active compounds, QCP7 and QCP8 slowed ring and trophozoite development affecting the haemozoin structure and both displayed a synergistic interaction with quinine. Seven compounds displayed minimal ovicidal activity (1-15%) against Anopheles arabiensis (KWAG), while twelve possessed low larvicidal activity (mortality range: 0 - 23%) compared to DDT. None of the compounds displayed anti-oxidant activity by chelating ferrous ions or scavenging the free radicals of DPPH•. The preliminary toxicity profile of the compounds indicated that thirteen compounds were toxic to human kidney epithelial cells (IC50 values range: 13.66 ± 0.46 to 36.77 ± 0.89 μM); whilst only QPQ8 was toxic to Artemia franciscana (1.05 ± 0.78 μM). Eighteen compounds had anticancer activity against chronic myelogenous leukaemia cells, with QCQ10 the most active at 4.00 ± 0.50 μM. The selectivity index ranged between 1.27 and 7.71 compared to the human kidney epithelial cells. In silico predictions indicated that the compounds displayed favourable drug-like properties with good ionisation and absorption. Although none of the compounds induced haemolysis, these quinoxaline compounds have been predicted in silico to have a high risk of being toxic as other in vivo tested quinoxaline derivatives. These findings indicated that compound QCP6, QCP7, QCP8, QCP9, QCP10 may have potential as antimalarial and anti-leukaemic agents and warrant further investigation.