The Effect of Quinoline Heterocyclic Derivatives on the Malaria Parasite and Anopheles Vector

Abstract

The World Health Organization estimated that in 2022 there were 249 million cases of malaria with 608,000 fatalities worldwide. The development of drug resistance by the Plasmodium parasite, as well as insecticide resistance in the Anopheles vector, has necessitated intense research to identify lead compounds. Quinoline derivatives have been used to generate a range of important antimalarial derivatives with promising activity. As such forty-two quinoline heterocyclic derivatives were designed, synthesised, purified and structures verified before being evaluated for in vitro antimalarial and insecticidal properties, in conjunction with a preliminary toxicological profile. The antimalarial activity was evaluated against chloroquine-sensitive (NF54) P. falciparum using the Plasmodium lactate dehydrogenase assay, with the insecticidal activity determined against Anopheles arabiensis (KWAG) larvae in accordance with the WHO insecticide testing guidelines. The toxicity of the derivatives was evaluated against Artemia franciscana, human kidney endothelial (HEK293) and human red blood cells. Of the forty-two heterocyclic derivatives, twenty-six possessed promising antimalarial activity (>50% growth inhibition) at 50μM. All derivatives had a direct effect on the intra-erythrocytic parasite, where there was minimal lysis of the red blood cell host. One Dihydroquinoline-Carbothioamide (DC14) (100%) and one Quinoline-3-Carboxamide (Q3C11) (89.15%) derivative displayed activity with IC50 values of 7.23 ± 1.17 and 7.99 ± 0.31 μM that were 85-fold less active than quinine. In combination with quinine, a synergistic and additive interaction were observed with compound DC14 and Q3C11, respectively. Both derivatives were found to possess negligible insecticidal activity at 0.05μM against the An. arabiensis 3 rd instar larvae (DC14: 6.67%; Q3C11: 11.67%) and eggs ( DC14: 16.25%; Q3C11: 8.13%) compared to 0.05μM DDT (100%) and 1% formalin (100%). In comparison, compounds DC14 and Q3C11 were 14.4- and 7.5-fold more toxic against Ar. Franciscana, with LC50 values of 2.678 μM and 7.83 μM, respectively. The derivatives were minimally toxic to the HEK293 cells, such that there was a selectivity index towards the malaria parasite of 11.13 and 7.55 for compounds DC14 and Q3C11, respectively. Although there was favourable antimalarial activity, pharmacokinetics and safety index for the quinoline heterocyclic compound DC14, further derivatisation is needed before this lead compound could be further considered for development as an antimalarial agent.