The Effect of Novel Azoles, Pyrimidone Analogues And Acetohydrazone Derivatives On The Life Cycle Of The Malaria Parasite

Abstract

iv Abstract Malaria is a life-threatening disease caused by the Plasmodium protozoa; where P. falciparum is one of the most common and deadliest species responsible for malaria infections in humans. The goal to eradicate malaria is threatened by parasite resistance to antimalarial drugs and Anopheles vector resistance to insecticides. As a result, new and safe antimalarials and insecticides are needed. This study aimed to evaluate the effects of three sets of novel compounds, quinoline-2-benzimidazole (QB1-QB12), 6-oxo-1,6 dihydropyrimidine (P1-P10) and 2-(quinolin-8-yloxy)acetohydrazone (QC1-QC11), as well as known benzimidazoles and imidazoles against P. falciparum and Anopheles life cycles. Five azoles displayed promising activity against the P. falciparum NF54 strain using the Plasmodium lactate dehydrogenase assay, where the IC 50 values ranged between 4.90 ± 0.41 and 77.81 ± 0.71 μM, in comparison to quinine (0.18 ± 0.01 μM). The two most active compounds (tioconazole and itraconazole) displayed antagonistic and additive interactions when combined with quinine, respectively. In comparison to quinine-treated parasites, haemozoin in the trophozoites of both tioconazole-treated and itraconazole- treated parasites appeared more scattered rather than compact units. None of the tested compounds displayed toxicity against the human epithelial cells (HEK-293) as determined by the tetrazolium viability assay and negligible haemolysis was displayed. Toxicity against Artemia franciscana after 72 hours of treatment was observed for compounds QB1, QB5, QB9, QB11, P3, mebendazole, albendazole, ketoconazole, tioconazole, clotrimazole and itraconazole. Unfortunately, none of the tested compounds showed potential as larvicidal or ovicidal agents against Anopheles arabiensis (KWAG) compared to formalin and DDT. This study highlighted the potential repurposing of known azole compounds against malaria P. falciparum NF54 strain and warrants further investigation.