Design and synthesis of NADH mimics that target mitochondrial electron transport of plasmodium parasite
Altharawi, Ali Ibrahim
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Malaria, particularly that caused by Plasmodium falciparum, remains one of the most deadly infectious diseases worldwide. Unfortunately, multi–drug resistance (MDR) to currently used antimalarials has spread worldwide and led to a failure to control malaria. Therefore, new chemotherapeutic agents that are affordable, easy to synthesize, and overcome resistant strains of parasites are urgently needed. Plasmodium mitochondria has attracted the attention of many projects as a potential target for malaria treatment, and provided atovaquone as treatment and prophylaxis of malaria. In this project, the advantage of a triphenylphosphonium (TPP) moiety in delivering biomolecules to mitochondria has been investigated to deliver NADH-mimic compounds as potential inhibitors of the mitochondrial electron transport chain (mtETC). A small library of phosphonium cations based on clopidal and amodiaquine (AQ) were synthesized and evaluated for antiparasitic activity against W2 chloroquine-resistant strain. The test results revealed that the phosphonium moiety reduced antiplasmodial efficacy, and phosphonium substituents (R = Me) were as effective as (TPP) moiety. It is hypothesized that re-routing the AQ-based phosphonium cation to the negatively-charged mitochondria by electrostatic attraction resulted in moderate antiplasmodial effects and the overall activities of the compounds in this study were the result of NADH dehydrogenase (Complex I) inhibition.