Parasitic Protozoans: Exploring the Potential of N,N'-Bis[2-(5-bromo-7-azabenzimidazol-1-yl)-2-oxoethyl]ethylene-1,3-Diamine and Its Cyclohexyl-1,2-diamine Analogue as TryR and Pf-DHODH Inhibitors.

Abstract

Major human parasitic protozoans, such as Plasmodium falciparum and Trypanosoma brucei, cause malaria and trypanosomiasis also known as sleeping sickness. In anti-parasitic drug discovery research, trypanothione reductase (TryR) and P. falciparum dihydroorotate dehydrogenase (Pf-DHODH) enzymes are key drug targets in T. brucei and P. falciparum, respectively. The possibility of co-infection of single host by T. brucei and P. falciparum is because both parasites exist in sub-Saharan Africa and the problem of parasite drug resistance necessitates the discovery of new scaffolds, which are strange to the organisms causing these infectious diseases-new scaffolds may help overcome established resistance mechanisms of the organisms. In this study, N,N'-bis[2-(5-bromo-7-azabenzimidazol-1-yl)-2-oxoethyl]ethylene-1,3-diamine and its cyclohexyl-1,2-diamine analogue were explored for their inhibitory potential against TryR and Pf-DHODH by engaging density functional study, molecular dynamic simulations, drug-likeness, in silico and in vitro studies RESULTS/CONCLUSION: Results obtained indicated excellent binding potential of the ligands to the receptors and good ADMET (adsorption, desorption, metabolism, excretion, and toxicity) properties.