Elucidation of the anti-plasmodial activity of novel imidazole and oxazole compounds through computational and in vivo experimental approaches.

The development of resistance to conventional antimalarial therapies, along with the unfavorable impact of the COVID-19 pandemic on the global malaria fight, necessitates a greater focus on the search for more effective antimalarial drugs. Targeting a specific enzyme of the malaria parasite to alter its metabolic pathways is a reliable technique for finding antimalarial drug candidates. In this study, we used an in silico technique to test four novel imidazoles and an oxazole derivative for inhibitory potential against Plasmodium lactate dehydrogenase (pLDH), a unique glycolytic enzyme necessary for parasite survival and energy production. The promising imidazole compounds and the oxazole derivative were then tested for anti-plasmodial efficacy in Plasmodium berghei -infected mice. With a binding energy of -6.593 kcal/mol, IM-3 had the best docking score against pLDH, which is close to that of NADH (-6.758 kcal/mol) and greater than that of chloroquine (-3.917 kcal/mol). The test compounds occupied the enzyme's NADH binding site, with IM-3 forming four hydrogen bonds with Thr-101, Pro-246, His-195 and Asn-140. Infected mice treatment with IM-3, IM-4 and OX-1 exhibited significantly reduced parasitemia over a four-day treatment period when compared to the infected untreated animals. At 5, 10 and 20 mg/kg, IM-3 demonstrated the highest anti-plasmodial activity, suppressing parasitemia by 86.13, 97.71 and 94.11%, respectively. PCV levels were restored by IM-3 and IM-4, and the three selected compounds reduced the lipid peroxidation induced by P. berghei infection in mice. Thus, these compounds may be considered for further development as antimalarial medicines.Communicated by Ramaswamy H. Sarma.