In silico appraisal of inhibitory activity of 1,2,4-triazolo[4,3-a]pyrazine derivatives against resistant malarial parasite (Plasmodium falciparum) via DFT, molecular docking, and ADMET approaches

Malaria remains a significant global health challenge, primarily transmitted to humans through bites from Plasmodium-infected female Anopheles mosquitoes. The emergence of antimalarial resistance driven by the selection of parasites with genetic mutations or gene amplifications has complicated treatment strategies often requiring higher doses or combinations of drugs. Despite these efforts, success in combating malaria remains limited, thus call for continuous research in design and development of new drugs to address these challenges. Therefore, in this study, in silico methods were used to evaluate the antimalarial activities of 14 hybrid compounds of 1,2,4-triazolo[4,3-a]pyrazine. The inhibitory effectiveness of these compounds against Plasmodium falciparum was assessed using density functional theory (DFT), molecular docking, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiling. Docking results of the compounds against P. falciparum myosin A reveal that compounds L2, L9, L10, and L14 are the ligands with highest binding affinities. The frontier orbitals and electrostatic potential reveal the role of 1,2,4-triazolo[4,3-a]pyrazine moiety as the main center that controls the therapeutic activity and that nitrogen atoms on 1,2,4-triazolo[4,3-a]pyrazine moiety are nucleophilic sites which can promote ligand-receptor interactions. ADMET analysis shows that L2, L9, L10, and SD2 (puromycin) can cross blood-brain barrier suggesting potential distribution to the central nervous system, however, critical analysis of physicochemical and pharmacokinetics reveal that the compound L6 could be best drug candidate.