Synthesis, molecular docking studies and ADME prediction of some new triazoles as potential antimalarial agents

The challenges concerning the control of malaria remain due to the continuous emergence of drug resistant strains. Over the years, the use, misuse, and abuse of antimalarials have created a conducive environment for the development of resistant Plasmodium falciparum strains. We herein report on the synthesis, characterization and antimalarial activity of a library of seven novel 1,2,3-triazoles as part of the drug discovery campaign against drug-resistant Plasmodium falciparum. The interactions of the triazoles with plasmepsin II, plasmepsin IV, falcipain-2 and the heme detoxifying protein-all key proteins of Plasmodium falciparum degradosequesterome (Dsq) were also investigated by molecular docking. The compounds 3a-d, 4-6 were synthesized by CuAAC click reaction in good to excellent yields of 73-98% and characterized by melting point, UVvisible, infrared and nuclear magnetic resonance (H-1 and C-13) and MS techniques. Compounds 3a-d displayed high in vitro potency (IC(50)s: 0.62-22.11 ug/ml) against the chloroquine-resistant Dd2 lab strain of Plasmodium falciparum and low toxicity (SI > 1 except compound 4) to human erythrocytes. Computational studies indicated that the compounds 3a-3d had an absorption of 76-91%, and they were category III acute oral toxins (LD50 from 500 to 5000 mg/kg). The molecular docking study suggests that compounds 3a-d interacted with plasmepsin IV and the heme detoxifying protein with high affinity and a moderate affinity for falcipain-2. (C) 2021 Published by Elsevier B.V. on behalf of African Institute of Mathematical Sciences / Next Einstein Initiative.