Development of Novel Benzimidazole-Triazole Hybrid Compounds as Dual-Target Antimalarial Agents: Synthesis, Pharmacokinetic Optimisation and Resistance Circumvention Studies

The global and Nigerian burden of Plasmodium falciparum malaria is increasingly complicated by the emergence of resistance to frontline artemisinin combination therapies, necessitating the discovery of structurally novel antimalarial agents with multi-target mechanisms. Benzimidazole and 1,2,4-triazole pharmacophores individually exhibit antimalarial properties, and their hybridisation offers a rational strategy for dual-target engagement to delay resistance emergence. This study designed, synthesised, and evaluated a novel series of twenty benzimidazole-triazole hybrids as dual-target antimalarial agents acting on PfDHFR and PfNDH2. Synthetic routes were optimised using microwave-assisted condensation and copper-catalysed azide-alkyne cycloaddition. All compounds were characterised by spectroscopic methods and evaluated for in vitro antimalarial activity against drug-susceptible and artemisinin-resistant P. falciparum strains. Pharmacokinetic properties were profiled by in vitro metabolic stability in human liver microsomes, Caco-2 permeability, and plasma protein binding assays. Structure-activity relationship analysis was performed to guide lead compound selection. Three hybrid compounds demonstrated sub-100 nM IC50 against both susceptible and resistant strains with selectivity indices above 100. Lead compound pharmacokinetic profiling indicated acceptable oral bioavailability and metabolic stability. Molecular dynamics simulation confirmed stable dual-target binding over 100 ns trajectories. These findings establish benzimidazole-triazole hybrids as a promising antimalarial scaffold warranting advancement into preclinical in vivo efficacy and safety studies. Keywords: benzimidazole-triazole hybrids, antimalarial, dual-target, synthesis, artemisinin resistance.