Advancements in diverse chemical scaffolds for antimalarial drug discovery: a ten-year hit-to-lead retrospective

Malaria remains one of the most devastating parasitic diseases worldwide, accounting for hundreds of millions of cases and significant mortality annually. Despite the availability of therapeutic interventions, the efficacy of current pharmacological treatments is increasingly compromised by the emergence and spread of multidrug-resistant Plasmodium strains, underscoring an urgent need for novel antimalarial agents. In this context, the transition from hit identification to lead optimization (hit-to‑lead) represents a pivotal stage in the drug discovery pipeline, ensuring that promising chemical scaffolds are refined for enhanced potency and safety. This review provides a comprehensive retrospective of hit-to‑lead advancements over the past decade, scrutinizing the pharmacological and structural evolution of diverse chemical classes. We detail the structure-activity relationships, in vitro potencies, pharmacokinetic properties, and in vivo efficacy and safety profiles of identified candidates, while addressing their inherent benefits and limitations. Our analysis covers 32 distinct chemical classes, of which 16 have suggested biological targets and 16 remain with unidentified mechanisms of action. Notably, 33 compounds emerged with demonstrated vivo activity, highlighting the significant progress made in delivering robust lead candidates. By consolidating these findings, this review underscores the critical importance of systematic hit-to‑lead optimization in the global effort to develop the next generation of antimalarial therapies.