From Small Molecules to Beyond-Rule-of-Five Chemical Space: Development of Novel Antiplasmodial Inhibitors

Malaria remains one of the most devastating infectious diseases worldwide, with an estimated 282 million cases and 610 000 deaths in 2024, the vast majority occurring in low‑ and middle‑income countries. The WHO African Region bears about 94% of global cases and 95% of malaria deaths, with children under five disproportionately affected. Despite major progress in vector control, chemoprevention and case management, the continuing rise in incidence and the spread of resistance to frontline artemisinin‑based combination therapies together with the poor availability of vaccines in the endemic area highlight the urgent need for new chemotypes and innovative therapeutic strategies against Plasmodium species. In this context, exploring both classical small molecules and beyond‑rule‑of‑five (bRo5) chemical space offers a promising avenue to expand the arsenal of potent, selective antimalarial agents. This Research Topic aims to address the dual challenges of sustained malaria burden and emerging multidrug resistance by showcasing advances in chemical biology and medicinal chemistry directed at Plasmodium species. Indeed, parasites have evolved resistance to nearly all major antimalarial classes, including ACTs, and in vitro evolution studies have revealed a complex “resistome” involving diverse targets. To counter this evolutionary arms race, we seek contributions that leverage cutting‑edge design strategies across drug‑like and bRo5 space, ranging from optimized small molecules to macrocycles, peptidomimetics, and other higher‑molecular‑weight scaffolds with tailored physicochemical and pharmacokinetic profiles. The goal of the current Research Topic is to elucidate structure–activity relationships, resistance mechanisms, and multi‑stage antiplasmodial activity, ultimately accelerating the development of robust candidates that overcome current therapeutic limitations and reduce malaria morbidity and mortality. We invite submissions spanning the discovery and optimization of potent inhibitors against Plasmodium species, including phenotypic and target‑based screening campaigns, hit‑to‑lead and lead‑optimization studies, as well as rational design informed by structural biology and computational modeling. Themes of interest can include novel small‑molecule and bRo5 chemotypes, mode‑of‑action elucidation, resistance profiling through in vitro evolution, ADME and pharmacokinetic characterization. Authors may contribute with Original Research Articles, Short Communications, Reviews, Mini‑Reviews and Perspectives, as well as methodological papers describing innovative screening platforms, profiling tools or modeling workflows relevant to antimalarial drug discovery. Topic editors: Federico Riu, Roberta Ibba, Matteo Lusardi Source: https://www.frontiersin.org/research-topics/85226/from-small-molecules-to-beyond-rule-of-five-chemical-space-development-of-novel-antiplasmodial-inhibitors