Harnessing antimalarial chemical space: the way forward
Sandeep Sundriyal, Animesh Majumdar · Expert Opinion on Drug Discovery · 2025
INTRODUCTION: Malaria remains a major health challenge, with increasing resistance to frontline chemotherapy. Recent cheminformatics studies have revealed that potent antiplasmodials occupy a distinct antimalarial chemical space (AMCS), defined by specific property cutoffs. AREAS COVERED: We show that only ~ 6-8% of compounds in the representative commercial libraries are AMCS-compliant, emphasizing the need for pre-filtering to improve their suitability for phenotypic screening. Most clinically used antimalarials and several clinically used oral drugs repurposed for antimalarial activity comply with AMCS indicating the important role AMCS can play in rationalizing drug repurposing studies. Furthermore, AMCS-guided scaffold modification offers a valuable strategy during lead optimization. With the help of recent literature examples we show how AMCS can be exploited for multimodal antimalarials or explain confounding structure-activity relationships. EXPERT OPINION: Due to the lack of funding and economically weaker patient population new antimalarials need to be cost-effective. The concept of AMCS can be harnessed to achieve this goal. Although there are inherent limitations associated with using hard cut offs and existing computational methodologies, the AMCS has strong potential to identify novel chemical matter for designing antimalarials that are resilient to resistance development.