Phytochemicals targeting diabetes and malaria: Chemical diversity, mechanistic insights, and prospects for dual-action therapeutics

Abstract

Diabetes mellitus and malaria are major health challenges in tropical and subtropical regions, creating a need for therapeutic strategies addressing metabolic and infectious disease processes. This review aimed to systematically identify and synthesise plant-derived compounds with reported antidiabetic, antimalarial, or dual antidiabetic–antimalarial activities, with emphasis on their chemical diversity, biological activities, proposed molecular mechanisms, and levels of supporting evidence. A structured literature search was conducted for studies published from January 2015 to December 2025 using Google Scholar, PubMed, ScienceDirect, SciELO, EMBASE, Scopus and Web of Science. Relevant studies reporting antidiabetic, antimalarial or dual activities of plant-derived compounds were evaluated and synthesised according to chemical class, biological activity and proposed molecular mechanisms. Of 2,313 records identified, 272 articles met the eligibility criteria. A total of 258 phytochemicals were identified, including 135 with reported antidiabetic activity, 109 with antimalarial activity and 14 chemically defined compounds with evidence of both activities. Antidiabetic effects involved inhibition of carbohydrate-hydrolysing enzymes, modulation of insulin signalling and glucose uptake, and attenuation of oxidative stress and inflammation. Antimalarial effects included inhibition of parasite enzymes and metabolic processes, interference with haem-associated pathways, and disruption of parasite cellular functions. The dual-action compounds represented diverse classes, including alkaloids, flavonoids, phenolics, terpenoids, triterpenoids and xanthones. The review consolidates the reported chemical and biological diversity of phytochemicals with antidiabetic and antimalarial activities and identifies a focused group of compounds with evidence of dual activity. This provides a basis for prioritising multifunctional natural-product leads while highlighting the need for stronger molecular target validation and translational evidence. Phytochemicals provide a diverse reservoir of compounds with potentially relevant activities against both diseases. The 14 dual-action compounds represent a focused discovery space for multifunctional natural-product leads. However, evidence remains heterogeneous and predominantly preclinical. Future studies should prioritise molecular target validation, structure–activity relationships, pharmacokinetics, bioavailability, safety and efficacy in disease-relevant diabetes–malaria models.