Natural products dominate antimalarial pipeline but few have in vivo or safety dataMalaria Drug Resistance Spurs Hunt for New Compounds

Resistance to available antimalarial drugs continues to emerge and spread and remains a major challenge for global health. This systematic review summarizes the progress made in the discovery of antimalarial and antiplasmodial compounds published from January 2024 to June 2026, including synthetic, semi-synthetic, and hybrid molecules; natural products; and computational and delivery technologies. A systematic search for primary record identification was performed in Scopus, Web of Science, PubMed/MEDLINE, EMBASE, Google Scholar Alerts, ClinicalTrials.gov, and WHO sources according to PRISMA 2020 guidelines. Only supplementary full-text retrieval and citation tracing were conducted using publisher/journal platforms. The search strategy and available audit information are provided in Supplementary File S1. The number of historical retrievals and database-specific search dates that could not be independently verified were not estimated. We excluded preprints that were not later published in peer-reviewed journals afterward. Only primary research with original antimalarial/antiplasmodial data was included quantitatively, while reviews were used for background and citation chasing. One reviewer extracted data using a piloted standardized form, with independent verification of 20% of studies by two co-reviewers. Stratified by design, a credibility appraisal was applied. Out of 252 eligible primary studies, 157 (62.3%) were natural product-derived compounds, 49 (19.4%) synthetic compounds, and 46 (18.3%) semi-synthetic or hybrid molecules. Key mechanistic themes include inhibition of hemozoin (β-hematin) formation, dihydrofolate reductase, histone deacetylases, kinases, and proteasomes, as well as host-directed strategies. Mechanisms were separated based on experimental validation vs. computational prediction. 84/252 studies (33.3%) evaluated chloroquine-resistant parasites, 19/252 (7.5%) artemisinin/K13-associated resistance, and 9/252 (3.6%) ACT partner-drug resistance. Several compounds demonstrated nanomolar potency in vitro, but few had supporting in vivo, pharmacokinetic, or toxicological data. Antimalarial discovery is increasingly integrating medicinal chemistry, molecular hybridization, computational approaches, host-directed therapies, and nanoparticle-based delivery. However, most candidates are still at an early stage of development and are not yet proven solutions to drug resistance. Further in vivo validation, resistance testing, pharmacokinetic and toxicological characterization, and independent replication are necessary prior to clinical development.