The scale of the effort is striking. The team screened seven different information sources, including Scopus, Web of Science, PubMed/MEDLINE, EMBASE, Google Scholar Alerts, ClinicalTrials.gov, and WHO publications, following the PRISMA 2020 reporting guidelines. After rigorous eligibility screening, 252 primary studies made the cut. Each was classified by chemical category, source organism, biological evaluation method, resistance phenotype, and how far along the development pipeline it stood. The verdict on the field’s direction is clear: natural products dominate the discovery landscape, accounting for 157 studies, or 62.3 percent of the corpus. Synthetic compounds made up 49 studies (19.4 percent), while semi-synthetic and hybrid molecules accounted for 46 studies (18.3 percent).

That dominance of natural product research reflects both the enormous biodiversity available in malaria-endemic regions and the continuing importance of ethnopharmacological knowledge. Artemisia remained the single most studied genus, with new work comparing the antiplasmodial activity of Artemisia annua teas, examining how extraction methods influence potency, and testing aqueous extracts of A. afra and A. annua against artemisinin-resistant parasites. Curcuma longa, Vernonia species, Alstonia species, and Solanum nigrum also received substantial attention, yielding new compounds such as Dobinin K, which showed activity against chloroquine-resistant Plasmodium falciparum. African plants contributed a large share of the leads, including metabolites from Pleiocarpa bicarpellata, Haematostaphis barteri, Croton macrostachyus, and Landolphia owariensis, alongside marine-derived and microbial compounds such as the peptaibols trichokonins VI and VIII and the bisindole alkaloid cyclosebistine A from Catharanthus roseus.

On the synthetic side, the quinoline scaffold remains the workhorse of antimalarial medicinal chemistry. Recent studies reported aminopropyl-linked quinoline-triazole hybrids that inhibit beta-hematin formation, the parasitic process by which the parasite crystallizes toxic free heme into hemozoin, as well as novel bisquinoline derivatives designed to combat drug-resistant strains. Quinazoline derivatives were developed as putative dihydrofolate reductase inhibitors, although the review authors emphasize that in these cases target engagement rested on computational docking and QSAR modeling rather than direct biochemical confirmation. Perhaps the most eye-catching synthetic result came from tetrahydroimidazopyridine (THIP) derivatives, one of which showed single-digit nanomolar potency against the asexual blood stage of the parasite, with an IC50 of 8.7 nanomolar, alongside a favorable early selectivity profile against mammalian cells. That is precisely the kind of potency that gets medicinal chemists excited, yet the authors caution that no in vivo efficacy or pharmacokinetic data existed for these compounds at the time of publication.

The semi-synthetic and hybrid category highlights the enduring centrality of the artemisinin pharmacophore. Researchers continue to fuse artemisinin or dihydroartemisinin with second, mechanistically distinct pharmacophores. Beta-carboline-artemisinin conjugates, sometimes called harmisinins, pair DNA intercalation and hemozoin inhibition with the radical alkylation typical of endoperoxide antimalarials. Steroid-tetraoxane hybrids and quinoline-ferrocene-tetrahydropyrimidine-triazole hybrids expand this strategy further, although their proposed mechanisms currently rest on computational predictions. Nanotechnology is also reshaping delivery: a dendrimer-based system co-encapsulating artesunate and fluconazole showed genuine in vivo efficacy in a murine malaria model, one of the strongest translational examples in the entire corpus, while oligochitosan conjugates of dihydroartemisinin and lumefantrine and polyethylene glycol-lumefantrine conjugates aim to reproduce the stage-sequential release logic of existing artemisinin-based combination therapies.

Computational tools now permeate every corner of the field. Molecular docking, quantitative structure-activity relationship modeling, molecular dynamics simulations, machine learning, and network pharmacology were employed in 96 of the 252 studies, roughly 38 percent of the corpus. But the review delivers a pointed methodological warning here. Among those 96 computational studies, only 39, or 40.6 percent, reported independent biochemical or biophysical corroboration of the proposed target. Only 35.4 percent described any form of external validation, and a mere 14.6 percent included a negative or scrambled-ligand control. The authors argue that docking scores and in silico predictions should be treated as hypothesis-generating tools rather than evidence of validated mechanism, a distinction that matters enormously when headlines claim a new compound ‘targets’ a particular parasite protein.

Drug resistance sits at the heart of why this research matters, and the review exposes a troubling gap. Although resistance is cited as the motivation for most of the reviewed work, only 33.3 percent of studies directly tested their compounds against chloroquine-resistant parasites, a historically standard but now less clinically urgent benchmark. Far fewer tested against the resistance phenotypes that matter most today: just 7.5 percent evaluated activity against artemisinin-resistant or Kelch13-mutant parasite lines, and only 3.6 percent addressed resistance to artemisinin combination therapy partner drugs. The rest relied on laboratory-sensitive reference strains. In other words, the field is largely producing compounds that clear an old hurdle while the parasite is climbing a new one, with reduced artemisinin susceptibility now documented in several African countries.

Quality appraisal revealed further caveats. Using design-stratified criteria, the reviewers rated only 61 studies (24.2 percent) as high quality, with 148 (58.7 percent) moderate and 43 (17.1 percent) low. Among the 41 in vivo rodent studies, randomization was reported in fewer than half and blinded parasitemia assessment in barely a quarter. Fewer than half of the natural-product studies, 45.2 percent, formally authenticated their source plant with a deposited voucher specimen, a gap the authors flag as an underappreciated source of uncertainty, since misidentified plant material would invalidate any downstream structure-activity conclusions. Publication bias likely inflates the apparent success rate of ethnopharmacological screening as well. Placed on a translational ladder from hit to lead to preclinical candidate, an estimated 70 to 75 percent of the compounds and interventions identified remain at the hit or lead stage, and only a small minority have any reported in vivo efficacy data.

The review also documents a quiet conceptual shift. Host-directed strategies, which target the human host environment the parasite depends on rather than the parasite itself, are emerging as a way to sidestep conventional resistance mechanisms. Carbazole-pyrimidines targeting the host protein Rac1, the repurposed kinase inhibitor AZD0156 acting on the parasite phosphatidylinositol 4-kinase PI4Kβ, and the steroid sulfatase inhibitor irosustat, which modulates host cholesterol-sulfate levels, all illustrate this multi-axis approach. Because these agents do not share targets with existing drugs, resistance to current therapies would theoretically not confer cross-resistance, though the authors stress this remains an untested hypothesis against clinically resistant isolates.

The overall message is one of vitality tempered by realism. The 2024 to 2026 literature reveals a field energetically integrating medicinal chemistry, molecular hybridization, computational prioritization, host-directed thinking, and nanoparticle delivery, with encouraging signs of research leadership from African institutions, which corresponding-authored nearly 64 percent of studies on African-sourced plants. But no compound in this corpus has yet demonstrated clinical-stage evidence of overcoming antimalarial drug resistance, and the distance between a molecule active in a petri dish and a medicine that survives in a patient remains long. The authors call for systematic isolation and structural characterization of active principles from crude extracts, rigorous testing against Kelch13-mutant parasites rather than legacy chloroquine benchmarks, biochemical validation of computationally predicted mechanisms, and preclinical toxicology for the most advanced nanoparticle platforms. For a disease that still kills more than half a million people a year, the pipeline is fuller than it has been in years, but the hard translational work has barely begun.

Subject of Research: Discovery and development of synthetic, semi-synthetic, and natural antimalarial compounds against drug-resistant malaria

Article Title: Antimalarial and antiplasmodial compounds (2024–2026): a systematic review of synthetic, semi-synthetic, and natural agents

Article References: Mikolo, B., Nsonde Ntandou, G. F., & Tabuna Nee Ntalani, H. (2026). Antimalarial and antiplasmodial compounds (2024–2026): a systematic review of synthetic, semi-synthetic, and natural agents. Frontiers in Tropical Diseases, 7, Article 1944733. https://doi.org/10.3389/fitd.2026.1944733

Image Credits: AI Generated

DOI: 10.3389/fitd.2026.1944733

Keywords: malaria, antimalarial drug discovery, Plasmodium falciparum, natural products, drug resistance, artemisinin, molecular hybridization, nanoparticles, computational drug discovery, host-directed therapy, quinoline, systematic review