Development of an Original Multi-Target Drug Scaffold Inspired by Nigerian Medicinal Plant Natural Products for Neglected Tropical Disease Treatment

Neglected tropical diseases including leishmaniasis, trypanosomiasis, and schistosomiasis impose disproportionate burdens on rural communities in Nigeria, yet treatment options remain limited, toxic, and increasingly compromised by drug resistance. The development of novel multi-target drug candidates inspired by the bioactive natural product chemistry of Nigerian medicinal plants offers an original strategy for addressing this treatment gap. This study designed, synthesised, and evaluated a series of hybrid molecules incorporating pharmacophoric fragments derived from the natural product families of Nigerian medicinal plants, specifically quassinoids from Quassia amara, alkaloids from Picralima nitida, and terpenoids from Nauclea latifolia, fused into single molecular scaffolds targeting multiple disease-relevant biological pathways. The hybrid design strategy was guided by molecular docking against Trypanosoma brucei phosphoglycerate kinase, Leishmania donovani dihydrofolate reductase, and Schistosoma mansoni thioredoxin glutathione reductase. Sixty hybrid compounds were synthesised using efficient, step-economical synthetic routes and fully characterised by high-resolution mass spectrometry and comprehensive nuclear magnetic resonance spectroscopy. In vitro antiprotozoal and antischistosomal activities were evaluated in collaboration with the London School of Hygiene and Tropical Medicine. Seventeen compounds showed IC50 values below 2 micromolar against Trypanosoma brucei. Eight compounds demonstrated submicromolar activity against Leishmania donovani with selectivity indices above 20 relative to mammalian cells. Four compounds showed stage-specific schistosomicidal activity. The most active compound demonstrated multi-target profiles consistent with the design intent. This original research programme establishes Nigerian natural product chemistry as a viable foundation for neglected tropical disease drug discovery.

Keywords: neglected tropical diseases, natural product-inspired drug design, hybrid molecules, antiprotozoal activity, Nigerian medicinal plants