Molecular Mechanisms of Natural Antiprotozoal Compounds: Emerging Strategies for Neglected Tropical Diseases

In numerous tropical countries, outbreaks of protozoan parasites are major contributors to illness and mortality. These include protozoa from the genus Trypanosoma, which cause Human African Trypanosomiasis (HAT) and Chagas Disease, and Leishmania, which causes several forms of Leishmaniasis. The World Health Organization (WHO) has identified seventeen "Neglected Tropical Diseases" (NTDs). While not formally classified as an NTD, malaria (caused by Plasmodium spp.) presents similar therapeutic challenges and is included due to its global burden. Numerous bioactive compounds found in plants, including marketed herbal medicinal preparations (HMPs), have demonstrated antiprotozoal activity against these diseases. This study aims to provide a thorough assessment of the potential of these plant-derived compounds, with emphasis on HMPs, as safe, affordable, and effective alternatives to current therapies. We conducted a comprehensive search using the terms "neglected disease," "topical disease," "immune modulation," "herbal medicine," and "mechanism of inhibition" across the following language-neutral electronic databases: Medline, EMBASE, AARP Ageline, AMED (Allied and Complementary Medicine), The Cochrane Database of Systematic Reviews, DARE (Database of Abstracts and Reviews), and Google Scholar. Current medicines face critical limitations, including resistance, safety concerns, and toxicity profiles, driving the need for novel solutions. The growing medicinal potential of herbal components, particularly those with established regulatory approval and traditional use, is the focus of this review. The key mechanisms of action (e.g., heme disruption in malaria, protease inhibition in Chagas disease, and immune modulation in leishmaniasis) and high-priority plant families (e.g., Annonaceae and Meliaceae) are highlighted, together with representative bioactive compounds such as artemisinin, quinine, iridoids, and flavonoids (quercetin and kaempferol). These plant-derived agents demonstrate significant potential as safe and effective alternatives for protozoan infections.