Natural products as transmission-blocking agents against malaria: a comprehensive review of bioactive compounds and their therapeutic potential.

Malaria eradication is hindered by the persistence of transmission stages of Plasmodium falciparum that enable parasite transfer from humans to mosquitoes. Current therapeutic strategies, such as artemisinin-based combination therapy (ACT) combined with primaquine, are insufficient due to limited efficacy on mature gametocytes and safety concerns in populations with glucose-6-phosphate dehydrogenase deficiency. This highlights the critical need for innovative, safe, and effective transmission-blocking interventions. This review explores the potential of natural sources, including medicinal plants, marine organisms, and microorganisms-as reservoirs of novel bioactive compounds with anti-malarial properties. A comprehensive literature search identified promising natural products with gametocytocidal and sporontocidal activity, validated through advanced bioassays. The review also evaluates various methodologies, such as colorimetric, microscopy, and flow cytometry assays, for assessing transmission-blocking efficacy. The findings emphasize the potent gametocytocidal effects of certain plant extracts, such as Azadirachta indica and Vernonia amygdalina, and microbial products, including ionophores and proteasome inhibitors. Despite promising in vitro and in vivo data, the transition of these compounds to clinical applications remains limited. Challenges include standardizing assays, addressing resistance to current therapies, and ensuring drug safety for endemic populations. The current review underscores the untapped potential of natural products as transmission-blocking agents and proposes a systematic, stage-specific screening cascade to identify and optimize these compounds. Addressing these gaps could significantly advance global malaria eradication efforts.