From synthetic design to biological evaluation: Small-molecules as strategies against zoonotic neglected tropical diseases.

Zoonotic neglected tropical diseases (zNTDs) constitute a major global health challenge, particularly in low- and middle-income countries, where close interactions between humans, animals, and environmental reservoirs sustain pathogen transmission. Collectively, these diseases affect millions of people worldwide and are associated with significant morbidity and mortality, yet they continue to receive comparatively limited attention in drug discovery. Therapeutic options are still limited and are often associated with high toxicity, prolonged treatment regimens, variable efficacy, and the emergence of drug resistance, underscoring the urgent need for the development of safer and more effective chemotherapeutic agents. This review summarizes recent advances in the synthesis and biological evaluation of small molecules against important zoonotic neglected tropical diseases, including Chagas disease, leishmaniasis, echinococcosis, sporotrichosis, schistosomiasis, taeniasis, fascioliasis, and rabies. Particular emphasis is placed on studies integrating rational synthetic strategies with biological evaluation, to identify promising molecular scaffolds and emerging structure-activity relationships. The analysis highlights recurrent chemical motifs, including naphthoquinones, 1,2,3-triazoles, nitrogen-containing heterocycles, and the increasing incorporation of chalcogen-based functionalities in bioactive compounds. In general, this review provides an updated medicinal chemistry perspective, highlighting recent advances, remaining challenges, and opportunities for the rational design of new therapeutic candidates against zoonotic neglected tropical diseases.