Abstract
Leishmaniasis represents a significant threat to global health as a neglected tropical disease. While therapeutic options exist, their high cost, safety concerns, and significant adverse effects necessitate the discovery of safer and more efficacious alternatives. Natural products, possessing diverse biological activities including inherent anti-leishmanial properties, constitute a vital resource for drug development. However, the intrinsic activity of these compounds is frequently suboptimal. Structural modification offers a potent strategy to significantly enhance their efficacy. This comprehensive review summarizes advances from 2010 to 2024 in the structural modification of natural products to improve anti-leishmanial activity, with particular emphasis on phenylpropanoid derivatives and other natural product classes, and provides detailed synthetic routes for each derivative. The findings demonstrate that strategic structural modifications can substantially increase potency, achieving IC(50) values in the nanomolar range for some derivatives. Furthermore, these optimized compounds exhibit promising safety profiles and favorable pharmacokinetic properties, underscoring their considerable potential for further development. These advancements not only offer promising avenues for novel anti-leishmanial drug discovery but also provide valuable insights applicable to natural product-based therapies for other diseases. Future research should prioritize elucidating mechanisms of action and conducting further structure-activity relationship optimization to develop more potent and less toxic anti-leishmanial agents.