The Synthesis and Testing of Halofuginone Derivatives for the Treatment of Mosquito-borne Diseases
Abstract
According to the World Health Organization, mosquito-borne diseases were responsible for over 400 million cases reported worldwide with almost 750,000 deaths in 2024. Of these reports, dengue and malaria, transmitted through the bite from Anopheles and Aedes mosquitoes, accounted for the majority of the diseases. Recently, halofuginone, a coccidiostat derived from an alkaloid used in Chinese herbal medicine, has been tested in the treatment of mosquito-borne diseases. As a prolyl-tRNA synthetase inhibitor (aaRS), it has shown much promise in controlling the cause of malaria, P. falciparum pathogens; however, it is prohibitively expensive to purchase halofuginone ($51,000/gram) from commercial suppliers. The following research pursues a novel derivative of halofuginone through chemical synthesis to access a cost-efficient structural analog which retains the biological activity of its parent structure. This approach aims to preserve halofuginone's therapeutic potential while overcoming the limitations imposed by its cost barrier.
Our first round of derivatives were generated via an eight-step convergent synthesis, in which a pelletierine scaffold and a substituted quinazolin-4-one were independently prepared and subsequently coupled. By derivatizing the four quadrants within halofuginone's structure, several simplified prototypes have been developed. To further improve production costs through increased yield and reduced steps, there is ongoing investigation into the optimization of the synthesis, upon which future derivatives can developed and sent for testing as an anti-malarial agent.