Computer-Aided Retrosynthesis for Greener and Optimal Total Synthesis of a Helicase-primase Inhibitor Active Pharmaceutical Ingredient

This study explores the application of computer-aided retrosynthesis (CAR) for developing greener and more efficient synthetic routes for the active pharmaceutical ingredient (API) IM-204, a helicase primase inhibitor with potential against Herpes simplex virus (HSV) infections. Using various CAR tools, several total synthetic routes were identified, evaluated, and experimentally validated, with the goal to maximize selectivity and yield and minimize the environmental impact. The selected route achieved a significant improvement in the overall yield of IM-204 synthesis from 8% to 35% while also enhancing GreenMotion metrics from 0 to 18 overall and reducing the cost of building blocks by 300-fold. This work demonstrates the potential of CAR in drug development, highlighting its capacity to streamline synthesis processes, reduce environmental footprint, and lower production costs, thereby advancing the field towards more efficient and sustainable practices.