Computer-Aided Retrosynthesis\nfor Greener and Optimal\nTotal Synthesis of a Helicase-Primase Inhibitor Active Pharmaceutical\nIngredient

This study leverages\nand upgrades the capabilities of\ncomputer-aided\nretrosynthesis (CAR) in the systematic development of greener and\nmore efficient total synthetic routes for the active pharmaceutical\ningredient (API) IM-204, a helicase-primase inhibitor that demonstrated\nenhanced efficacy against Herpes simplex virus (HSV) infections. Using\nvarious CAR tools, several total synthetic routes were uncovered,\nevaluated, and experimentally validated, with the goal to maximize\nselectivity and yield and minimize the environmental impact. The CAR\ntools revealed several synthetic options under different constraints,\nwhich can overperform the patented synthetic route used as a reference.\nThe selected CAR-based route demonstrated a significant improvement\nof the total yield from 8% (patented route) to 26%, along with a moderate\nimprovement in the overall green performance. It was also shown that\na human-in-the-loop approach can be synergistically combined with\nCAR to drive further improvements and deliver greener synthetic alternatives.\nThis strategy further enhanced the green metrics by substituting solvents\nand merging two steps into one. These changes led to a significant\nimprovement in the overall yield of IM-204 synthesis from 8 to 35%.\nAdditionally, the green performance score, based on the GreenMotion\nmetrics, was improved from 0 to 18, and the total cost of the building\nblocks was reduced by 550-fold. This work demonstrates the potential\nof CAR in drug development, highlighting its capacity to streamline\nsynthesis processes, reduce environmental footprint, and lower production\ncosts, thereby advancing the field toward more efficient and sustainable\npractices.