Reinforcing the supply chain of umifenovir and other antiviral drugs with retrosynthetic software

Abstract

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C–H bonds into C–C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.

AI-Driven Synthetic Route Design Incorporated with Retrosynthesis Knowledge

“…These results clearly show that retrosynthesis knowledge effectively contributes to retrosynthetic analyses using ReTReK. However, the experimental validations with targets that chemists are interested in and blind assessments by trained chemists are not performed in this study; thus we plan to perform these validations to evaluate the performance of ReTReK on actual chemical synthesis in future work. Considering these evaluations and demonstrations, the ReTReK framework with integrated retrosynthesis knowledge has the potential to further improve the performance of data-driven CASP applications.…”

Bayesian Optimization of Computer-Proposed Multistep Synthetic Routes on an Automated Robotic Flow Platform

“…There is growing interest in experimentally validating CASP suggestions and integrating CASP tools with automated synthesis platforms. Experimental validation of CASP recommendations has been demonstrated via batch synthesis − and on a robotic continuous flow synthesis platform, and disclosed examples still remain rare. The main obstacle to direct implementation of CASP-designed routes without human intervention is that synthesis procedures require a fully defined set of instructions (a recipe) specifying the sequence of unit operations and corresponding reaction conditions (e.g., concentrations, temperature, time, stoichiometry) with a level of precision that exceeds what can currently be learned or extracted from limited data .…”

Optimized synthesis of anti-COVID-19 drugs aided by retrosynthesis software

“…There have been successful cases of using retrosynthetic software to design and optimize the synthetic routes for anti-COVID-19 drugs hydroxychloroquine, remdesivir, and umifenovir. 35,36 Therefore, we used it to design synthetic routes for favipiravir.…”