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

Yingfu Lin,Rui Zhang,Zirong Zhang,Sarah Trice,Nadia Brugger,Di Wang,Yuning Shen,Andrew Mcgrath,Babak Mahjour,Shashi Jasty,Eunjae Shim,Tim Cernak,Rachel Turnbull

doi:10.1038/s41467-021-27547-3

Yingfu Lin, Rui Zhang + Show 11 more

Open Access

https://doi.org/10.1038/s41467-021-27547-3

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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.

Highlights

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals
We focused our experimental attention on umifenovir (2), which had been used against SARS-CoV1, and is effective against SARS-CoV2 in vitro[9]
We identify distinct raw materials that are of comparable cost, and which feature in routes of comparable length to known routes to the 12 diverse targets

Summary

Introduction

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. We present predicted retrosynthetic routes to twelve diverse COVID-19 therapeutic candidates that initiate, as frequently as possible, with starting materials that are distinct from those used in published or patented syntheses. Each search result contained 50 route proposals, and the user-defined search heuristic was generally set to minimize starting material cost.

Results

Conclusion