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

• Published in: Nature communications 2021-12, Vol.12 (1), p.7327-7327, Article 7327
• Main Authors: Lin, Yingfu, Zhang, Zirong, Mahjour, Babak, Wang, Di, Zhang, Rui, Shim, Eunjae, McGrath, Andrew, Shen, Yuning, Brugger, Nadia, Turnbull, Rachel, Trice, Sarah, Jasty, Shashi, Cernak, Tim
• Format: Article
• Language: English
• Subjects: 639/638/549; 639/638/630; Anti-inflammatory agents; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - therapeutic use; Antiviral drugs; Chemical synthesis; Computer programs; Coronaviruses; Covalent bonds; COVID-19; COVID-19 - drug therapy; Drug Repositioning; Drugs; Fragility; Functional groups; Humanities and Social Sciences; Humans; Indoles - chemistry; Indoles - therapeutic use; Inflammation; Intermediates; multidisciplinary; Pandemics; Pharmaceuticals; Raw materials; SARS-CoV-2 - drug effects; Science; Science (multidisciplinary); Software; Supply chains
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27547-3

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. COVID-19 has exposed the fragility of supply chains, particularly for goods that are essential or may suddenly become essential, such as repurposed pharmaceuticals. Here the authors develop a methodology to provide routes to pharmaceutical targets that allow low-supply starting materials or intermediates to be avoided, with representative pathways validated experimentally.