Multicomponent reaction-derived covalent inhibitor space

Fandi Sutanto, Shabnam Shaabani, Constantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Pravin Patil, Ehsan Ghonchepour, Alexander Dömling*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
27 Downloads (Pure)

Abstract

The area of covalent inhibitors is gaining momentum due to recently introduced clinical drugs, but libraries of these compounds are scarce. Multicomponent reaction (MCR) chemistry is well known for its easy access to a very large and diverse chemical space. Here, we show that MCRs are highly suitable to generate libraries of electrophiles based on different scaffolds and three-dimensional shapes and highly compatible with multiple functional groups. According to the building block principle of MCR, acrylamide, acrylic acid ester, sulfurylfluoride, chloroacetic acid amide, nitrile, and alpha,beta-unsaturated sulfonamide warheads can be easily incorporated into many different scaffolds. We show examples of each electrophile on 10 different scaffolds on a preparative scale as well as in a high-throughput synthesis mode on a nanoscale to produce libraries of potential covalent binders in a resource-and time-saving manner. Our operational procedure is simple, mild, and step economical to facilitate future covalent library synthesis.

Original languageEnglish
Article number9307
Number of pages11
JournalScience Advances
Volume7
Issue number6
DOIs
Publication statusPublished - Feb-2021

Keywords

  • HIGH-THROUGHPUT EXPERIMENTATION
  • ISOCYANIDE SYNTHESIS
  • DISCOVERY
  • ISONITRILE
  • DESIGN
  • LIBRARIES
  • AFFINITY
  • MOIETIES
  • PROFILE
  • TARGET

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