Thieno[2,3‐d]pyrimidine‐Core Compounds Show Activity against Clinically Relevant Gram‐Positive Bacteria

Thieno[2,3‐d]pyrimidines represent a novel antibacterial prodrug scaffold, previously identified through a screening campaign against Mycobacterium tuberculosis in which the formation of highly antimycobacterial metabolites catalyzed by the nitroreductase Mrx2 is suggested to be the relevant killing mechanism. As analogous activation pathways may also be employed in other prokaryotes, in this work we explored general antibacterial effects of this compound class. Through exploration of the chemical space by different synthetic strategies, 51 novel derivatives were generated, biologically evaluated and thus enabled initial conclusions about structure‐activity relationships. Remarkably, anti‐Gram‐positive activity can be well modulated, particularly towards Staphylococci (MRSA) and even slightly against some Gram‐negative strains. The two most promising hit compounds showed good pharmacokinetic properties in vitro as well as acceptable toxicity in HeLa cells, qualifying them as starting points for lead‐generation campaigns.

• Publication year

  2022

• Venue

  ChemMedChem

• Publication date

  2022-07-26

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1002/cmdc.202200207PMID 35880634
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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