4.5 Article

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

期刊

CHEMMEDCHEM
卷 17, 期 17, 页码 -

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202200207

关键词

antimicrobial; drug discovery; Gram-positive bacteria; MRSA; structure-activity relationships; thieno[2; 3-d]pyrimidine

资金

  1. Federal Ministry of Education and Research (BMBF) of Germany [FKZ 03ZZ0835 A, 03ZZ0826 A]
  2. Russian Science Foundation [21-15-00042]

向作者/读者索取更多资源

Thieno[2,3-d]pyrimidines represent a novel antibacterial prodrug scaffold with potential antibacterial effects against Gram-positive bacteria, particularly Staphylococci (MRSA). The two most promising hit compounds demonstrate good pharmacokinetic properties in vitro and acceptable toxicity, qualifying them as starting points for lead-generation campaigns.
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.

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