We explored general antibacterial effects of the thieno[2,3-d]pyrimidine compound class. By exploring the chemical space with different synthetic strategies, 51 new derivatives were generated, enabling initial conclusions about structure-activity relationships. Remarkably, anti-Gram-positive activity can be well modulated, particularly toward 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.
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.
Conflict of interest
The authors declare no conflict of interest.
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
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