Structure based design, synthesis and evaluation of new thienopyrimidine derivatives as anti-bacterial agents

TrmD, tRNA-(N(1)G37) methyltransferase, a member of SpoU-TrmD (SPOUT) RNA methyltransferase family, is one of the key enzymes responsible for the growth of Staphylococcus aureus, Pseudomonas aeruginosa, Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mab). A number of TrmD inhibitors including thienopyrimidines and fused thienopyrimidines are reported as potent anti-bacterial and antimycobacterial agents. In the current study, a library of similar to 200 structurally diverse thienopyrimidines were designed and subjected to preliminary in silico studies. 22 of the compounds were selected, synthesized and were evaluated for their inhibitory activities against a panel of pathogens consisting E. coli, S. aureus, K. pneuminiae, A. baumannii and P. aeruginosa and M. tuberculosis (ATCC 27294). Among the tested compounds, 13b, 18a-e were found to inhibit M. tuberculosis (ATCC 27294) with the MIC of 16-32 mu g/mL. The compound 18f was found to be selective against S. aureus with the MIC of 4 mu g/mL and moderate activity against M. tuberculosis. The selected compounds were further subjected to docking, 3D-QSAR and ADME/T studies to understand the mechanism of action and also their physico chemical profile. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

TrmD, a tRNA-(N(1)G37) methyltransferase, is essential for the growth of various bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Mycobacterium tuberculosis, and Mycobacterium abscessus. In this study, a library of around 200 structurally diverse thienopyrimidines was designed, synthesized, and evaluated for their inhibitory activities against multiple pathogens. Several compounds showed promising inhibitory effects against M. tuberculosis and S. aureus, with compound 18f demonstrating selectivity against the latter. Further studies were conducted to understand the mechanism of action and physico-chemical properties of the selected compounds.