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Synthesis and mycobacterial evaluation of 5‐substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido‐[2,3‐ d ]pyrimidin‐4(3 H )‐one derivatives
Author(s) -
Agre Neha,
Degani Mariam,
Gupta Antima,
Bhakta Sanjib,
Ray Mukti Kanta
Publication year - 2019
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201900068
Subject(s) - efflux , staphylococcus aureus , mycobacterium tuberculosis , cytotoxicity , chemistry , cell culture , escherichia coli , antibacterial activity , biochemistry , minimum inhibitory concentration , mycobacterium , microbiology and biotechnology , in vitro , amino acid , bacteria , tuberculosis , biology , gene , medicine , genetics , pathology
5‐Substituted‐6‐acetyl‐2‐amino‐7‐methyl‐5,8‐dihydropyrido[2,3‐ d ]pyrimidin‐4(3 H )‐one derivatives were synthesized and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium aurum , Escherichia coli , and Staphylococcus aureus as well as a human monocyte‐derived macrophage (THP‐1), and murine macrophage (RAW 264.7) cell lines to assess their antibacterial and cytotoxic potential, respectively. The compounds showed activity in the range of 1.95–125 µg/ml against M. tuberculosis but showed no activity against M. aurum , E. coli , and S. aureus , indicating selectivity towards slow‐growing mycobacterial pathogens. The compounds exhibited very low to no cytotoxicity up to 500 µg/ml concentration against eukaryotic cell lines. The most potent molecule, 2l , showed a minimum inhibitory concentration of 1.95 µg/ml against M. tuberculosis H37Rv and a selectivity index of >250 against both the eukaryotic cell lines. Furthermore, 2l showed moderate inhibition of whole‐cell mycobacterial drug‐efflux pumps when compared to verapamil, a known potent inhibitor of efflux pumps. Thus, derivative 2l was identified as an antituberculosis hit molecule, which could be used to yield more potent lead molecules.