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Design, Synthesis and Evaluation of Triazole‐Pyrimidine Analogues as SecA Inhibitors
Author(s) -
Cui Jianmei,
Jin Jinshan,
Chaudhary Arpana Sagwal,
Hsieh Yinghsin,
Zhang Hao,
Dai Chaofeng,
Damera Krishna,
Chen Weixuan,
Tai Phang C.,
Wang Binghe
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500447
Subject(s) - efflux , chromosomal translocation , virtual screening , chemistry , antimicrobial , pyrimidine , multiple drug resistance , escherichia coli , target protein , combinatorial chemistry , bacteria , biochemistry , drug discovery , biology , antibiotics , genetics , organic chemistry , gene
SecA, a key component of the bacterial Sec‐dependent secretion pathway, is an attractive target for the development of new antimicrobial agents. Through a combination of virtual screening and experimental exploration of the surrounding chemical space, we identified a hit bistriazole SecA inhibitor, SCA‐21, and studied a series of analogues by systematic dissections of the core scaffold. Evaluation of these analogues allowed us to establish an initial structure–activity relationship in SecA inhibition. The best compounds in this group are potent inhibitors of SecA‐dependent protein‐conducting channel activity and protein translocation activity at low‐ to sub‐micromolar concentrations. They also have minimal inhibitory concentration (MIC) values against various strains of bacteria that correlate well with the SecA and protein translocation inhibition data. These compounds are effective against methicillin‐resistant Staphylococcus aureus strains with various levels of efflux pump activity, indicating the capacity of SecA inhibitors to null the effect of multidrug resistance. Results from studies of drug‐affinity‐responsive target stability and protein pull‐down assays are consistent with SecA as a target for these compounds.