Design,Synthesis and Evaluation of Triazole‐Pyrimidine Analogues as SecA Inhibitors |
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| Authors: | Jianmei Cui Jinshan Jin Arpana Sagwal Chaudhary Ying‐hsin Hsieh Hao Zhang Chaofeng Dai Krishna Damera Weixuan Chen Phang C. Tai Binghe Wang |
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| Affiliation: | 1. Department of Chemistry, Georgia State University, Atlanta, GA, USA;2. Department of Biology, Center for Biotechnology and Drug Design, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA |
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| Abstract: | 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. |
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| Keywords: | antimicrobials protein secretion pyrimidines SecA inhibitors triazoles |
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