Identification of 2-Amino Benzothiazoles with Bactericidal Activity against Mycobacterium tuberculosis.
Identification of 2-Amino Benzothiazoles with Bactericidal Activity against Mycobacterium tuberculosis.
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DOI：
10.1128/spectrum.04974-22
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发表时间：
2023-02-14
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
We identified an amino-benzothiazole scaffold from a whole-cell screen against recombinant Mycobacterium tuberculosis under expressing the essential signal peptidase LepB. The seed molecule had 2-fold higher activity against the LepB hypomorph. Through a combination of purchase and chemical synthesis, we explored the structure-activity relationship for this series; 34 analogs were tested for antitubercular activity and for cytotoxicity against eukaryotic cells. We identified molecules with improved potency and reduced cytotoxicity. However, molecules did not appear to target LepB directly and did not inhibit protein secretion. Key compounds showed good permeability, low protein binding, and lack of CYP inhibition, but metabolic stability was poor with short half-lives. The seed molecule showed good bactericidal activity against both replicating and nonreplicating bacteria, as well as potency against intracellular M. tuberculosis in murine macrophages. Overall, the microbiological properties of the series are attractive if metabolic stability can be improved, and identification of the target could assist in the development of this series. IMPORTANCE Mycobacterium tuberculosis, the causative agent of tuberculosis, is a serious global health problem requiring the development of new therapeutics. We previously ran a high-throughput screen and identified a series of compounds with antitubercular activity. In this paper, we test analogs of our hit molecules for activity against M. tuberculosis, as well as for activity against eukaryotic cells. We identified molecules with improved selectivity. Our molecules killed both replicating and nonreplicating bacteria but did not work by targeting protein secretion.
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影响因子：
5.2
作者：
Vijay S;Vinh DN;Hai HT;Ha VTN;Dung VTM;Dinh TD;Nhung HN;Tram TTB;Aldridge BB;Hanh NT;Thu DDA;Phu NH;Thwaites GE;Thuong NTT
通讯作者：
Thuong NTT
DOI：
10.1080/14756360600991082
发表时间：
2007-02-01
影响因子：
5.6
作者：
Abdel-Rahman, Hamdy M.;Morsy, Mohamed A.
通讯作者：
Morsy, Mohamed A.
影响因子：
4.9
作者：
Silva-Miranda, Mayra;Ekaza, Euloge;Altare, Frederic
通讯作者：
Altare, Frederic
影响因子：
3.7
作者：
Gold B;Nathan C
通讯作者：
Nathan C
影响因子：
5.3
作者：
Early, Julie;Ollinger, Juliane;Parish, Tanya
通讯作者：
Parish, Tanya