Novel trisubstituted benzimidazoles, targeting Mtb FtsZ, as a new class of antitubercular agents.
Novel trisubstituted benzimidazoles, targeting Mtb FtsZ, as a new class of antitubercular agents.
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DOI：
10.1021/jm1012006
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发表时间：
2011-01-13
影响因子：
7.3
通讯作者：
Ojima I
中科院分区：
文献类型：
--
作者：
Kumar K;Awasthi D;Lee SY;Zanardi I;Ruzsicska B;Knudson S;Tonge PJ;Slayden RA;Ojima I
通过合理的药物设计创建了新型三取代苯并咪唑化合物库。其中许多苯并咪唑类药物对 Mtb H37Rv 菌株的抗菌活性表现出良好的 MIC 值，范围为 0.5-6 μg/mL (2-15 μM)。此外，五种先导化合物还对具有不同耐药性的临床结核分枝杆菌菌株表现出优异的活性。所有先导化合物均未表现出针对 Vero 细胞的明显细胞毒性 (IC50 >200 μM)，该细胞毒性以剂量依赖性方式抑制 Mtb FtsZ 组装。这两种先导化合物出乎意料地显示出 Mtb FtsZ 的 GTPase 活性增强。结果强烈表明，GTPase 活性的增加会破坏 FtsZ 组装的稳定性，从而有效抑制 FtsZ 聚合和丝形成。分别用先导化合物处理的 Mtb FtsZ 和 Mtb 细胞的 TEM 和 SEM 分析强烈表明，铅苯并咪唑具有抑制 Mtb FtsZ 组装和 Z 环形成的新作用机制。
Libraries of novel trisubstituted benzimidazoles were created through rational drug design. A good number of these benzimidazoles exhibited promising MIC values in the range of 0.5-6 μg/mL (2-15 μM) for their antibacterial activity against Mtb H37Rv strain. Moreover, five of the lead compounds also exhibited excellent activity against clinical Mtb strains with different drug-resistance profiles. All lead compounds do not show appreciable cytotoxicity (IC50 >200 μM) against Vero cells, which inhibit Mtb FtsZ assembly in a dose dependent manner. The two lead compounds unexpectedly showed enhancement of the GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly and Z-ring formation.
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影响因子：
3.2
作者：
White, EL;Ross, LJ;Borhani, DW
通讯作者：
Borhani, DW
影响因子：
2.8
作者：
Slayden, Richard A.;Knudson, Dennis L.;Belisle, John T.
通讯作者：
Belisle, John T.
影响因子：
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作者：
Jaiswal, Richa;Beuria, Tushar K.;Panda, Dulal
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影响因子：
3.6
作者：
Slayden, RA;Lee, RE;Barry, CE
通讯作者：
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影响因子：
7.3
作者：
Huang, Q;Kirikae, F;Ojima, I
通讯作者：
Ojima, I