A trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacterium tuberculosis.
A trisubstituted benzimidazole cell division inhibitor with efficacy against Mycobacterium tuberculosis.
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DOI：
10.1371/journal.pone.0093953
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Slayden RA
中科院分区：
文献类型：
--
作者：
Knudson SE;Awasthi D;Kumar K;Carreau A;Goullieux L;Lagrange S;Vermet H;Ojima I;Slayden RA
三取代苯并咪唑已显示出对革兰氏阳性和革兰氏阴性细菌的效力。此前，为了高通量筛选，构建了一个新的三取代苯并咪唑文库，并鉴定了具有抗结核分枝杆菌H37Rv和临床分离株的活性且对Vero细胞无毒的化合物。在合成孔径雷达的基础上，合成了一系列新的2-环己基-5-酰氨基-6-N，N-二甲氨基苯并咪唑类化合物。筛选出具有抗结核活性的化合物。该系列的先导化合物SB-P17G-A20具有0.16微克/毫升的最低抑菌浓度，并在小鼠结核病急性感染模型中显示出疗效，当给药剂量为50 mg/kg，每日两次(Ip)时，肺和脾的细菌负荷分别减少1.73±0.24log10cfu和2.68±log10cfu。Sb-P17G-A20的活性具有浓度依赖性，在小鼠、人血浆和肝微粒体中具有良好的稳定性。总之，这些研究表明，SB-P17G-A20在动物感染模型中具有不同的敏感性和有效性的抗结核分枝杆菌临床菌株的效力，三取代苯并咪唑继续成为开发有效的新型抑制剂的平台。
Trisubstituted benzimidazoles have demonstrated potency against Gram-positive and Gram-negative bacterial pathogens. Previously, a library of novel trisubstituted benzimidazoles was constructed for high throughput screening, and compounds were identified that exhibited potency against M. tuberculosis H37Rv and clinical isolates, and were not toxic to Vero cells. A new series of 2-cyclohexyl-5-acylamino-6-N, N-dimethylaminobenzimidazoles derivatives has been developed based on SAR studies. Screening identified compounds with potency against M. tuberculosis. A lead compound from this series, SB-P17G-A20, was discovered to have an MIC of 0.16 µg/mL and demonstrated efficacy in the TB murine acute model of infection based on the reduction of bacterial load in the lungs and spleen by 1.73±0.24 Log10 CFU and 2.68±Log10 CFU, respectively, when delivered at 50 mg/kg by intraperitoneal injection (IP) twice daily (bid). The activity of SB-P17G-A20 was determined to be concentration dependent and to have excellent stability in mouse and human plasma, and liver microsomes. Together, these studies demonstrate that SB-P17G-A20 has potency against M. tuberculosis clinical strains with varying susceptibility and efficacy in animal models of infection, and that trisubstituted benzimidazoles continue to be a platform for the development of novel inhibitors with efficacy.
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影响因子：
2.8
作者：
Slayden, Richard A.;Knudson, Dennis L.;Belisle, John T.
通讯作者：
Belisle, John T.
DOI：
10.1016/j.tube.2013.04.002
发表时间：
2013-07
期刊：
Tuberculosis (Edinburgh, Scotland)
影响因子：
--
作者：
Mathew B;Ross L;Reynolds RC
通讯作者：
Reynolds RC
影响因子：
7.3
作者：
Kumar K;Awasthi D;Lee SY;Zanardi I;Ruzsicska B;Knudson S;Tonge PJ;Slayden RA;Ojima I
通讯作者：
Ojima I
影响因子：
3.6
作者：
Slayden, RA;Lee, RE;Barry, CE
通讯作者：
Barry, CE
影响因子：
7.3
作者：
Huang, Q;Kirikae, F;Ojima, I
通讯作者：
Ojima, I