The structure-activity relationship of urea derivatives as anti-tuberculosis agents.
The structure-activity relationship of urea derivatives as anti-tuberculosis agents.
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DOI：
10.1016/j.bmc.2011.07.034
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发表时间：
2011-09-15
影响因子：
3.5
通讯作者：
Lee, Richard E.
中科院分区：
文献类型：
--
作者：
Brown, Joshua R.;North, Elton J.;Hurdle, Julian G.;Morisseau, Christophe;Scarborough, Jerrod S.;Sun, Dianqing;Kordulakova, Jana;Scherman, Michael S.;Jones, Victoria;Grzegorzewicz, Anna;Crew, Rebecca M.;Jackson, Mary;McNeil, Michael R.;Lee, Richard E.
由于耐药性的日益普遍，结核病的治疗变得更加困难。因此，必须发现和开发具有独特作用机制的新型抗结核药物。小化合物库的直接抗结核测试导致金刚烷基脲命中化合物1的发现。在这项研究中，通过合成优化库来跟踪命中。通过用相似的部分系统地替换分子的每个部分直到获得关于抗结核活性的明确的结构活性关系来产生该文库。该系列中最好的化合物含有1-金刚烷基-3-苯基脲核心，并且具有有效的抗结核分枝杆菌活性以及可接受的治疗指数。值得注意的是，鉴定的化合物和开发的药效团与环氧化物水解酶家族的抑制剂一致。因此，测试化合物对代表性环氧化物水解酶的抑制：M.结核EphB和EphE;和人可溶性环氧化物水解酶。许多优化的抑制剂显示出有效的EphB和EphE抑制，表明抗结核活性是通过抑制多种环氧化物水解酶。这些抑制剂还显示出对人可溶性环氧化物水解酶的有效抑制，但有限的细胞毒性，这表明未来的研究必须朝着增加环氧化物水解酶抑制对M.结核酶
The treatment of tuberculosis is becoming more difficult due to the ever increasing prevalence of drug resistance. Thus, it is imperative that novel anti-tuberculosis agents, with unique mechanisms of action, be discovered and developed. The direct anti-tubercular testing of a small compound library led to discovery of adamantyl urea hit compound 1. In this study, the hit was followed up through the synthesis of an optimization library. This library was generated by systematically replacing each section of the molecule with a similar moiety until a clear structure activity relationship was obtained with respect to anti-tubercular activity. The best compounds in this series contained a 1-adamantyl-3-phenyl urea core and had potent activity against Mycobacterium tuberculosis plus an acceptable therapeutic index. It was noted that the compounds identified and the pharmacophore developed is consistent with inhibitors of epoxide hydrolase family of enzymes. Consequently, the compounds were tested for inhibition of representative epoxide hydrolases: M. tuberculosis EphB and EphE; and human soluble epoxide hydrolase. Many of the optimized inhibitors showed both potent EphB and EphE inhibition suggesting the antitubercular activity is through inhibition of multiple epoxide hydrolyase enzymes. The inhibitors also showed potent inhibition of humans soluble expoxide hydrolyase, but limited cytotoxicity suggesting that future studies must be towards increasing the selectivity of epoxide hydrolyase inhibition towards the M. tuberculosis enzymes.
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影响因子：
5.6
作者：
Biswal, Bichitra K.;Morisseau, Christophe;James, Michael N. G.
通讯作者：
James, Michael N. G.
影响因子：
5.2
作者：
Protopopova, M;Hanrahan, C;Nacy, CA
通讯作者：
Nacy, CA
影响因子：
2.8
作者：
Usha, Veeraraghavan;Gurcha, Sudagar S.;Besra, Gurdyal S.
通讯作者：
Besra, Gurdyal S.
影响因子：
--
作者：
Lee, RE;Protopopova, M;Barry, CE
通讯作者：
Barry, CE
影响因子：
56.9
作者：
Andries, K;Verhasselt, P;Jarlier, V
通讯作者：
Jarlier, V