Colorado State University, Department of Microbiology, Immunology and Pathology, 1682 Campus Delivery Ft. Collins, CO 80523-1682, USA.
Bioorg Med Chem. 2012 May 15;20(10):3255-62. doi: 10.1016/j.bmc.2012.03.058. Epub 2012 Mar 31.
Adamantyl ureas were previously identified as a group of compounds active against Mycobacterium tuberculosis in culture with minimum inhibitor concentrations (MICs) below 0.1 μg/ml. These compounds have been shown to target MmpL3, a protein involved in secretion of trehalose mono-mycolate. They also inhibit both human soluble epoxide hydrolase (hsEH) and M. tuberculosis epoxide hydrolases. However, active compounds to date have high cLogP's and are poorly soluble, leading to low bioavailability and thus limiting any therapeutic application. In this study, a library of 1600 ureas (mostly adamantyl ureas), which were synthesized for the purpose of increasing the bioavailability of inhibitors of hsEH, was screened for activity against M. tuberculosis. 1-Adamantyl-3-phenyl ureas with a polar para substituent were found to retain moderate activity against M. tuberculosis and one of these compounds was shown to be present in serum after oral administration to mice. However, neither it, nor a closely related analog, reduced M. tuberculosis infection in mice. No correlation between in vitro potency against M. tuberculosis and the hsEH inhibition were found supporting the concept that activity against hsEH and M. tuberculosis can be separated. Also there was a lack of correlation with cLogP and inhibition of the growth of M. tuberculosis. Finally, members of two classes of adamantyl ureas that contained polar components to increase their bioavailability, but lacked efficacy against growing M. tuberculosis, were found to taken up by the bacterium as effectively as a highly active apolar urea suggesting that these modifications to increase bioavailability affected the interaction of the urea against its target rather than making them unable to enter the bacterium.
先前已鉴定出金刚烷基脲类化合物是一组对培养中的结核分枝杆菌有活性的化合物，其最低抑菌浓度（MIC）低于 0.1μg/ml。这些化合物已被证明靶向 MmpL3，一种参与海藻糖单-我的colate 分泌的蛋白质。它们还抑制人可溶性环氧化物水解酶（hsEH）和结核分枝杆菌环氧化物水解酶。然而，迄今为止，活性化合物的 cLogP 值较高，溶解度较差，导致生物利用度低，从而限制了任何治疗应用。在这项研究中，为提高 hsEH 抑制剂的生物利用度而合成了 1600 个脲类化合物（主要是金刚烷基脲）库，对其进行了抗结核分枝杆菌活性筛选。发现具有极性对位取代基的 1-金刚烷基-3-苯基脲类化合物对结核分枝杆菌仍具有中等活性，其中一种化合物在给小鼠口服后被证明存在于血清中。然而，它既没有，也没有一个密切相关的类似物，能降低小鼠体内结核分枝杆菌的感染。未发现体外对结核分枝杆菌的效力与 hsEH 抑制之间存在相关性，这支持了这样的概念，即对 hsEH 和结核分枝杆菌的活性可以分开。此外，与 cLogP 和结核分枝杆菌生长抑制之间也缺乏相关性。最后，发现两类金刚烷基脲类化合物的成员含有增加其生物利用度的极性成分，但缺乏对抗生长的结核分枝杆菌的疗效，它们被细菌摄取的效率与高度有效的非极性脲类化合物一样高，这表明这些增加生物利用度的修饰影响了脲类化合物与其靶标的相互作用，而不是使它们无法进入细菌。
