Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives
Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives
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DOI：
10.1016/j.bmc.2004.11.045
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发表时间：
2005-02-15
影响因子：
3.5
通讯作者：
Baba, M
中科院分区：
文献类型：
--
作者：
Masuda, N;Yamamoto, O;Baba, M
在之前的研究中，我们描述了一系列噻唑烷苯磺酰胺衍生物的构效关系（sar）。这些化合物被发现是野生型（WT）和Y181C突变型逆转录酶（RTs）的高效抑制剂和K 103N RT的适度抑制剂。因此，这些分子被认为是一类新的非核苷类HIV-1 RT抑制剂（NNRTIs）。在本文中，我们研究了取代基对噻唑烷和苯磺酰胺基团的影响。在这些片段中引入2-氰苯基环可显著增强抗hiv -1活性，而2-羟基苯基则赋予抗RTs（包括K103N和Y181C突变体）的有效活性。在被检测的一系列分子中，101和18b (m -228855)， 2-氰苯基和4-甲基-5-异丙基噻唑的组合，显示出极强的抗hiv -1活性。101和18b的EC50值分别为0.0017和0.0018 muM。这些数值低于依非韦伦(3)。化合物11g （YM-215389）是2-羟基苯基和4-氯-5-异丙基噻唑基团的组合，对K103N和Y181C RTs的IC50值分别为0.043和0.013 muM。(C) 2004 Elsevier Ltd.版权所有。
In a previous study, we described the structure-activity relationships (SARs) for a series of thiazolidenebenzenesulfonamide derivatives. These compounds were found to be highly potent inhibitors of the wild type (WT) and Y181C mutant reverse transcriptases (RTs) and modest inhibitors of K 103N RT. These molecules are thus considered to be a novel class of non-nucleoside HIV-1 RT inhibitors (NNRTIs). In this paper, we have examined the effects of substituents on both the thiazolidene and benzenesulfonamide moieties. Introduction of a 2-cyanophenyl ring into these moieties significantly enhanced anti-HIV-1 activity, whereas a 2-hydroxyphenyl group endowed potent activity against RTs, including K103N and Y181C mutants. Among the series of molecules examined, 101 and 18b (YM-228855), combinations of 2-cyanophenyl and 4-methyl-5-isopropylthiazole moieties, showed extremely potent anti-HIV-1 activity. The EC50 values of 101 and 18b were 0.0017 and 0.0018 muM, respectively. These values were lower than that of efavirenz (3). Compound 11g (YM-215389), a combination of 2-hydroxyphenyl and 4-chloro-5-isopropylthiazole moieties, proved to be the most active against both K103N and Y181C RTs with IC50 values of 0.043 and 0.013 muM, respectively. (C) 2004 Elsevier Ltd. All rights reserved.