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Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives. 2005
Naoyuki Masuda, and
Osamu Yamamoto, and
Masahiro Fujii, and
Tetsuro Ohgami, and
Jiro Fujiyasu, and
Toru Kontani, and
Ayako Moritomo, and
Masaya Orita, and
Hiroyuki Kurihara, and
Hironobu Koga, and
Shunji Kageyama, and
Mitsuaki Ohta, and
Hiroshi Inoue, and
Toshifumi Hatta, and
Masafumi Shintani, and
Hiroshi Suzuki, and
Kenji Sudo, and
Yasuaki Shimizu, and
Eiichi Kodama, and
Masao Matsuoka, and
Masatoshi Fujiwara, and
Tomoyuki Yokota, and
Shiro Shigeta, and
Masanori Baba
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. masuda.naoyuki@yamanouchi.co.jp
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 K103N 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, 10l 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 microM, 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 microM, respectively.
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