title: Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.
abstract: 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.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. masuda.naoyuki@yamanouchi.co.jp
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Masuda
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamamoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujii
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ohgami
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujiyasu
authors.forename: Toru
authors.initials: T
authors.lastname: Kontani
authors.forename: Ayako
authors.initials: A
authors.lastname: Moritomo
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Hironobu
authors.initials: H
authors.lastname: Koga
authors.forename: Shunji
authors.initials: S
authors.lastname: Kageyama
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Hatta
authors.forename: Masafumi
authors.initials: M
authors.lastname: Shintani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kenji
authors.initials: K
authors.lastname: Sudo
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yokota
authors.forename: Shiro
authors.initials: S
authors.lastname: Shigeta
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
mesh_terms: D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides