Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: Synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives

Naoyuki Masuda, Osamu Yamamoto, Masahiro Fujii, Tetsuro Ohgami, Jiro Fujiyasu, Toru Kontani, Ayako Moritomo, Masaya Orita, Hiroyuki Kurihara, Hironobu Koga, Shunji Kageyama, Mitsuaki Ohta, Hiroshi Inoue, Toshifumi Hatta, Masafumi Shintani, Hiroshi Suzuki, Kenji Sudo, Yasuaki Shimizu, Eiichi Kodama, Masao MatsuokaMasatoshi Fujiwara, Tomoyuki Yokota, Shiro Shigeta, Masanori Baba

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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 μM, 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 μM, respectively.

Original languageEnglish
Pages (from-to)949-961
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number4
DOIs
Publication statusPublished - 2005 Feb 15
Externally publishedYes

Keywords

  • Non-nucleoside HIV-1 reverse transcriptase inhibitor
  • Thiazolidenebenzenesulfonamide
  • YM-215389

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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