Studies of nonnucleoside HIV-1 reverse transcriptase inhibitors. Part 1: Design and synthesis of thiazolidenebenzenesulfonamides

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

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

A series of thiazolidenebenzenesulfonamides have been discovered as nonnucleoside reverse transcriptase inhibitors. Compound 17a exhibited the most potent inhibitory activity against the Y181C mutant reverse transcriptase (RT). The introduction of the 4-chloro-5-isopropyl moiety (17k) markedly increased the activity against the wild type RT. Both 17a and 17k strongly inhibited HIV-1 replication. A random high-throughput screening (HTS) program to discover novel nonnucleoside reverse transcriptase inhibitors (NNRTIs) has been carried out with MT-4 cells against a nevirapine-resistant virus, HIV-1 IIIB-R. The primary hit, a thiazolidenebenzenesulfonamide derivative, possessed good activity. A systematic modification program examining various substituents at the 3-, 4-, and 5-positions on the thiazole ring afforded compounds with enhanced anti-HIV-1 and reverse transcriptase (RT) inhibitory activities. These results confirm the important role of the substituents at these positions and the thiazolidenebenzenesulfonamide motif as a valuable lead series for the next generation NNRTIs.

Original languageEnglish
Pages (from-to)6171-6182
Number of pages12
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number23
DOIs
Publication statusPublished - 2004 Dec 1
Externally publishedYes

Keywords

  • Benzenesulfonamide
  • Nonnucleoside HIV-1 reverse transcriptase inhibitor
  • Thiazolidene

ASJC Scopus subject areas

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

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