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

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 4; pp. 949 - 961
• Main Authors: Masuda, Naoyuki, Yamamoto, Osamu, Fujii, Masahiro, Ohgami, Tetsuro, Fujiyasu, Jiro, Kontani, Toru, Moritomo, Ayako, Orita, Masaya, Kurihara, Hiroyuki, Koga, Hironobu, Kageyama, Shunji, Ohta, Mitsuaki, Inoue, Hiroshi, Hatta, Toshifumi, Shintani, Masafumi, Suzuki, Hiroshi, Sudo, Kenji, Shimizu, Yasuaki, Kodama, Eiichi, Matsuoka, Masao, Fujiwara, Masatoshi, Yokota, Tomoyuki, Shigeta, Shiro, Baba, Masanori
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.02.2005; Elsevier Science
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Cell Line; HIV-1 - drug effects; Humans; Magnetic Resonance Spectroscopy; Medical sciences; Microbial Sensitivity Tests; Non-nucleoside HIV-1 reverse transcriptase inhibitor; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Spectrometry, Mass, Fast Atom Bombardment; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thiazolidenebenzenesulfonamide; YM-215389; YM-215389; Thiazolidenebenzenesulfonamide; Non-nucleoside HIV-1 reverse transcriptase inhibitor; Sulfur nitrogen heterocycle; Nitrile; RNA-directed DNA polymerase; Sulfonamide; HIV-1 virus; Enzyme; Transferases; Non nucleoside compound; Thiazole derivatives; Benzene derivatives; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Virus; Nucleotidyltransferases; Structure activity relation; Chlorine Organic compounds; Reverse transcriptase inhibitor; Antiviral; Bromine Organic compounds; Human immunodeficiency virus; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2004.11.045

A series of thiazolidenebenzenesulfonamides was prepared and evaluated for their inhibitory effects on the WT, Y181C, and K103N reverse transcriptase (RT) activity and HIV-1 replication. The cyano derivatives 10l and 18b (YM-228855) showed extremely potent anti-HIV-1 activity. Compound 11g (YM-215389) showed the most potent activity against the WT and the two mutant RTs. Furthermore, this compound was also a highly potent inhibitor of HIV-1 replication. 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 EC 50 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 IC 50 values of 0.043 and 0.013 μM, respectively.