Studies of non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 2: synthesis and structure-activity relationships of 2-cyano and 2-hydroxy thiazolidenebenzenesulfonamide derivatives.
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.
Masuda
Naoyuki
N
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. masuda.naoyuki@yamanouchi.co.jp
Yamamoto
Osamu
O
Fujii
Masahiro
M
Ohgami
Tetsuro
T
Fujiyasu
Jiro
J
Kontani
Toru
T
Moritomo
Ayako
A
Orita
Masaya
M
Kurihara
Hiroyuki
H
Koga
Hironobu
H
Kageyama
Shunji
S
Ohta
Mitsuaki
M
Inoue
Hiroshi
H
Hatta
Toshifumi
T
Shintani
Masafumi
M
Suzuki
Hiroshi
H
Sudo
Kenji
K
Shimizu
Yasuaki
Y
Kodama
Eiichi
E
Matsuoka
Masao
M
Fujiwara
Masatoshi
M
Yokota
Tomoyuki
T
Shigeta
Shiro
S
Baba
Masanori
M
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*
D018894:Reverse Transcriptase Inhibitors; D013449:Sulfonamides