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Synthesis and Biological Evaluation of 6‐Substituted 5‐Alkyl‐2‐(phenylaminocarbonylmethylthio)pyrimidin‐4(3 H )‐ones as Potent HIV‐1 NNRTIs
Author(s) -
Yu Mingyan,
Li Zhenyu,
Liu Shuai,
Fan Erkang,
Pannecouque Christophe,
De Clercq Erik,
Liu Xinyong
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000555
Subject(s) - pyrimidine , stereochemistry , reverse transcriptase , alkyl , chemistry , strain (injury) , structure–activity relationship , human immunodeficiency virus (hiv) , virus , ring (chemistry) , nucleoside , broad spectrum , biology , in vitro , virology , biochemistry , combinatorial chemistry , rna , organic chemistry , gene , anatomy
A series of new 5‐alkyl‐2‐phenylaminocarbonylmethylthiopyrimidin‐4(3 H )‐ones bearing variously substituted arylmethyl moieties at the C6 position of the pyrimidine ring were synthesized and evaluated for anti‐HIV activity in MT‐4 cells. Most of these new congeners exhibited moderate to good activities against the wild‐type virus, with EC 50 values in the range of 1.40–0.19 μ M . Among them, 2‐[(4‐cyanophenylamino)carbonylmethylthio]‐6‐(2‐chloro‐6‐fluorobenzyl)‐5‐ethylpyrimidin‐4(3 H )‐one 4 b6 is one of the compounds endowed with the highest broad‐spectrum HIV‐1 inhibitory activity, with EC 50 values of 0.19±0.005 μ M against the wild‐type virus, 1.05±0.24 μ M (twofold resistance) against the E138K strain, and 2.38±0.13 μ M (4.5‐fold resistance) against the Y181C strain. Furthermore, reverse transcriptase (RT) inhibition assays against wild‐type HIV‐1 RT were performed with selected derivatives, confirming that the main target of these compounds is HIV‐1 RT and that these new S ‐DABO analogues act as non‐nucleoside RT inhibitors (NNRTIs). Structure–activity relationship and molecular modeling analyses of these new congeners are also discussed.