title: Synthesis and biological evaluation of 6-substituted 5-alkyl-2-(phenylaminocarbonylmethylthio)pyrimidin-4(3H)-ones as potent HIV-1 NNRTIs.
abstract: A series of new 5-alkyl-2-phenylaminocarbonylmethylthiopyrimidin-4(3H)-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 μM. Among them, 2-[(4-cyanophenylamino)carbonylmethylthio]-6-(2-chloro-6-fluorobenzyl)-5-ethylpyrimidin-4(3H)-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 μM against the wild-type virus, 1.05±0.24 μM (twofold resistance) against the E138K strain, and 2.38±0.13 μM (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.
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, PR China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Yu
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.forename: Erkang
authors.initials: E
authors.lastname: Fan
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Xinyong
authors.initials: X
authors.lastname: Liu
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002460:Cell Line; D003198:Computer Simulation; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C560345:2-((4-cyanophenylamino)carbonylmethylthio)-6-(2-chloro-6-fluorobenzyl)-5-ethylpyrimidin-4(3H)-one; D019380:Anti-HIV Agents; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase