title: The design and synthesis of N-1-alkylated-5-aminoarylalkylsubstituted-6-methyluracils as potential non-nucleoside HIV-1 RT inhibitors.
abstract: Novel compounds 1a-u, which can be considered as hybrid analogues of MKC-442 and pyridinon, have been synthesized and evaluated as inhibitors of HIV-1 reverse transcriptase (HIV-1 RT). Starting from 6-methyluracil 2, 1-alkylated-5-bromomethyl-6-methyluracils 8 was prepared in four steps by hydroxymethylation, etherification, N-1 alkylation, and bromination. Finally, compounds 1a-u were achieved in the displacement of 5-bromomethyl group by nucleophiles with amino compounds. Some of compounds 1a-u showed potent inhibitory activity against HIV-1 RT. The most active compounds showed activity in the low micromolecular range with IC(50) values (IC(50) 0.82-5.09 microM) comparable to that of nevirapine (IC(50) 10.60 microM). The biological testing results are in accordance with the docking.
authors.affiliation: Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100083, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.forename: Yanli
authors.initials: Y
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Guo
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Liu
authors.forename: Yawei
authors.initials: Y
authors.lastname: Shi
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Zhili
authors.initials: Z
authors.lastname: Zhang
authors.forename: Junyi
authors.initials: J
authors.lastname: Liu
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; C008378:6-methyluracil; D054303:HIV Reverse Transcriptase