title: Synthesis and evaluation of novel 3-(3,5-dimethylbenzyl)uracil analogs as potential anti-HIV-1 agents.
abstract: A novel series of uracil derivatives with a 3,5-dimethylbenzyl group at the N(3)-position were synthesized and evaluated as non-nucleoside HIV-1 reverse transcriptase inhibitors. Some of these compounds showed good-to-moderate activity with EC50 values in the submicromolar range. Among them, compound 10c showed significant potency against HIV-1 activity with an EC50 value of 0.03 μM and a high selectivity index of 2863. Preliminary structure-activity relationships and molecular modeling analyses were used to explore the major interactions between HIV-1 reverse transcriptase and the potent inhibitor 10c, which may serve as an important lead for further optimization.
authors.affiliation: Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki City, Japan.
authors.forename: Norikazu
authors.initials: N
authors.lastname: Sakakibara
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hamasaki
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Demizu
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
authors.forename: Kohji
authors.initials: K
authors.lastname: Irie
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Iwai
authors.forename: Eriko
authors.initials: E
authors.lastname: Asada
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kato
authors.forename: Tokumi
authors.initials: T
authors.lastname: Maruyama
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D056004:Molecular Dynamics Simulation; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C527156:3-(3,5-dimethylbenzyl)uracil; C587144:6-amino-3-(3,5-dimethylbenzyl)-1-(4-picolyl)uracil; D010848:Picolinic Acids; D018894:Reverse Transcriptase Inhibitors; D014498:Uracil; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Anti-HIV-1 agents; HIV-1 RT; Molecular modeling analysis; NNRTIs; Uracil analogs