title: Synthesis and antiviral activity of 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) as potent and selective anti-HIV-1 agents.
abstract: Several 6-benzyl analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (1; HEPT) were synthesized and evaluated for their anti-HIV-1 activity. LDA (lithium diisopropylamide) lithiation of 5-ethyluracil derivatives 7 and 8 and subsequent reaction with an aryl aldehyde gave 6-(arylhydroxymethyl)-5-ethyluracil derivatives 9-12. 6-(Arylhydroxymethyl)-5-isopropyluracil derivatives 15-18 were prepared from the 5-isopropyl-2-thiouracil derivatives 13 and 14 by the above procedure following oxidative hydrolysis of the thione. Preparation of the target 5-alkyl-1-(alkoxymethyl)-6-benzyluracil derivatives 27-34 was carried out by acetylation of 9-14 followed by Pd-catalyzed hydrogenolysis. The 1-butyl- (37 and 39) and 1-(2-methoxyl)- (38 and 40) 5-alkyl-6-benzyluracils were synthesized by 1-alkylation of the 3-phenacyl derivatives 35 and 36 with alkyl halides followed by deprotection of the 3-phenacyl group. Compounds synthesized in this study inhibited HIV-1 replication in MT-4 cells in the submicromolar to namomolar concentration range. From this series of compounds, 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil (33) was selected for clinical evaluation.
authors.affiliation: School of Pharmaceutical Science, Showa University, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: H
authors.initials: H
authors.lastname: Takashima
authors.forename: M
authors.initials: M
authors.lastname: Ubasawa
authors.forename: K
authors.initials: K
authors.lastname: Sekiya
authors.forename: N
authors.initials: N
authors.lastname: Inouye
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: S
authors.initials: S
authors.lastname: Shigeta
authors.forename: R T
authors.initials: RT
authors.lastname: Walker
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: T
authors.initials: T
authors.lastname: Miyasaka
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D001593:Benzyl Compounds; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; D013941:Thymine