title: Nonnucleoside HIV-1 reverse transcriptase inhibitors: Part I. Synthesis and structure-activity relationship of 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils as HEPT analogues.
abstract: 1-alkoxymethyl-5-alkyl-6-naphthylmethyl uracils, which are novel 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) analogues, were synthesized for evaluation as selective and potent nonnucleoside human immunodeficiency virus (HIV)-1 reverse transcriptase inhibitors. The anti-HIV-1 activity of these compounds was assayed in vitro using HIV-1 infected MT-4 and CEM bioassays. The EC50, CC50 and SI were recorded and calculated. The appropriate position, especially in the 1-position of the naphthyl ring, led to dramatic increases in potency, in both MT-4 and CEM cellular assays. The most important compounds in this series, 1-ethoxymethyl-5-isopropyl-6-(1-naphthylmethyl)thymine 8l (IC50=17 nM, CC50=38332 nM, SI=2229) and 1-benzyloxymethyl-5-ethyl-6-(1-naphthylmethyl)thymine 8n (IC50=17 nM, CC50=32560 nM, SI=1889) were significantly more potent than HEPT (EC50=7.0 microM, CD50=740 microM) in the anti-HIV-1 in vitro cellular assay.
authors.affiliation: Department of Chemistry, Fudan University, Shanghai, PR China.
authors.forename: Ge
authors.initials: G
authors.lastname: Meng
authors.forename: Fen-Er
authors.initials: FE
authors.lastname: Chen
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
mesh_terms: D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014498:Uracil / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D018894:Reverse Transcriptase Inhibitors; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; D014498:Uracil; D054303:HIV Reverse Transcriptase; D013941:Thymine