title: Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines: novel non-nucleoside reverse transcriptase inhibitors of the S-DABO series.
abstract: Novel compounds related to 2-(cyclohexylthio)-3,4-dihydro-5-methyl-6-(3-methylbenzyl)-4-ox opyrimidine (3c, MC 639) have been synthesized and tested as inhibitors of human immunodeficiency virus type-1 (HIV-1). Reaction of thiourea with ethyl arylmethylacetoacetates furnished 5-alkyl-6-(arylmethyl)-3,4-dihydro-2-mercapto-4-oxopyrimidines which were then alkylated at the sulfur atom to afford the required 2-alkylthio or 2-cycloalkylthio derivatives (S-DABOs). Chemical modifications at N-3, C-4, and C-6 of the pyrimidine ring were attempted with the aim of improving antiretroviral activity. In particular, replacement of the benzyl group with the 1-naphthylmethyl moiety enhanced the activity of S-DABOs, whereas N-3 alkylation and C=O transformation into C=S at position 4 of the pyrimidine ring led to compounds devoid of anti-HIV-1 activity. Lower activity was generally observed when 1-naphthylmethyl was replaced by the isomeric 2-naphthylmethyl moiety. The most active compounds showed activity in the low micromolar range with EC50 values comparable to that of nevirapine.
authors.affiliation: Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mai
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: G
authors.initials: G
authors.lastname: Sbardella
authors.forename: S
authors.initials: S
authors.lastname: Quartarone
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: A G
authors.initials: AG
authors.lastname: Loi
authors.forename: A
authors.initials: A
authors.lastname: De Montis
authors.forename: F
authors.initials: F
authors.lastname: Scintu
authors.forename: M
authors.initials: M
authors.lastname: Putzolu
authors.forename: P
authors.initials: P
authors.lastname: La Colla
mesh_terms: D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase