title: Design and synthesis of novel inhibitors of HIV-1 reverse transcriptase.
abstract: A variety of N1-substituted pyrimido[5,4-f]benzo[1,4]thiazepines, 5, designed as conformationally constrained analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymidine HEPT (1), were synthesized and evaluated for their inhibition of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). The preparation of these compounds was carried out based on a Mannich-type cyclization of 6-[(2-aminophenyl)thio]uracils followed by alkylation at N1 by a one-pot Vorbruggen reaction. The pyrimidobenzothiazepines were developed to give molecules with IC50 values in the micromolar range, as exemplified by [[(2-ethoxyethyl)oxy]methyl]-pyrimido[5,4- f]benzo[1,4]thiazepine, 25, (IC50 = 0.64 microM), the most active compound of this series. The structural and electronic features of this novel class of HIV-1 RT inhibitors are presented and compared with those of HEPT (1), TIBO (2), and nevirapine (3).
authors.affiliation: Chemistry Department, State University of New York at Stony Brook 11794-3400, USA.
authors.forename: H
authors.initials: H
authors.lastname: Maruenda
authors.forename: F
authors.initials: F
authors.lastname: Johnson
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000201:enzymology*; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018894:Reverse Transcriptase Inhibitors; D013841:Thiazepines; D054303:HIV Reverse Transcriptase