title: Synthesis and anti-HIV-1 integrase activities of 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines.
abstract: A series of novel 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines 15-28 as potential HIV-1 integrase (IN) inhibitors have been synthesized by the reduction of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines 1-14 with benzenesulfonyl hydrazide. All the compounds 15-28 inhibited IN mediated strand transfer reaction with IC(50) values ranging from 3 to 30 microM. The 3-(4-bromobenzoyl)-6-chloro-7-methyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazine 17 with the IC(50) values of 4+/-1 and 3+/-1 microM for 3'-processing and strand transfer, respectively, was the most potent. Compound 17 as well its analogues were 5-20-fold less potent in Y99S and H114A mutants, implicating these residues as potential drug-binding site. This is a first report implicating Y99S and H114A of IN core domain in drug-binding interactions.
authors.affiliation: Department of Chemical Technology of Drugs, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland.
authors.forename: Zdzisław
authors.initials: Z
authors.lastname: Brzozowski
authors.forename: Franciszek
authors.initials: F
authors.lastname: Saczewski
authors.forename: Jarosław
authors.initials: J
authors.lastname: Sławiński
authors.forename: Tino
authors.initials: T
authors.lastname: Sanchez
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D019427:HIV Integrase / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D020125:Mutation, Missense; D013843:Thiazines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D001555:Benzene Derivatives; D019428:HIV Integrase Inhibitors; D013843:Thiazines; D019427:HIV Integrase