Synthesis and anti-HIV-1 integrase activities of 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines

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 IC50 values ranging from 3 to 30 μM. The 3-(4-bromobenzoyl)-6-chloro-7-methyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazine 17 with the IC50 values of 4 ± 1 and 3 ± 1 μM 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.

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