title: Investigations of possible prodrug structures for 2-(2-mercaptophenyl)tetrahydropyrimidines: reductive conversion from anti-HIV agents with pyrimidobenzothiazine and isothiazolopyrimidine scaffolds.
abstract: 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) and 3,4-dihydro-2H-benzo[4,5]isothiazolo[2,3-a]pyrimidine are the heterocyclic antiretroviral agents against human immunodeficiency virus type 1 (HIV-1) infection. On the basis of similar structure-activity relationships of anti-HIV activities toward the early-stage of viral infection between these unique scaffolds, the transformations under the bioassay conditions were investigated. The distinctive S-N bond in the isothiazolopyrimidine scaffold was immediately cleaved under reductive conditions in the presence of GSH to generate a thiophenol derivative. A similar rapid conversion of PD 404182 into the same thiophenol derivative was observed, suggesting that pyrimidobenzothiazine and isothiazolopyrimidine scaffolds may work as prodrug forms of the common bioactive thiophenol derivatives.
authors: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. soishi@pharm.kyoto-u.ac.jp nfujii@pharm.kyoto-u.ac.jp.
authors: Shiho
authors: S
authors: Okazaki
authors: Shinya
authors: S
authors: Oishi
authors: Tsukasa
authors: T
authors: Mizuhara
authors: Kazuya
authors: K
authors: Shimura
authors: Hiroto
authors: H
authors: Murayama
authors: Hiroaki
authors: H
authors: Ohno
authors: Masao
authors: M
authors: Matsuoka
authors: Nobutaka
authors: N
authors: Fujii
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D001581:Benzothiadiazines / Q000737:chemistry; D002626:Chemistry, Pharmaceutical; D015195:Drug Design; D005978:Glutathione / Q000737:chemistry; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007097:Imines / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D009584:Nitrogen / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry; D013843:Thiazines / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry
chemical_list: C586214:6H-6-imino-(2,3,4,5-tetrahydropyrimido)(1,2-c)-(1,3)benzothiazine; D019380:Anti-HIV Agents; D001581:Benzothiadiazines; D007097:Imines; D011355:Prodrugs; D011743:Pyrimidines; D013843:Thiazines; D013844:Thiazoles; D013455:Sulfur; D005978:Glutathione; D009584:Nitrogen