title: Concise synthesis and anti-HIV activity of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles.
abstract: 3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is a virucidal heterocyclic compound active against various viruses, including HCV, HIV, and simian immunodeficiency virus. Using facile synthetic approaches that we developed for the synthesis of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic derivatives, the parallel structural optimizations of the central 1,3-thiazin-2-imine core, the benzene part, and the cyclic amidine part of PD 404182 were investigated. Replacement of the 6-6-6 pyrimido[1,2-c][1,3]benzothiazin-6-imine framework with 5-6-6 or 6-6-5 derivatives led to a significant loss of anti-HIV activity, and introduction of a hydrophobic group at the 9- or 10-positions improved the potency. In addition, we demonstrated that the PD 404182 derivative exerts anti-HIV effects at an early stage of viral infection.
authors: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Japan.
authors: Tsukasa
authors: T
authors: Mizuhara
authors: Shinya
authors: S
authors: Oishi
authors: Hiroaki
authors: H
authors: Ohno
authors: Kazuya
authors: K
authors: Shimura
authors: Masao
authors: M
authors: Matsuoka
authors: Nobutaka
authors: N
authors: Fujii
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013843:Thiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D007097:Imines; D011743:Pyrimidines; D013843:Thiazines