Structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives for potent anti-HIV agents.

Abstract

3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is an antiretroviral agent with submicromolar inhibitory activity against human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. In the current study, the structure-activity relationships of accessory groups at the 3- and 9-positions of pyrimido[1,2-c][1,3]benzothiazin-6-imine were investigated for the development of more potent anti-HIV agents. Several different derivatives containing a 9-aryl group were designed and synthesized using Suzuki-Miyaura cross-coupling and Ullmann coupling reactions. Modification of the m-methoxyphenyl or benzo[d][1,3]dioxol-5-yl group resulted in improved anti-HIV activity. In addition, the 2,4-diazaspiro[5.5]undec-2-ene-fused benzo[e][1,3]thiazine derivatives were designed and tested for their anti-HIV activities. The most potent 9-(benzo[d][1,3]dioxol-5-yl) derivative was two-threefold more effective against several strains of HIV-1 and HIV-2 than the parent compound, PD 404182.

• Authors: Tsukasa Mizuhara, Shinya Oishi, Hiroaki Ohno, Kazuya Shimura, Masao Matsuoka, Nobutaka Fujii
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 20 Issue 21 Pg. 6434-41 (Nov 01 2012) ISSN: 1464-3391 [Electronic] England
• PMID: 23022280 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Anti-HIV Agents
• Imines
• Pyrimidines
• pyrimido(1,2-c)(1,3)benzothiazin-6-imine

Topics

• Anti-HIV Agents (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• HIV-1 (drug effects)
• HeLa Cells
• Humans
• Imines (chemical synthesis, chemistry, pharmacology)
• Microbial Sensitivity Tests
• Molecular Structure
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship