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: Shiho Okazaki, Shinya Oishi, Tsukasa Mizuhara, Kazuya Shimura, Hiroto Murayama, Hiroaki Ohno, Masao Matsuoka, Nobutaka Fujii
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 13 Issue 16 Pg. 4706-13 (Apr 28 2015) ISSN: 1477-0539 [Electronic] England
• PMID: 25800792 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 6H-6-imino-(2,3,4,5-tetrahydropyrimido)(1,2-c)-(1,3)benzothiazine
• Anti-HIV Agents
• Benzothiadiazines
• Imines
• Prodrugs
• Pyrimidines
• Thiazines
• Thiazoles
• Sulfur
• Glutathione
• Nitrogen

Topics

• Anti-HIV Agents (chemistry)
• Benzothiadiazines (chemistry)
• Chemistry, Pharmaceutical
• Drug Design
• Glutathione (chemistry)
• HIV Infections (drug therapy)
• HIV-1 (drug effects)
• Humans
• Imines (chemistry)
• Magnetic Resonance Spectroscopy
• Nitrogen (chemistry)
• Prodrugs (chemistry)
• Pyrimidines (chemistry)
• Structure-Activity Relationship
• Sulfur (chemistry)
• Thiazines (chemistry)
• Thiazoles (chemistry)