2. Academic Validation
  3. Design, synthesis and biological evaluation of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives as HIV-1 NNRTIs

Design, synthesis and biological evaluation of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives as HIV-1 NNRTIs

  • Bioorg Med Chem. 2013 Nov 15;21(22):7091-100. doi: 10.1016/j.bmc.2013.09.009.
Wenmin Chen 1,  Peng Zhan,  Erik De Clercq,  Christophe Pannecouque,  Jan Balzarini,  Xin Jiang,  Xinyong Liu
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44, West Culture Road, 250012 Jinan, Shandong, PR China.
PMID: 24119448 DOI: 10.1016/j.bmc.2013.09.009
Abstract

A series of N2,N4-disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine derivatives (PTTDs) was designed and synthesized by a facile route. The biological assay results showed that five most potent compounds displayed inhibitory activity against HIV-1 at low micromolar concentrations (EC50=5.1-8.9 μM). Structure-activity relationship analysis indicated that N2-(3-halogenated-benzyl) analogues were more potent than N2-(unsubstituted-benzyl) analogues. The N4-substitutions contributed to the Antiviral activity in the following order: 2-/3-cyano substituted benzyl > 2-/3-halogenated benzyl > non-substituted benzyl > 4-halogenated benzyl. Docking studies of the representative compound revealed the binding conformation of these compounds and provided critical insights for the further development of PTTD analogues.

Keywords

Drug design; HIV; Heterocycle; NNRTIs; Pyrrolothiatriazine; Reverse transcriptase; Thienothiadiazine.

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