Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

Ghosh, Arun K.; Jadhav, Ravindra D.; Simpson, Hannah; Kovela, Satish; Osswald, Heather; Agniswamy, Johnson; Wang, Yuan-Fang; Hattori, Shin-ichiro; Weber, Irene T.; Mitsuya, Hiroaki

doi:10.1016/j.ejmech.2018.09.046

Title: Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

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Abstract

We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.

Authors:

^[1]; Jadhav, Ravindra D. ^[1]; Simpson, Hannah ^[1]; Kovela, Satish ^[1]; Osswald, Heather ^[1]; Agniswamy, Johnson ^[2]; Wang, Yuan-Fang ^[2]; Hattori, Shin-ichiro ^[3]; Weber, Irene T. ^[2]; Mitsuya, Hiroaki ^[4]

Purdue Univ., West Lafayette, IN (United States)
Georgia State Univ., Atlanta, GA (United States)
National Center for Global Health & Medicine Research Inst., Tokyo (Japan)
National Center for Global Health & Medicine Research Inst., Tokyo (Japan); Kumamoto University Graduate School of Medical and Pharmaceutical Sciences (Japan); National Inst. of Health (NIH), Bethesda, MD (United States)

Publication Date:: 2018-09-18

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States)

Sponsoring Org.:: USDOE Office of Science (SC); National Inst. of Health

OSTI Identifier:: 1482242

Grant/Contract Number:: GM53386; GM62920

Resource Type:: Accepted Manuscript

Journal Name:: European Journal of Medicinal Chemistry

Additional Journal Information:: Journal Volume: 160; Journal Issue: C; Journal ID: ISSN 0223-5234

Publisher:: Elsevier

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; HIV-1 protease inhibitors; P2 ligand; drug resistance; design and synthesis; X-ray crystal structure

Citation Formats


                    Ghosh, Arun K., Jadhav, Ravindra D., Simpson, Hannah, Kovela, Satish, Osswald, Heather, Agniswamy, Johnson, Wang, Yuan-Fang, Hattori, Shin-ichiro, Weber, Irene T., and Mitsuya, Hiroaki. Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands.  United States: N. p., 2018. 
Web.  doi:10.1016/j.ejmech.2018.09.046.

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                    Ghosh, Arun K., Jadhav, Ravindra D., Simpson, Hannah, Kovela, Satish, Osswald, Heather, Agniswamy, Johnson, Wang, Yuan-Fang, Hattori, Shin-ichiro, Weber, Irene T., & Mitsuya, Hiroaki. Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands.  United States.  https://doi.org/10.1016/j.ejmech.2018.09.046

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                    Ghosh, Arun K., Jadhav, Ravindra D., Simpson, Hannah, Kovela, Satish, Osswald, Heather, Agniswamy, Johnson, Wang, Yuan-Fang, Hattori, Shin-ichiro, Weber, Irene T., and Mitsuya, Hiroaki. Tue .  
"Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands".  United States.  https://doi.org/10.1016/j.ejmech.2018.09.046.  https://www.osti.gov/servlets/purl/1482242.

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@article{osti_1482242,

  title        = {Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands},

  author       = {Ghosh, Arun K. and Jadhav, Ravindra D. and Simpson, Hannah and Kovela, Satish and Osswald, Heather and Agniswamy, Johnson and Wang, Yuan-Fang and Hattori, Shin-ichiro and Weber, Irene T. and Mitsuya, Hiroaki},

  abstractNote = {We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.},

  doi          = {10.1016/j.ejmech.2018.09.046},

  journal      = {European Journal of Medicinal Chemistry},

  number       = C,

  volume       = 160,

  place        = {United States},

  year         = {2018},

  month        = {9}

}

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