Design, Synthesis and X‐Ray Structural Studies of Potent HIV‐1 Protease Inhibitors Containing C‐4 Substituted Tricyclic Hexahydro‐Furofuran Derivatives as P2 Ligands

Ghosh, Arun K.; Kovela, Satish; Sharma, Ashish; Shahabi, Dana; Ghosh, Ajay K.; Hopkins, Denver R.; Yadav, Monika; Johnson, Megan E.; Agniswamy, Johnson; Wang, Yuan‐Fang; Hattori, Shin‐Ichiro; Higashi‐Kuwata, Nobuyo; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

doi:10.1002/cmdc.202200058

Design, Synthesis and X‐Ray Structural Studies of Potent HIV‐1 Protease Inhibitors Containing C‐4 Substituted Tricyclic Hexahydro‐Furofuran Derivatives as P2 Ligands

Journal Article · Fri Mar 04 00:00:00 EST 2022 · ChemMedChem

DOI:https://doi.org/10.1002/cmdc.202200058· OSTI ID:1847444

^[1]; Kovela, Satish ^[1]; Sharma, Ashish ^[1]; Shahabi, Dana ^[1]; Ghosh, Ajay K. ^[1]; Hopkins, Denver R. ^[1]; Yadav, Monika ^[1]; Johnson, Megan E. ^[1]; Agniswamy, Johnson ^[2]; Wang, Yuan‐Fang ^[2]; Hattori, Shin‐Ichiro ^[3]; Higashi‐Kuwata, Nobuyo ^[3]; Aoki, Manabu ^[4]; Amano, Masayuki ^[4]; Weber, Irene T. ^[2]; Mitsuya, Hiroaki ^[5]

Department of Chemistry and Department of Medicinal Chemistry Purdue University West Lafayette IN 47907 USA
Departments of Biology and Chemistry Molecular Basis of Disease Georgia State University Atlanta GA 30303 USA
Department of Refractory Viral Infections National Center for Global Health &, Medicine Research Institute Shinjuku Tokyo 162-8655 Japan
Departments of Hematology and Infectious Diseases School of Medicine Kumamoto University Kumamoto 860-8556 Japan
Departments of Hematology and Infectious Diseases School of Medicine Kumamoto University Kumamoto 860-8556 Japan, Experimental Retrovirology Section HIV and AIDS Malignancy Branch National Cancer Institute Bethesda MD 20892 USA, Center for Clinical Sciences National Center for Global Health and Medicine Shinjuku Tokyo 162-8655 Japan, Department of Refractory Viral Infections National Center for Global Health and Medicine Shinjuku Tokyo 162-8655 Japan

Abstract

The design, synthesis, X‐ray structural, and biological evaluation of a series of highly potent HIV‐1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane‐fused tricyclic bis ‐tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2′ ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2′ ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug‐resistant HIV‐1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso ‐diols as the key step. To obtain molecular insight, two high‐resolution X‐ray structures of inhibitor‐bound HIV‐1 protease were determined and structural analyses have been highlighted.

View Accepted Manuscript (Publisher)

Sponsoring Organization:: USDOE

OSTI ID:: 1847444

Alternate ID(s):: OSTI ID: 1867472

Journal Information:: ChemMedChem, Journal Name: ChemMedChem Journal Issue: 9 Vol. 17; ISSN 1860-7179

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: France

Language:: English

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