Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands

Journal Article · · Bioorganic and Medicinal Chemistry Letters
 [1];  [1];  [1];  [1];  [1];  [2];  [2];  [3];  [3];  [2];  [4]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Georgia State Univ., Atlanta, GA (United States)
  3. Kumamoto Univ. of Medicine (Japan)
  4. Kumamoto Univ. of Medicine (Japan); National Cancer Inst., Bethesda, MD (United States); National Center for Global Health and Medicine, Tokyo (Japan)
+ Show Author Affiliations
We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2–P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2–P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11 Å resolution. Lastly, this structure revealed important molecular insight into the inhibitor–HIV-1 protease interactions in the active site.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
W-31109-ENG-38
OSTI ID:
1224016
Alternate ID(s):
OSTI ID: 1250394
Journal Information:
Bioorganic and Medicinal Chemistry Letters, Journal Name: Bioorganic and Medicinal Chemistry Letters Journal Issue: 21 Vol. 25; ISSN 0960-894X
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (32)

Darunavir, a New PI with Dual Mechanism: From a Novel Drug Design Concept to New Hope against Drug-Resistant HIV book January 2010
Enhancing Protein Backbone Binding-A Fruitful Concept for Combating Drug-Resistant HIV journal January 2012
Bis-Tetrahydrofuran: a Privileged Ligand for Darunavir and a New Generation of HIV Protease Inhibitors That Combat Drug Resistance journal September 2006
Probing Multidrug-Resistance and Protein-Ligand Interactions with Oxatricyclic Designed Ligands in HIV-1 Protease Inhibitors journal September 2010
Structural implications of drug-resistant mutants of HIV-1 protease: High-resolution crystal structures of the mutant protease/substrate analogue complexes journal January 2001
Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV journal December 2007
Potent memapsin 2 (β-secretase) inhibitors: Design, synthesis, protein-ligand X-ray structure, and in vivo evaluation journal February 2008
High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical Strains journal April 2004
Molecular Analysis of the HIV-1 Resistance Development: Enzymatic Activities, Crystal Structures, and Thermodynamics of Nelfinavir-resistant HIV Protease Mutants journal December 2007
Design and Synthesis of Hydroxyethylene-Based Peptidomimetic Inhibitors of Human β-Secretase journal January 2004
Structure-Based Design:  Synthesis and Biological Evaluation of a Series of Novel Cycloamide-Derived HIV-1 Protease Inhibitors journal May 2005
Structure-Based Design of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance journal August 2006
Design, Synthesis, and X-ray Structure of Potent Memapsin 2 (β-Secretase) Inhibitors with Isophthalamide Derivatives as the P 2 - P 3 -Ligands journal May 2007
Design and Synthesis of Potent HIV-1 Protease Inhibitors Incorporating Hexahydrofuropyranol-Derived High Affinity P 2 Ligands: Structure−Activity Studies and Biological Evaluation journal January 2011
Flexible Cyclic Ethers/Polyethers as Novel P2-Ligands for HIV-1 Protease Inhibitors: Design, Synthesis, Biological Evaluation, and Protein−Ligand X-ray Studies journal September 2008
Harnessing Nature’s Insight: Design of Aspartyl Protease Inhibitors from Treatment of Drug-Resistant HIV to Alzheimer’s Disease † journal April 2009
Transition-metal-catalyzed asymmetric organic synthesis via polymer-attached optically active phosphine ligands. 5. Preparation of amino acids in high optical yield via catalytic hydrogenation journal July 1981
Design and synthesis of potent macrocyclic HIV-1 protease inhibitors involving P1–P2 ligands journal January 2014
Prevention of HIV-1 Infection with Early Antiretroviral Therapy journal August 2011
Calcium Borohydride: A Reagent for Facile Conversion of Carboxylic Esters to Alcohols and Aldehydes journal June 1995
Long-Term Effectiveness of Highly Active Antiretroviral Therapy on the Survival of Children and Adolescents with HIV Infection: A 10-Year Follow-Up Study journal February 2008
Emergence of Drug Resistance in HIV Type 1–Infected Patients after Receipt of First‐Line Highly Active Antiretroviral Therapy: A Systematic Review of Clinical Trials journal September 2008
Improvements in antiretroviral therapy outcomes over calendar time journal January 2009
MOLREP an Automated Program for Molecular Replacement journal December 1997
A short history of SHELX journal December 2007
PRODRG : a tool for high-throughput crystallography of protein–ligand complexes journal July 2004
Overview of the CCP 4 suite and current developments journal March 2011
A simple, continuous fluorometric assay for HIV protease journal December 1990
Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro journal September 2003
Demonstration of Sustained Drug-Resistant Human Immunodeficiency Virus Type 1 Lineages Circulating among Treatment-Naive Individuals journal January 2009
HAART in treatment-experienced patients in the 21st century: the audacity of hope journal January 2009
Thirty Years of HIV and AIDS: Future Challenges and Opportunities journal June 2011

Cited By (6)

A fission yeast cell-based system for multidrug resistant HIV-1 proteases journal January 2017
Synthesis and Biological Evaluation of New Multifunctional Oxazolone Scaffolds Incorporating Phenyl Benzoate Moiety: Synthesis and Biological Evaluation of New Multifunctional Oxazolone Scaffolds Incorporating Phenyl Benzoate Moiety journal March 2018
Development of methodologies for the regioselective synthesis of four series of regioisomer isoxazoles from β-enamino diketones journal January 2018
Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents journal November 2019
Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents text January 2019
Amide derivatives of 4-azaindole: Design, synthesis, and EGFR targeting anticancer agents text January 2019

Similar Records

Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex
Journal Article · Sat Apr 08 20:00:00 EDT 2017 · Bioorganic and Medicinal Chemistry · OSTI ID:1418041
Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir
Journal Article · Sun Nov 05 19:00:00 EST 2017 · ChemMedChem · OSTI ID:1422231
Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands
Journal Article · Tue Sep 05 20:00:00 EDT 2017 · Bioorganic and Medicinal Chemistry Letters · OSTI ID:1409115

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV-1 protease
antiviral
design
inhibitors
isophthalamide
synthesis