Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2-ligand: Structure-activity studies and biological evaluation
- PMID: 28554091
- DOI: 10.1016/j.ejmech.2017.05.024
Design and synthesis of potent HIV-1 protease inhibitors with (S)-tetrahydrofuran-tertiary amine-acetamide as P2-ligand: Structure-activity studies and biological evaluation
Abstract
The design, synthesis, and SAR study of a new series of HIV-1 protease inhibitors incorporating stereochemically defined tetrahydrofuran-tertiary amine-acetamide P2-ligand are described. Various substituent effects on the tertiary amine P2-ligand and phenylsulfonamide P2'-ligand were investigated to maximize the ligand-binding site interactions in the protease active site. Most of inhibitors displayed low nanomolar to subnanomolar inhibitory potency. Inhibitor 20e containing N-(S-tetrahydrofuran)-N-(2-methoxyethyl)acetamide as P2-ligand along with 4-methoxylphenylsulfonamide as P2'-ligand displayed the most potent enzyme inhibitory activity (IC50 = 0.35 nM) and remarkably low cytotoxicity (CC50 = 305 μM).
Keywords: Design; Enzyme; HIV-1 protease; Inhibitors; P2 ligand.
Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Similar articles
-
Synthesis and biological evaluation of novel HIV-1 protease inhibitors using tertiary amine as P2-ligands.Bioorg Med Chem Lett. 2015 May 1;25(9):1880-3. doi: 10.1016/j.bmcl.2015.03.047. Epub 2015 Mar 24. Bioorg Med Chem Lett. 2015. PMID: 25838144
-
Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants.Eur J Med Chem. 2020 Jan 1;185:111866. doi: 10.1016/j.ejmech.2019.111866. Epub 2019 Nov 9. Eur J Med Chem. 2020. PMID: 31734023
-
Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies.J Med Chem. 2020 May 14;63(9):4867-4879. doi: 10.1021/acs.jmedchem.0c00202. Epub 2020 Apr 29. J Med Chem. 2020. PMID: 32348139 Free PMC article.
-
Design of HIV protease inhibitors targeting protein backbone: an effective strategy for combating drug resistance.Acc Chem Res. 2008 Jan;41(1):78-86. doi: 10.1021/ar7001232. Epub 2007 Aug 28. Acc Chem Res. 2008. PMID: 17722874 Review.
-
Structure-based design of non-peptide HIV protease inhibitors.Farmaco. 2001 Jan-Feb;56(1-2):29-32. doi: 10.1016/s0014-827x(01)01025-4. Farmaco. 2001. PMID: 11347961 Review.
Cited by
-
Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands.Eur J Med Chem. 2018 Dec 5;160:171-182. doi: 10.1016/j.ejmech.2018.09.046. Epub 2018 Sep 18. Eur J Med Chem. 2018. PMID: 30340140 Free PMC article.
-
Design, Synthesis and X-Ray Structural Studies of Potent HIV-1 Protease Inhibitors Containing C-4 Substituted Tricyclic Hexahydro-Furofuran Derivatives as P2 Ligands.ChemMedChem. 2022 May 4;17(9):e202200058. doi: 10.1002/cmdc.202200058. Epub 2022 Mar 4. ChemMedChem. 2022. PMID: 35170223 Free PMC article.
-
Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.J Med Chem. 2018 May 24;61(10):4561-4577. doi: 10.1021/acs.jmedchem.8b00298. Epub 2018 May 15. J Med Chem. 2018. PMID: 29763303 Free PMC article.
-
The Pseudo-Symmetric N-benzyl Hydroxyethylamine Core in a New Series of Heteroarylcarboxyamide HIV-1 Pr Inhibitors: Synthesis, Molecular Modeling and Biological Evaluation.Biomolecules. 2021 Oct 26;11(11):1584. doi: 10.3390/biom11111584. Biomolecules. 2021. PMID: 34827582 Free PMC article.
-
Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance.Chem Commun (Camb). 2022 Oct 20;58(84):11762-11782. doi: 10.1039/d2cc04541a. Chem Commun (Camb). 2022. PMID: 36200462 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Chemical Information
Miscellaneous
