Second‐Generation Approved HIV Protease Inhibitors for the Treatment of HIV/AIDS

Ghosh, Arun K.; Chapsal, Bruno D.

doi:10.1002/9783527630943.ch7

Cited by 13 publications

(36 citation statements)

References 105 publications

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“…14,15 One of our key strategies of molecular design involves incorporation of cyclic ether and polyether-like templates where the ether oxygens are positioned to make specific hydrogen bonds with the backbone atoms of active site residues. 16,17 Our molecular design strategy is based upon the evidence that a protease cannot alter its overall backbone conformation without compromising its catalytic fitness for viral replication.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2′ ligands, are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2′ ligand and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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“…In darunavir, we incorporated a 3( R ), 3 a ( S ), 6 a ( R )-bis-tetrahydrofuranyl urethane (bis-THF) and a hydroxyethylsulfonamide isostere. 15,16 Darunavir exhibited excellent activity against a wide range of multidrug-resistant HIV-1 variants. 17,18 Our X-ray structural studies of darunavir-bound HIV-1 protease revealed extensive hydrogen bonding interactions with the active site backbone atoms of HIV-1 protease.…”

Section: Introductionmentioning

confidence: 99%

“…The backbone hydrogen bonds from the S2 to S2′-subsites are conceivably responsible for darunavir’s effectiveness against multidrug-resistant HIV-1 variants. 15, 16 …”

Section: Introductionmentioning

confidence: 99%

Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Studies

et al. 2015

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Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.

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confidence: 99%

“…1 These include renin inhibitors for hypertension, HIV protease inhibitors for HIV/AIDS and β- and γ-secretase inhibitors for Alzheimer’s disease. 1–3 The β-secretase inhibitors are particularly receiving much attention due to their potential for the treatment of Alzheimer’s disease (AD). 4 BACE1 is a membrane anchored aspartic acid protease, responsible for the initial cleavage of amyloid precursor protein to neurotoxic amyloid-β-peptides in the brain.…”

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confidence: 99%

Highly stereoselective asymmetric aldol routes to tert-butyl-2-(3,5-difluorophenyl)-1-oxiran-2-yl)ethyl)carbamates: Building blocks for novel protease inhibitors

Ghosh

Cárdenas

Brindisi

2017

Tetrahedron Letters

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Enantioselective syntheses of tert-butyl ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate and ((S)-2-(3,5-difluorophenyl)-1-((R)-oxiran-2-yl)ethyl)carbamate are described. We utilized asymmetric syn- and anti-aldol reactions to set both stereogenic centers. We investigated ester-derived Ti-enolate aldol reactions as well as Evans’ diastereoselective syn-aldol reaction for these syntheses. We have converted optically active ((S)-2-(3,5-difluorophenyl)-1-((S)-oxiran-2-yl)ethyl)carbamate to a potent β-secretase inhibitor.

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Second‐Generation Approved HIV Protease Inhibitors for the Treatment of HIV/AIDS

Cited by 13 publications

References 105 publications

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

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

Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein–Ligand X-ray Studies

Highly stereoselective asymmetric aldol routes to tert-butyl-2-(3,5-difluorophenyl)-1-oxiran-2-yl)ethyl)carbamates: Building blocks for novel protease inhibitors

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