Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies.

Darunavir / pharmacology HIV-1 HIV Protease Inhibitors Amides / pharmacology HIV Protease / metabolism Chloroacetates / pharmacology Crystallography, X-Ray Drug Design Structure-Activity Relationship
Darunavir HIV-1 protease Inhibitor Synthesis X-ray structure

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
01 03 2023
Historique:
received: 08 11 2022
revised: 13 01 2023
accepted: 30 01 2023
pmc-release: 01 03 2024
pubmed: 5 2 2023
medline: 3 3 2023
entrez: 4 2 2023
Statut: ppublish

Résumé

We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.

Identifiants

DOI: 10.1016/j.bmcl.2023.129168 PMID: 36738797 PMC: PMC10061991
pubmed: 36738797
pii: S0960-894X(23)00046-X
doi: 10.1016/j.bmcl.2023.129168
pmc: PMC10061991
mid: NIHMS1875209
pii:
doi:

Substances chimiques

Darunavir YO603Y8113
HIV Protease Inhibitors 0
p16 protease, Human immunodeficiency virus 1 EC 3.4.23.-
Amides 0
HIV Protease EC 3.4.23.-
Chloroacetates 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

129168

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM053386
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI150466
Pays : United States
Organisme : NIGMS NIH HHS
ID : R37 GM053386
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI150461
Pays : United States

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Auteurs

Arun K Ghosh (AK)

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. Electronic address: akghosh@purdue.edu.

Dana Shahabi (D)

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.

Maya Kipfmiller (M)

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.

Ajay K Ghosh (AK)

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.

Megan Johnson (M)

Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA.

Yuan-Fang Wang (YF)

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

Johnson Agniswamy (J)

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

Masayuki Amano (M)

Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan; Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556, Japan.

Irene T Weber (IT)

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.

Hiroaki Mitsuya (H)

Department of Refractory Viral Diseases, National Center for Global Health and Medicine, Shinjuku, Tokyo 162-8655, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch National Cancer Institute, Bethesda, MD 20892, USA; Division of Clinical Sciences, Kumamoto University Hospital, Kumamoto 860-8556, Japan.

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Classifications MeSH

questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Furanes › Darunavir › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Virus › Virus à ARN › Retroviridae › Lentivirus › Lentivirus des primates › VIH (Virus de l'Immunodéficience Humaine) › VIH-1 (Virus de l'Immunodéficience Humaine de type 1) › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Inhibiteurs de protéases virales › Inhibiteurs de protéase du VIH › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Composés chimiques organiques › Amides › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales non structurales › Protéases virales › Protéase du VIH › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures halogénés › Hydrocarbures chlorés › Chloroacétates › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › Evaluation of darunavir-derived HIV-1 protease...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Evaluation of darunavir-derived HIV-1 protease...