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Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration

Phospholipase A2 (PLA2) promotes inflammation via lipid mediators and releases arachidonic acid (AA), and these enzymes have been found to be elevated in a variety of diseases, including rheumatoid arthritis, sepsis, and atherosclerosis. The mobilization of AA by PLA2 and subsequent synthesis of pro...

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Autores principales: Bakht, Md. Afroz, Pooventhiran, Thangaiyan, Thomas, Renjith, Kamal, Mehnaz, Din, Israf Ud, Rehman, Najeeb Ur, Ali, Imtiaz, Ajmal, Noushin, Ahsan, Mohamed Jawed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963251/
https://www.ncbi.nlm.nih.gov/pubmed/36838935
http://dx.doi.org/10.3390/molecules28041944
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author Bakht, Md. Afroz
Pooventhiran, Thangaiyan
Thomas, Renjith
Kamal, Mehnaz
Din, Israf Ud
Rehman, Najeeb Ur
Ali, Imtiaz
Ajmal, Noushin
Ahsan, Mohamed Jawed
author_facet Bakht, Md. Afroz
Pooventhiran, Thangaiyan
Thomas, Renjith
Kamal, Mehnaz
Din, Israf Ud
Rehman, Najeeb Ur
Ali, Imtiaz
Ajmal, Noushin
Ahsan, Mohamed Jawed
author_sort Bakht, Md. Afroz
collection PubMed
description Phospholipase A2 (PLA2) promotes inflammation via lipid mediators and releases arachidonic acid (AA), and these enzymes have been found to be elevated in a variety of diseases, including rheumatoid arthritis, sepsis, and atherosclerosis. The mobilization of AA by PLA2 and subsequent synthesis of prostaglandins are regarded as critical events in inflammation. Inflammatory processes may be treated with drugs that inhibit PLA2, thereby blocking the COX and LOX pathways in the AA cascade. To address this issue, we report herein an efficient method for the synthesis of a series of octahydroquinazolinone compounds (4a–h) in the presence of the catalyst Pd-HPW/SiO(2) and their phospholipase A2, as well as protease inhibitory activities. Among eight compounds, two of them exhibited overwhelming results against PLA2 and protease. By using FT-IR, Raman, NMR, and mass spectroscopy, two novel compounds were thoroughly studied. After carefully examining the SAR of the investigated compounds against these enzymes, it was found that compounds (4a, 4b) containing both electron-donating and electron-withdrawing groups on the phenyl ring exhibited higher activity than compounds with only one of these groups. DFT studies were employed to study the electronic nature and reactivity properties of the molecules by optimizing at the BLYP/cc-pVDZ. Natural bond orbitals helped to study the various electron delocalizations in the molecules, and the frontier molecular orbitals helped with the reactivity and stability parameters. The nature and extent of the expressed biological activity of the molecule were studied using molecular docking with human non-pancreatic secretory phospholipase A2 (hnps-PLA2) (PDB ID: 1DB4) and protease K (PDB ID: 2PWB). The drug-ability of the molecule has been tested using ADMET, and pharmacodynamics data have been extracted. Both the compounds qualify for ADME properties and follow Lipinski’s rule of five.
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spelling pubmed-99632512023-02-26 Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration Bakht, Md. Afroz Pooventhiran, Thangaiyan Thomas, Renjith Kamal, Mehnaz Din, Israf Ud Rehman, Najeeb Ur Ali, Imtiaz Ajmal, Noushin Ahsan, Mohamed Jawed Molecules Article Phospholipase A2 (PLA2) promotes inflammation via lipid mediators and releases arachidonic acid (AA), and these enzymes have been found to be elevated in a variety of diseases, including rheumatoid arthritis, sepsis, and atherosclerosis. The mobilization of AA by PLA2 and subsequent synthesis of prostaglandins are regarded as critical events in inflammation. Inflammatory processes may be treated with drugs that inhibit PLA2, thereby blocking the COX and LOX pathways in the AA cascade. To address this issue, we report herein an efficient method for the synthesis of a series of octahydroquinazolinone compounds (4a–h) in the presence of the catalyst Pd-HPW/SiO(2) and their phospholipase A2, as well as protease inhibitory activities. Among eight compounds, two of them exhibited overwhelming results against PLA2 and protease. By using FT-IR, Raman, NMR, and mass spectroscopy, two novel compounds were thoroughly studied. After carefully examining the SAR of the investigated compounds against these enzymes, it was found that compounds (4a, 4b) containing both electron-donating and electron-withdrawing groups on the phenyl ring exhibited higher activity than compounds with only one of these groups. DFT studies were employed to study the electronic nature and reactivity properties of the molecules by optimizing at the BLYP/cc-pVDZ. Natural bond orbitals helped to study the various electron delocalizations in the molecules, and the frontier molecular orbitals helped with the reactivity and stability parameters. The nature and extent of the expressed biological activity of the molecule were studied using molecular docking with human non-pancreatic secretory phospholipase A2 (hnps-PLA2) (PDB ID: 1DB4) and protease K (PDB ID: 2PWB). The drug-ability of the molecule has been tested using ADMET, and pharmacodynamics data have been extracted. Both the compounds qualify for ADME properties and follow Lipinski’s rule of five. MDPI 2023-02-17 /pmc/articles/PMC9963251/ /pubmed/36838935 http://dx.doi.org/10.3390/molecules28041944 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bakht, Md. Afroz
Pooventhiran, Thangaiyan
Thomas, Renjith
Kamal, Mehnaz
Din, Israf Ud
Rehman, Najeeb Ur
Ali, Imtiaz
Ajmal, Noushin
Ahsan, Mohamed Jawed
Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration
title Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration
title_full Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration
title_fullStr Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration
title_full_unstemmed Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration
title_short Synthesis and Biological Evaluation of Octahydroquinazolinones as Phospholipase A2, and Protease Inhibitors: Experimental and Theoretical Exploration
title_sort synthesis and biological evaluation of octahydroquinazolinones as phospholipase a2, and protease inhibitors: experimental and theoretical exploration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963251/
https://www.ncbi.nlm.nih.gov/pubmed/36838935
http://dx.doi.org/10.3390/molecules28041944
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