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

Author:

Bakht Md. Afroz1ORCID,Pooventhiran Thangaiyan23ORCID,Thomas Renjith2,Kamal Mehnaz4ORCID,Din Israf Ud1,Rehman Najeeb Ur5ORCID,Ali Imtiaz6,Ajmal Noushin7,Ahsan Mohamed Jawed8ORCID

Affiliation:

1. Department of Chemistry, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia

2. Department of Chemistry, St Berchmans College (Autonomous), Mahatma Gandhi University, Changanassery 686101, Kerala, India

3. Department of Mechanical Engineering, University Centre for Research & Development, Chandigarh University, Gharuan, Mohali 140413, Punjab, India

4. Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia

5. Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia

6. Preparatory College, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia

7. Department of Basic Science and Humanities, Pratap University, Jaipur 303104, Rajasthan, India

8. Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Ambabari Circle, Jaipur 302039, Rajasthan, India

Abstract

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/SiO2 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.

Funder

Prince Sattam bin Abdulaziz University

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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