Design, Synthesis, In Silico and POM Studies for the Identification of the Pharmacophore Sites of Benzylidene Derivatives

Mohammad I Hosen; Yousef E Mukhrish; Ahmed Hussain Jawhari; Ismail Celik; Meryem Erol; Emad M Abdallah; Mohammed Al-Ghorbani; Mohammed Baashen; Faisal A Almalki; Hamid Laaroussi; Taibi Ben Hadda; Sarkar M A Kawsar

doi:10.3390/molecules28062613

Design, Synthesis, In Silico and POM Studies for the Identification of the Pharmacophore Sites of Benzylidene Derivatives

Molecules. 2023 Mar 13;28(6):2613. doi: 10.3390/molecules28062613.

Authors

Affiliations

¹ Laboratory of Carbohydrate and Nucleoside Chemistry (LCNC), Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh.
² Department of Chemistry, Faculty of Science, Jazan University, Jazan 45142, Saudi Arabia.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38280, Turkey.
⁴ Department of Science Laboratories, College of Science and Arts, Qassim University, Ar Rass 51921, Saudi Arabia.
⁵ Department of Chemistry, Faculty of Science and Arts, Ulla, Taibah University, Medina 41477, Saudi Arabia.
⁶ Department of Chemistry, Science and Humanities College, Shaqra University, Ad-Dawadmi 11911, Saudi Arabia.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁸ Laboratory of Applied Chemistry & Environment, Faculty of Sciences, Mohammed Premier University, Oujda 60000, Morocco.

Abstract

Due to the uneven distribution of glycosidase enzyme expression across bacteria and fungi, glycoside derivatives of antimicrobial compounds provide prospective and promising antimicrobial materials. Therefore, herein, we report the synthesis and characterization of six novel methyl 4,6-O-benzylidene-α-d-glucopyranoside (MBG) derivatives (2-7). The structures were ascertained using spectroscopic techniques and elemental analyses. Antimicrobial tests (zone of inhibition, MIC and MBC) were carried out to determine their ability to inhibit the growth of different Gram-positive, Gram-negative bacteria and fungi. The highest antibacterial activity was recorded with compounds 4, 5, 6 and 7. The compounds with the most significant antifungal efficacy were 4, 5, 6 and 7. Based on the prediction of activity spectra for substances (PASS), compounds 4 and 7 have promising antimicrobial capacity. Molecular docking studies focused on fungal and bacterial proteins where derivatives 3 and 6 exhibited strong binding affinities. The molecular dynamics study revealed that the complexes formed by these derivatives with the proteins L,D-transpeptidase Ykud and endoglucanase from Aspergillus niger remained stable, both over time and in physiological conditions. Structure-activity relationships, including in vitro and in silico results, revealed that the acyl chains [lauroyl-(CH₃(CH₂)₁₀CO-), cinnamoyl-(C₆H₅CH=CHCO-)], in combination with sugar, were found to have the most potential against human and fungal pathogens. Synthetic, antimicrobial and pharmacokinetic studies revealed that MBG derivatives have good potential for antimicrobial activity, developing a therapeutic target for bacteria and fungi. Furthermore, the Petra/Osiris/Molinspiration (POM) study clearly indicated the presence of an important (O1^δ-----O2^δ-) antifungal pharmacophore site. This site can also be explored as a potential antiviral moiety.

Keywords: PASS prediction; POM theory; antimicrobial; identification of pharmacophore sites; methyl 4,6-O-benzylidene-α-d-glucopyranoside; molecular dynamics.

MeSH terms

Anti-Bacterial Agents / chemistry
Anti-Infective Agents* / chemistry
Antifungal Agents* / chemistry
Bacteria
Benzylidene Compounds
Humans
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Pharmacophore
Structure-Activity Relationship

Substances

Antifungal Agents
Benzylidene Compounds
Anti-Infective Agents
Anti-Bacterial Agents

Grants and funding

2022-2023/University of Chittagong