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

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 (O1δ−----O2δ−) antifungal pharmacophore site. This site can also be explored as a potential antiviral moiety.

Synthesis, Characterization, and Evaluation of Tetrazole Derivatives with Pyrrole‐2,5‐Dione Moieties as Urease Inhibitors: Exploring Structure‐Activity Relationships and Computational Insights

“…The utilization of the Osisis and Molinspiration theory has significantly streamlined the process of identifying and refining pharmacophore sites, crucial for drug discovery [64,65] . This method enhances efficiency by systematically assessing each site individually, taking into consideration their distinct physico‐chemical characteristics, such as molecular size, shape, and charge distribution, along with the electronic charge distribution associated with relevant heteroatoms [66] .…”

“…The utilization of the Osisis and Molinspiration theory has significantly streamlined the process of identifying and refining pharmacophore sites, crucial for drug discovery. [64,65] This method enhances efficiency by systematically assessing each site individually, taking into consideration their distinct physicochemical characteristics, such as molecular size, shape, and charge distribution, along with the electronic charge distribution associated with relevant heteroatoms. [66] Importantly, this innovative approach has demonstrated success not only in the initial application but also in its extension to diverse biotargets, signifying its versatility and effectiveness in optimizing molecular interactions and advancing drug discovery efforts.…”

In silico evaluation of anti-colorectal cancer inhibitors by Resveratrol derivatives targeting Armadillo repeats domain of APC: molecular docking and molecular dynamics simulation

“…Pa and Pi values can range from 0.00 to 1.0, and notably, Pa+Pi≠1, demonstrating that a molecule cannot be simultaneously active and inactive at the same time (30). In this investigation, total 50 Resveratrol derivatives were taken, and analysis pass prediction (Supplementary Table 1).…”