Medicinal Chemistry - Volume 21, Issue 5, 2025

In the present work, a series of novel pyridine carboxamides 3(a-h) were synthesized and screened with antibacterial activity. This research explores the application of Density Functional Theory (DFT) in studying biological systems at the quantum mechanical level, particularly in the context of drug design. DFT offers a streamlined approach to quantum mechanical calculations, making it indispensable in various scientific fields, and for its exceptional accuracy, reduced computational time, and cost-effectiveness has become a pivotal tool in computational chemistry. This research work highlights the integration of DFT studies with POM analyses, which effectively identify pharmacophoric sites. Moreover, the research incorporates in silico pharmacokinetics analyses to assess the pharmacokinetic properties of synthesized compounds. The paper focused on a series of compounds previously reported, aiming to provide a comprehensive understanding of their electronic structure, pharmacophoric features, and potential as drug candidates. This study not only contributes to the evolving field of computational chemistry but also holds implications for advancing drug design processes by combining theoretical insights with practical analyses.

The compounds 3(a-h) were subjected to Density Functional Theory (DFT) computations using the B3LYP/6-31G(d) basis set to get optimized geometric structures. GaussViewis used to display the contributions of the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). The determination of energy gaps was conducted using Gaussian 09W. The pharmacokinetic profiles were evaluated using existing techniques such as Osiris, Petra, and Molinspiration, as well as a novel platform called POM Analyse.

The computational studies DFT, POM and in silico pharmacokinetics studies revealed that the studied compounds are biologically active, non-toxic, non-carcinogenic in nature and may be utilized as drug candidates.

Density functional theory (DFT) investigations emphasize the exceptional stability of complex 3d, which possesses the biggest energy gap and the lowest softness. In contrast, compound 3h demonstrates poorer stability among the tested compounds, characterized by the lowest energy gap and the highest softness values. These findings are further substantiated by absolute energy calculations. The negligible energy difference in compound 3h indicates an increased transfer of electric charge within the molecule, which is associated with its enhanced biological effectiveness. The drug-likeness of the compounds is confirmed by POM and in silico pharmacokinetics investigations, with compound 3h being identified as the most biologically active among the investigated compounds.

Alzheimer's disease, akin to coronary artery disease of the heart, is a progressive brain disorder driven by nerve cell damage.

This study utilized computational methods to explore 14 anti-acetylcholinesterase (AChE) derivatives (1 ̶ 14) as potential treatments. By scrutinizing their interactions with 11 essential target proteins (AChE, Aβ, BChE, GSK-3β, MAO B, PDE-9, Prion, PSEN-1, sEH, Tau, and TDP-43) and comparing them with established drugs such as donepezil, galantamine, memantine, and rivastigmine, ligand 14 emerged as notable. During molecular dynamics simulations, the protein boasting the strongest bond with the critical 1QTI protein and exceeding drug-likeness criteria also exhibited remarkable stability within the enzyme's pocket across diverse temperatures (300- 320 K). In addition, we utilized density functional theory (DFT) to compute dipole moments and molecular orbital properties, including assessing the thermodynamic stability of AChE derivatives.

This finding suggests a well-defined, potentially therapeutic interaction further supported by theoretical and future in vitro and in vivo investigations.

Ligand 14 thus emerges as a promising candidate in the fight against Alzheimer's disease.

Cholinesterase enzymes play a pivotal role in hydrolyzing acetylcholine, a neurotransmitter crucial for memory and cognition, into its components, acetic acid, and choline. A primary approach in addressing Alzheimer's disease symptoms is by inhibiting the action of these enzymes.

With this context, our study embarked on a mission to pinpoint potential Cholinesterase (ChE) inhibitors using a comprehensive computational methodology. A total of 49 phytoconstituents derived from Cannabis sativa L underwent in silico screening via molecular docking, pharmacokinetic and pharmacotoxicological analysis, to evaluate their ability to inhibit cholinesterase enzymes. Out of these, two specific compounds, namely tetrahydrocannabivarin and Δ-9-tetrahydrocannabinol, belonging to cannabinoids, stood out as prospective therapeutic agents against Alzheimer's due to their potential as cholinesterase inhibitors. These candidates showcased commendable binding affinities with the cholinesterase enzymes, highlighting their interaction with essential enzymatic residues.

They were predicted to exhibit greater binding affinities than Rivastigmine and Galantamine. Their ADMET assessments further classified them as viable oral pharmaceutical drugs. They are not expected to induce any mutagenic or hepatotoxic effects and cannot produce skin sensitization. In addition, these phytoconstituents are predicted to be BBB permeable and can reach the central nervous system (CNS) and exert their therapeutic effects. To delve deeper, we explored molecular dynamics (MD) simulations to examine the stability of the complex formed between the best candidate (Δ-9-tetrahydrocannabinol) and the target proteins under simulated biological conditions. The MD study affirmed that the ligand-ChE recognition is a spontaneous reaction leading to stable complexes.

Our research outcomes provide valuable insights, offering a clear direction for the pharmaceutical sector in the pursuit of effective anti-Alzheimer treatments.

The approval of Sucrose Fatty Acid Esters (SFAEs) as food additives/preservatives with antimicrobial potential has triggered enormous interest in discovering new biological applications. Accordingly, many researchers reported that SFAEs consist of various sugar moieties, and hydrophobic side chains are highly active against certain fungal species.

This study aimed to conduct aregioselective synthesis of SAFE and check the effect of chain length and site of acylation (i.e., C-6 vs. C-2, C-3, C-4, and long-chain vs. short-chain) on antimicrobial potency.

A direct acylation method maintaining several conditions was used for esterification. In vitro tests, molecular docking, and in silico studies were conducted using standard procedures.

In vitro tests revealed that the fatty acid chain length in mannopyranoside esters significantly affects the antifungal activity, where C12 chains are more potent against Aspergillus species. In terms of acylation site, mannopyranoside esters with a C8 chain substituted at the C-6 position are more active in antifungal inhibition. Molecular docking also revealed that these mannopyranoside esters had comparatively better stable binding energy and hence better inhibition, with the fungal enzymes lanosterol 14-alpha-demethylase (3LD6), urate oxidase (1R51), and glucoamylase (1KUL) than the standard antifungal drug fluconazole. Additionally, the thermodynamic, orbital, drug-likeness, and safety profiles of these mannopyranoside esters were calculated and discussed, along with the Structure-Activity Relationships (SAR).

This study thus highlights the importance of the acylation site and lipid-like fatty acid chain length that govern the antimicrobial activity of mannopyranoside-based SFAE.

There is an urgent need for new antimicrobial compounds with alternative modes of action for the treatment of drug-resistant bacterial and fungal pathogens.

Carbohydrates and their derivatives are essential for biochemical and medicinal research because of their efficacy in the synthesis of biologically active drugs.

In the present study, a series of methyl α-D-mannopyranoside (MMP) derivatives (2-6) were prepared via direct acylation, and their biological properties were characterized.

The structures of synthesized compounds were established by analyzing their physicochemical, elemental, and spectroscopic data and evaluating their in vitro antimicrobial activities through in silico studies.

In the antibacterial study, compound 3 was found to be mostly active toward most of the organisms, exhibiting maximum inhibition of S. abony and minimum inhibition of P. aeruginosa. However, the MIC and MBC values revealed that this compound is highly effective against Bacillus subtilis (MIC of 0.5 µg/L and MBC of 256 µg/L). In terms of antifungal activity, 3 and 6 showed the most promising activity toward Aspergillus flavus, with an inhibition of 95.90 ± 1.0% for compound 3 and 96.72 ± 1.1% for compound 6. Moreover, density functional theory (DFT) in conjunction with the BLYP/6-311G (d) basis sets was used to calculate the dipole moment and total energy for each compound, and the molecular electrostatic potential and Mulliken charge were considered to study the electrophilicity and nucleophilicity of the groups in each compound. For dipole moment calculations, the dipole moments are in the following order: 6 < 3 < 1 < 5 < 2 < 4, inferring that compounds 2 and 4 possess a high dipole moment in comparison with the other inhibitor systems. Furthermore, molecular docking was performed against threonine synthase from B. subtilis ATCC 6633 (PDB: 6CGQ) to identify the active site of the compounds, with compound 3 showing a maximum binding energy of -10.3 kcal/mol and compound 4 exhibiting a binding energy of -10.2 kcal/mol. In addition, a 100 ns MD simulation was performed, and the results revealed a stable conformation and binding pattern within the stimulating environment.

Our synthetic, antimicrobial, and in silico experiments revealed that MMP derivatives exhibit potential activity, providing a therapeutic target for bacteria and fungi.

In this research aiming at combating COVID-19, we employed advanced computer-based methods to identify potential inhibitors of SARS-CoV-2 helicase from a pool of 3009 clinical and FDA-approved drugs.

To narrow down the candidates, we focused on VXG, the helicase’s co-crystallized ligand, and sought compounds with chemical structures akin to VXG within the examined drugs. The initial phase of our study involved molecular fingerprinting in addition to structure similarity studies.

Once the compounds most closely resembling VXG (29 compounds) were identified, we conducted various studies to investigate and validate the binding potential of these selected compounds to the protein’s active site. The subsequent phase included molecular docking, molecular dynamic (MD) simulations, and MM-PBSA studies against the SARS-CoV-2 helicase (PDB ID: 5RMM).

Based on our analyses, we identified nine compounds with promising potential as SARS-CoV-2 helicase inhibitors, namely aniracetam, aspirin, chromocarb, cinnamic acid, lawsone, loxoprofen, phenylglyoxylic acid, and antineoplaston A10. The findings of this research help the scientific community to further investigate these compounds, both in vitro and in vivo.