Background: 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. Objective: The principal objective was to the regioselective synthesis of SAFE and to 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. Methods: 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. Results: 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). Conclusion: 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.

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 (1GOS, 1H8F, 1IYT, 1QLX, 1QTI, 2KR6, 2MZ7, 4BDS, 4G2J, 5AKX, and 5MRG) 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.

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 co-crystallized ligand of the helicase protein, and sought compounds with similar chemical structures from the examined drug set. The initial phase of our study involved molecular fingerprints and structure similarity studies. Once the most similar compounds (30 compounds) identified, we conducted various studies to investigate and validate the binding potential of these selected compounds to the active site of the helicase protein. while the subsequent phase included molecular docking against SARS-CoV-2 helicase (PDB ID: 5RMM), molecular dynamics (MD) simulations, and MM-PBSA studies. Based on our analyses, we identified nine compounds with promising potential as inhibitors of SARS-CoV-2 helicase: Aniracetam, Aspirin, Chromocarb, Loxoprofen, Cinnamic acid, Lawsone, Loxoprofen sodium, Phenylglyoxylic acid, and Antineoplaston A10. We are sharing the findings of this research with the scientific community to encourage further investigations, both in vitro and in vivo, on these selected compounds.

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.