Dimebolin hydrochloride

Riboflavin (RF) serves as a precursor for the biosynthesis of 5,6-dimethylbenzimidazole (DMBI), the lower ligand of vitamin B12, in Propionibacterium freudenreichii. Nicotinamide (NAM) has been reported to enhance this biosynthetic pathway. In this study, we investigated the effect of RF and NAM supplementation on vitamin B12 production by P. freudenreichii DSM 20271 in barley malt extract-based model medium. A medium containing 10 % (w/v) concentrated malt extract supplemented with lactate and tryptone supported superior growth and B12 production. RF (1, 3 and 40 μM with 27 mM NAM), and NAM (0.1, 0.6 and 27 mM with 3 μM RF) were evaluated for their impact, with 100 μM DMBI used as a reference. RF concentrations ≥3 μM significantly enhanced B12 production, while NAM was effective only at 27 mM. Growth and metabolite profiles were largely unaffected, suggesting that increased B12 synthesis resulted from improved precursor availability rather than enhanced biomass. Transcriptomic analysis revealed significant downregulation of RF biosynthesis genes, consistent with feedback inhibition from exogenous RF, while B12 biosynthesis genes remained transcriptionally stable, indicating that the observed increase in B12 production is primarily regulated at the metabolic rather transcriptional level. These findings demonstrate that B12 production in P. freudenreichii can be enhanced using RF and NAM precursors, but practical applications must balance efficacy with NAM safety limits for use in B12-enriched fermented foods.

Alzheimer's disease is a type of dementia that affects neuronal function, leading to a decline in cognitive functions. Serotonin-6 (5HT6) receptors are implicated in the etiology of neurological diseases. 5HT6 receptor antagonists act as anti-dementia agents. PDB ID: 7YS6 represents a membrane protein, and amplification and overexpression of this protein are associated with Alzheimer's disease. Coumarin-fused phenothiazines are significant anti-Alzheimer's agents due to their inhibitory activity on the Serotonin- 6 receptor.

Numerous previously unreported Coumarin-substituted Phenothiazines [A2 to A50] were designed using in-silico methods to evaluate their 5HT6 receptor antagonistic activity. Molecular modeling techniques were employed to study the ligands [A2 to A50] in interaction with the Serotonin-6 receptor (PDB ID: 7YS6) using Schrödinger Suite 2019-4.

Molecular modeling studies of the designed ligands [A2 to A50] were conducted using the Glide module. In-silico ADMET screening was performed using the QikProp module, and binding free energy calculations were carried out using the Prime MM-GBSA module within the Schrödinger Suite. The binding affinity of the designed ligands [A2 to A50] towards 5HT6 receptors was determined based on Glide scores. Subsequently, ligand A31 underwent a 100 ns molecular dynamics simulation using the Desmond module of Schrödinger Suite 2020-1, which is based in New York, NY.

The majority of the designed ligands exhibited strong hydrogen bonding interactions and hydrophobic associations with the serotonin-6 receptor, which hinder its activity. These ligands achieved remarkable Glide scores within the range of -4.2859 to -7.7128, in comparison to reference standards such as Idalopirdine (-7.78149), Intepirdine (-5.20103), Latrepirdine (-5.54853), and the co-crystallized ligand (-7.02889). In-silico ADMET properties for these ligands fell within the recommended values for drug-likeness. It is worth noting that the MMGBSA binding free energy of the most potent inhibitor was positive, indicating a strong binding interaction. Additionally, the dynamic behavior of the protein (7YS6)-ligand (A31) complex was studied by subjecting ligand A31 to a 100 ns molecular dynamics simulation.

The results of this study reveal strong evidence supporting the potential of coumarin- substituted phenothiazine derivatives as effective Serotonin-6 receptor antagonists. Ligands [A2 to A50], which exhibited noteworthy Glide scores, hold promise for significant anti- Alzheimer activity. Further in-vitro and in-vivo investigations are warranted to explore and confirm their therapeutic potential.