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Monoamine oxidase B (MAO-B) plays a pivotal role in the deamination process of monoamines, encompassing crucial neurotransmitters like dopamine and norepinephrine. The heightened interest in MAO-B inhibitors emerged after the revelation that this enzyme could potentially catalyze the formation of neurotoxic compounds from endogenous and exogenous sources. Computational screening methodologies serve as valuable tools in the quest for novel inhibitors, enhancing the efficiency of this pursuit. In this study, 43 acefylline derivatives were docked against the MAO-B enzyme for their chemotherapeutic potential and binding affinities that yielded GOLD fitness scores ranging from 33.21 to 75.22. Among them, five acefylline derivatives, namely, MAO-B14, MAO-B15, MAO-B16, MAO-B20, and MAO-B21, displayed binding affinities comparable to the both standards istradefylline and safinamide. These derivatives exhibited hydrogen-bonding interactions with key amino acids Phe167 and Ile197/198, suggesting their strong potential as MAO-B inhibitors. Finally, molecular dynamics (MD) simulations were conducted to evaluate the stability of the examined acefylline derivatives over time. The simulations demonstrated that among the examined acefylline derivatives and standards, MAO-B21 stands out as the most stable candidate. Density functional theory (DFT) studies were also performed to optimize the geometries of the ligands, and molecular docking was conducted to predict the orientations of the ligands within the binding cavity of the protein and evaluate their molecular interactions. These results were also validated by simulation-based binding free energies via the molecular mechanics energies combined with generalized Born and surface area solvation (MM-GBSA) method. However, it is necessary to conduct in vitro and in vivo experiments to confirm and validate these findings in future studies. [ABSTRACT FROM AUTHOR]

Paraoxonase 1 (PON1) is an antioxidant enzyme that prevents lipid oxidation by hydrolysing lipid peroxides in the oxidised low‐density lipoprotein (LDL) structure, bound to high‐density lipoprotein (HDL) in serum, and exhibits esterase and lactonase activity. In this work, the hPON1 enzyme was purified from human serum using a hydrophobic gel with Sepharose 4B‐L‐tyrosine‐naphthylamine, and the affinity of some steroid derivatives previously isolated from fungal steroid biotransformations was examined on the pure hPON1 enzyme. The results indicate that all these derivaties activate the hPON1 enzyme to a different extent. Additionally, the binding potential of the most active five steroid derivatives to the PON1 enzyme to form a stable complex was explored through molecular docking and molecular dynamics (MD) simulation. The compounds with the highest potency in the enzymatic assay, S‐8 and S‐20, had the highest binding potential to the enzyme. The stability of the complexes formed by the two compounds was assessed and compared to the stability of the unbound enzyme structure. The enzyme‐compound complexes generally had similar stability to the unbound enzyme structure. Together with this, the MD simulation revealed that compound S‐8 would remain inside the enzyme's binding site during the simulation period, unlike compound S‐20. This situation varies according to the respective derivatives' functional groups and hydrophobic characteristics. [ABSTRACT FROM AUTHOR]

In our quest to develop new treatments for cancer, we synthesized and tested a series of urea‐functionalized aminothiazole‐benzazole analogs. Our primary focus was assessing their ability to inhibit the growth of breast cancer (MCF‐7) and lung adenocarcinoma (A549) cells. Using 1H NMR, 13C NMR spectra, and high resolution mass spectrometry (HRMS), we confirmed the chemical structures of these compounds. Among them, compound 8a demonstrated significant cytotoxicity against MCF‐7 cells, achieving an IC50 value of 9.6±0.6 μM. Similarly, compound 8e exhibited potent cytotoxicity against A549 cells, with an IC50 value of 9.2±1.1 μM. We further investigated the antimigration properties of all compounds that showed promising antiproliferative effects in both MCF‐7 and A549 cells. Additionally, we evaluated how these compounds impact key apoptosis‐related proteins: Caspase‐7, PARP‐1, BAX, and Bcl‐2. These proteins play crucial roles in the regulation of programmed cell death. Overall, our findings suggest that these urea‐functionalized aminothiazole‐benzazole analogs hold promise as potential anticancer agents, warranting further exploration into their mechanisms of action and therapeutic potential. [ABSTRACT FROM AUTHOR]

Considering the complex pathogenesis of Alzheimer's disease (AD), the multi-target ligand strategy is expected to provide superior effects for the treatment of the neurological disease compared to the classic single target strategy. Thus, one novel pyrrole-based hydrazide (vh0) and four corresponding hydrazide–hydrazones (vh1-4) were synthesized by applying highly efficient MW-assisted synthetic protocols. The synthetic pathway provided excellent yields and reduced reaction times under microwave conditions compared to conventional heating. The biological assays indicated that most of the novel pyrroles are selective MAO-B inhibitors with IC50 in the nanomolar range (665 nM) and moderate AChE inhibitors. The best dual-acting MAO-B/AChE inhibitor (IC50 hMAOB–0.665 μM; IC50 eeAChE—4.145 μM) was the unsubstituted pyrrole-based hydrazide (vh0). Importantly, none of the novel molecules displayed hMAOA-blocking capacities. The radical-scavenging properties of the compounds were examined using DPPH and ABTS in vitro tests. Notably, the hydrazide vh0 demonstrated the best antioxidant activities. In addition, in silico simulations using molecular docking and MM/GBSA, targeting the AChE (PDB ID: 4EY6) and MAO-B (PDB: 2V5Z), were utilized to obtain active conformations and to optimize the most prominent dual inhibitor (vh0). The ADME and in vitro PAMPA studies demonstrated that vh0 could cross the blood–brain barrier, and it poses good lead-like properties. Moreover, the optimized molecular structures and the frontier molecular orbitals were examined via DFT studies at 6-311G basis set in the ground state. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Faculty of Pharmacy of Ankara University / Ankara Üniversitesi Eczacilik Fakültesi Dergisi is the property of Ankara University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Journal of Agriculture & Nature / Kahramanmaraş Sütçü İmam Üniversitesi Tarım & Doğa Dergisi is the property of Kahramanmaras Sutcu Imam Universitesi and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The emergence of bacteria resistant to conventional antibiotics and the inability of these antibiotics to treat bacterial biofilm-induced infections cause millions of deaths every year. This situation has prompted scientists to develop alternative strategies to combat infectious diseases. Among these, researches on phytochemicals to reduce bacterial virulence in Pseudomonas aeruginosa have gained momentum in recent years. The main reasons behind this are the production of virulence factors and biofilm formation, all of which are under the control of quorum sensing (QS) system. Hence, inhibition of the QS pathways is an eligible strategy for the control of microbial pathogenesis. For the first time in the present study, the methanolic seed extract of avocado was evaluated for its anti-QS activity against P. aeruginosa PAO1. The results of the experiments carried out proved that the extract has inhibitory activity on the regulation of virulence and biofilm formation. Phytochemical analysis resulted in the identification of epicatechin, catechin, chlorogenic acid, caffeic acid, quercetin, kaempferol, vanillin, ferulic acid in the extract. Then, the mechanism of action for the extract was investigated through molecular docking. Docking outcomes demonstrated that the major components, catechin, epicatechin, chlorogenic acid, could bind to the receptors of QS competitively. Hence, the mode of action for the extract might be through the inhibition of the QS. Considering the computational analysis results and the literature, it is thought that the anti-QS activity of the extract prepared from avocado seeds may be related to the synergistic effect of the phytochemicals it contains. [ABSTRACT FROM AUTHOR]