Design, synthesis and biological assessment of new 1-benzyl-4-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium derivatives (BOPs) as potential dual inhibitors of acetylcholinesterase and butyrylcholinesterase

Alzheimer's disease (AD), is among the most growing neurodegenerative diseases, which is mainly caused by the acetylcholine neurotransmitter loss in the hippocampus and cortex. Emerging of the dual Acetylcholinesterase (AChE)/Butyrylcholinesterase (BuChE) inhibitors has increased for treating Alzheimer disease. In this study, we would like to report the design and synthesis of a new sequence of 1-benzyl-4-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium derivatives (BOPs) assessed as BuChE and AChE inhibitors. Ellman's approach was used for the evaluation of AChE and BuChE inhibitory activities. Moreover, docking research was conducted to predict the action mechanism. Among all synthesized compounds, 1-(3-bromobenzyl)-3-((4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium bromide (BOP-1) was found to be the most active compound with dual activity for inhibition of AChE (IC50 = 5.90 ± 0.07μM), and BuChE (IC50 = 6.76 ± 0.04μM) and 1-(4-chlorobenzyl)-3-((6,7-dimethoxy-4-oxoquinazolin-3(4H)-yl)methyl) pyridin-1-ium chloride (BOP-8) showed the highest AChE inhibitory activity (IC50s = 1.11 ± 0.09 μM). The synthesized compounds BOP-1 and BOP-8 could be proposed as valuable lead compounds for further drug discovery development against AD. © 2021 The Author(s

Performance of solvent resistant nanofiltration membranes for purification of residual solvent in the pharmaceutical industry: Experiments and simulation

This study explores the possibility of developing a sustainable extraction method for use in pharmaceutical production, based on purification with membrane processes. Two types of commercial polymeric organic solvent nanofiltration membranes (StarMem122 and DuraMem150) were selected and tested for their abilities to recover the solvent from a pharmaceutical/solvent mixture (5, 10, 50 mg L -1). Five different pharmaceutical compounds have been selected in this work, namely: Imatinib mesylate, Riluzole, Donepezil HCl, Atenolol and Alprazolam. Solvents tested in the experiment were those used in the manufacturing process, i.e., methanol, ethanol, iso-propanol and ethyl acetate. An acceptable performance (rejection over 90%) was obtained for DuraMem150 in all tested pharmaceutical and solvent mixtures except for iso-propanol. No flux was observed for iso-propanol over the DuraMem150 due to its high viscosity. No separation was observed by using StarMem122 for Imatinib mesylate in iso-propanol (over 80%). Commercially available solvent resistant nanofiltration (SRNF) membranes (StarMem™122 and DuraMem™150) show promising performances as alternative tools to traditional separation units such as distillation columns for the recovery of solvents. Furthermore, to evaluate the potential of SRNF as a substitution for traditional solvent recovery, a model was developed for nanofiltration membrane units and implemented in a common process simulation software (Aspen Plus). These models were based on the pore flow mechanism and describe a single membrane module. A membrane module is not available in Aspen Plus and in its Model Library. In this study, this shortcoming was overcome through implementation of the NF membrane module within the Aspen Custom Modeler link to Aspen Plus. The model has been tested for two model solutes (Disperse orange 3 and Disperse red 19) since the pharmaceutical physical properties are not included in the Aspen Properties Database. The results presented here confirm the value of the Aspen Custom Modeler as a simulation tool for the use of NF as a novel and sustainable tool in pharmaceutical manufacturing

Design, Synthesis, and in Vitro and in Vivo Evaluation of Novel Fluconazole-Based Compounds with Promising Antifungal Activities

Demand has arisen for developing new azole antifungal agents with the growth of the resistant rate of infective fungal species to current azole antifungals in recent years. Accordingly, the present study reports the synthesis of novel fluconazole (FLC) analogues bearing urea functionality that led to discovering new azole agents with promising antifungal activities. In particular, compounds 8b and 8c displayed broad-spectrum activity and superior in vitro antifungal capabilities compared to the standard drug FLC against sensitive and resistant Candida albicans (C. albicans). The highly active compounds 8b and 8c had potent antibiofilm properties against FLC-resistant C. albicans species. Additionally, these compounds exhibited very low toxicity for three mammalian cell lines and human red blood cells. Time-kill studies revealed that our synthesized compounds displayed a fungicidal mechanism toward fungal growth. Furthermore, a density functional theory (DFT) calculation, additional docking, and independent gradient model (IGM) studies were performed to analyze their structure-activity relationship (SAR) and to assess the molecular interactions in the related target protein. Finally, in vivo results represented a significant reduction in the tissue fungal burden and improvements in the survival rate in a mice model of systemic candidiasis along with in vitro and in silico studies, demonstrating the therapeutic efficiency of compounds 8b and 8c as novel leads for candidiasis drug discovery. © 2021 The Authors. Published by American Chemical Society.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Synthesis and In Vitro Cytotoxic Activity of 2-Amino-7-(dimethylamino)-4-[(trifluoromethyl)phenyl]-4H-chromenes

Three 2-amino-4-(trifluoromethylphenyl)-3-cyano-7-(dimethylamino) -4H-chromene derivatives were synthesized and their cytotoxic activities were determined against six human tumor cell lines using MTT assay. Condensation of 3-(dimethylamino)phenol, trifluoromethybenzaldehydes and malonitrile in ethanol containing piperidine afforded corresponding chromenes (4a-c). The structure of the synthesized compound was confirmed by 1H NMR, IR and Mass spectral data. Among compounds tested, 3-trifluoromethyl analogue (3b) was the most active against all human tumor cell lines (IC50=12-45 nM)

Design and synthesis of benzodiazepine-1,2,3-triazole hybrid derivatives as selective butyrylcholinesterase inhibitors

Abstract: A new series of compounds based on benzodiazepine-1,2,3-triazole were synthesized and evaluated as cholinesterase inhibitors by Ellman�s method. The compounds proved to be selective inhibitors of butyrylcholinesterase (BuChE) over acetylcholinesterase. The most potent compound was 3,3-dimethyl-11-(3-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-2,3,4,5,10,11-hexahydro-1H-dibenzob,e1,4diazepin-1-one, identified as a submicromolar inhibitor of BuChE with IC50 value of 0.2 µM. In addition, the amyloid-β self-aggregation evaluation studies for selected compounds showed potent inhibitory effects compared to donepezil. The docking and cell viability studies supported the potential of compound 9b-6 as significant BuChE inhibitor. Graphic abstract: Figure not available: see fulltext. © 2019, Springer Nature Switzerland AG