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This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Globally, lung cancer and tuberculosis are considered to be very serious and complex diseases. Evidence suggests that chronic infection with tuberculosis (TB) can often lead to lung tumors; therefore, developing drugs that target both diseases is of great clinical significance. In our study, we designed and synthesized a suite of 14 new quinazolinones (5a-n) and performed biological investigations of these compounds in Mycobacterium tuberculosis (MTB) and cancer cell lines. In addition, we conducted a molecular modeling study to determine the mechanism of action of these compounds at the molecular level. Compounds that showed anticancer activity in the preliminary screening were further evaluated in three cancer cell lines (A549, Calu-3, and BT-474 cells) and characterized in an epidermal growth factor receptor (EGFR) binding assay. Cytotoxicity in noncancerous lung fibroblast cells was also evaluated to obtain safety data. Our theoretical and experimental studies indicated that our compounds showed a mechanism of action similar to that of erlotinib by inhibiting the EGFR tyrosine kinase. In turn, the antituberculosis activity of these compounds would be produced by the inhibition of enoyl-ACP-reductase. From our findings, we were able to identify two potential lead compounds (5i and 5l) with dual activity and elevated safety toward noncancerous lung fibroblast cells. In addition, our data identified three compounds with excellent anti-TB activities (compounds 5i, 5l, and 5n)., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

The synthesis of inhibitors of SphK2 with novel structural scaffolds is reported. These compounds were designed from a molecular modeling study, in which the molecular interactions stabilizing the different complexes were taken into account. Particularly interesting is that 7-bromo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, which is a selective inhibitor of SphK2, does not exert any cytotoxic effects and has a potent anti-inflammatory effect. It was found to inhibit mononuclear cell adhesion to the dysfunctional endothelium with minimal impact on neutrophil-endothelial cell interactions. The information obtained from our theoretical and experimental study can be useful in the search for inhibitors of SphK2 that play a prominent role in different diseases, especially in inflammatory and cardiovascular disorders., (© 2019 Deutsche Pharmazeutische Gesellschaft.)

The synthesis, in vitro evaluation and conformational study of several small-size peptides acting as antibacterial agents are reported. Among the compounds evaluated, the peptides Arg-Gln-Ile-Lys-Ile-Trp-Arg-Arg-Met-Lys-Trp-Lys-Lys-NH2 , Arg-Gln-Ile-Lys-Ile-Arg-Arg-Met-Lys-Trp-Arg-NH2 , and Arg-Gln-Ile-Trp-Trp-Trp-Trp-Gln-Arg-NH2 exhibited significant antibacterial activity. These were found to be very active antibacterial compounds, considering their small molecular size. In order to better understand the antibacterial activity obtained for these peptides, an exhaustive conformational analysis was performed, using both theoretical calculations and experimental measurements. Molecular dynamics simulations using two different media (water and trifluoroethanol/water) were employed. The results of these theoretical calculations were corroborated by experimental circular dichroism measurements. A brief discussion on the possible mechanism of action of these peptides at molecular level is also presented. Some of the peptides reported here constitute very interesting structures to be used as starting compounds for the design of new small-size peptides possessing antibacterial activity., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

New nitrosopyrimidines were synthesized and evaluated as potential antibacterial agents. Different compounds structurally related with 4,6-bis(alkyl or arylamino)-5-nitrosopyrimidines were evaluated. Some of these nitrosopyrimidines displayed significant antibacterial activity against human pathogenic bacteria. Among them compounds 1c, 2a-c, and 9a-c exhibited remarkable activity against methicillin-sensitive and -resistant Staphylococcus aureus, Escherichia coli, Yersinia enterocolitica, and Salmonella enteritidis. A detailed structure-activity relationship study, supported by theoretical calculations, aided us to identify and understand the minimal structural requirements for the antibacterial action of the nitrosopyrimidines reported here. Thus, our results have led us to identify a topographical template that provides a guide for the design of new nitrosopyrimidines with antibacterial effects., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)