Selected Class of Enamides Bearing Nitro Functionality as Dual-Acting with Highly Selective Monoamine Oxidase-B and BACE1 Inhibitors.

A small series of nitro group-bearing enamides was designed, synthesized (NEA1-NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and ß-site amyloid precursor protein cleaving enzyme 1 (ß-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC50 value = 0.0092 and 0.016 µM, respectively) than the standards (IC50 value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with Ki values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC50 values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood-brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.

Drug repurposing by in silico prediction of cyclizine derivatives as antihyperlipemic agents.

Cardiovascular diseases are the primary factor for increased mortality rates around the world. Atherosclerosis brought on by high serum cholesterol can result in coronary heart disease (CHD). The risk of CHD is markedly reduced by lowering serum cholesterol levels. Scientists across the world are inventing new treatment regimens for lowering blood lipid levels. In this work, we repurposed the already established drugs, i.e., cyclizine derivatives as antihyperlipidemic agents. The repurposing was done based on the similarity of the selected cyclizine derivatives with the already established antihyperlipidemic drug, fenofibrate. Computational studies were performed and the 16 cyclizine derivatives docked against PPAR. alpha scored higher than fenofibrate. Lifarizine and medibazine outperform fenofibrate inmmgbsa. Fenofibrate, etodroxizine, meclizine, and cinnarizine had similar mmgbsa scores. The ADME properties of these compounds were performed and from that etodroxizine and levocetirizine were found to have better properties. The computational studies were performed using the Schrodinger software, maestro 12.8. The "Protein Preparation Wizard" module in the Maestro panel was used to create the protein structure and OPLS4 force field was used for energy minimization. The maestro builder panel's "Ligprep", "Receptor Grid Generation" and "Ligand Docking" modules were then used to prepare ligands, receptor grids and to perform docking respectively. MMGBSA was performed on the "prime MMGBSA" segment. Using the "Qikprop" setting in the maestro panel, a number of ADMET properties were predicted, and the program was run in default mode using vsgb as the solvation model.

Design of enamides as new selective monoamine oxidase-B inhibitors.

OBJECTIVES: To develop of new class of selective and reversible MAO-B inhibitors from enamides. METHODS: Syntheses of the titled derivatives (AD1-AD11) were achieved by reacting cinnamoyl chloride and various primary and secondary amines in basic medium. All eleven compounds were investigated for in vitro inhibitory activities against recombinant human MAO-A and MAO-B. The reversibilities of lead compound inhibitions were analysed by dialysis. MTT assays of lead compounds were performed using normal VERO cell lines. KEY FINDINGS: Compounds AD3 and AD9 exhibited the greatest inhibitory activity against MAO-B with IC50 values of 0.11 and 0.10 µm, respectively, and were followed by AD2 and AD1 (0.51 and 0.71 µm, respectively). Most of the compounds weakly inhibited MAO-A, with the exceptions AD9 and AD7, which had IC50 values of 4.21 and 5.95 µm, respectively. AD3 had the highest selectivity index (SI) value for MAO-B (>363.6) and was followed by AD9 (SI 42.1). AD3 and AD9 were found to be competitive inhibitors of MAO-B with Ki values of 0.044 ± 0.0036 and 0.039 ± 0.0047 µm, respectively. Reversibility experiments showed AD3 and AD9 were reversible inhibitors of MAO-B; dialysis restored the activity of MAO-B to the reference level. MTT assays revealed AD3 and AD9 were non-toxic to normal VERO cell lines with IC50 values of 153.96 and 194.04 µg/ml, respectively. Computational studies provided hypothetical binding modes for AD3 and AD9 in the binding cavities of MAO-A and MAO-B. CONCLUSIONS: These results encourage further studies on the enamide scaffold as potential drug candidates for the treatment of Alzheimer's and Parkinson's diseases.