A series of halogenated coumarin−chalcones were synthesized, characterized, and their inhibitory activities against monoamine oxidases (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) were evaluated. Compound CC2 most potently inhibited MAO-B with an IC 50 value of 0.51 μM, followed by CC1 (IC 50 = 0.69 μM), with a selectivity index (SI) of >78.4 and >58.0, respectively, over MAO-A. However, none of the compounds effectively inhibited MAO-A, AChE, and BChE, except for CC2 and CC3 inhibiting BChE with IC 50 values of 7.00 (SI > 5.73 over AChE) and 11.8 μM, respectively. CC1 and CC2 were found to be reversible and competitive inhibitors of MAO-B, with K i values of 0.50 ± 0.06 and 0.53 ± 0.04 μM, respectively, and CC2 was also a reversible and competitive inhibitor of BChE, with a K i value of 2.84 ± 0.09 μM. The parallel artificial membrane permeability assay (PAMPA) method showed that lead candidates can cross the blood−brain barrier (BBB). The in vitro toxicity analysis on the Vero cell line (Normal African green monkey kidney epithelial cells) by MTT confirmed that both CC1 and CC2 were nontoxic up to 100 μg/mL, which is almost equivalent to 100 times of their effective concentration used in biological studies. In addition, CC1 and CC2 attenuated H 2 O 2induced cellular damage via their reactive oxygen species (ROS) scavenging effect. These results suggest that CC1 and CC2 are selective and competitive inhibitors of MAO-B, and that CC2 is a selective and competitive inhibitor of BChE. Molecular docking studies of lead compounds provided the possible type of interactions in the targeted enzymes. Based on the findings, both compounds, CC1 and CC2, can be considered plausible drug candidates against neurodegenerative disorders.
A simple, sensitive and rapid assay method has been developed and validated as per regulatory guidelines for the estimation of enasidenib on mouse dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electrospray ionization in the positive-ion mode. The method employs liquid extraction of enasidenib from DBS disks of mouse whole blood followed by chromatographic separation using 0.2% formic acid-acetonitrile (25:75, v/v) at a flow rate of 1.0 mL/min on an Atlantis dC 18 column with a total run time of 2.0 min. The MS/MS ion transitions monitored were m/z 474.0 → 267.1 for enasidenib and m/z 309.2 → 251.3 for the internal standard (warfarin). The assay was linear in the range of 1.01-3044 ng/mL. The within-run and between-run precisions were in the range of 3.18-9.06 and 4.66-8.69%, respectively. Stability studies showed that enasidenib was stable on DBS cards for 1 month. This novel method has been applied to analyze the DBS samples of enasidenib obtained from a pharmacokinetic study in mice.
Two series of dimethoxy-halogenated chalcones (DM1–DM20) were synthesized and tested for their ability to inhibit monoamine oxidase (MAOs). Compound DM2 exhibited the most significant inhibition against MAO-B with an IC50 value of 0.067 µM, followed by compound DM18 (IC50 = 0.118 µM), with selectivity index (SI) values of 93.88 and >338.98, respectively. However, none of the substances successfully inhibited MAO-A. The MAO-B inhibitors DM2 and DM18 were competitive and reversible, with Ki values of 0.032 ± 0.004 and 0.045 ± 0.001 µM, respectively. DM2 was non-toxic below 100 µg/mL in the cytotoxic test using the Vero epithelial cell line by the MTT method. According to molecular docking studies, DM2 and DM18 formed very similar conformations within the MAO-B binding pocket, with the ortho-chlorine and ortho-fluorine aromatic rings sandwiched between F168 and Y326. These conformations were predicted to show better interactions with the targeted MAO-B than MAO-A. In particular, the induced-fit docking of the dimethoxy phenyl ring of DM2 facing the hydrophobic pocket made up of FAD, Y398, and Y435 had an impact on F168 in the docking pocket. Taken together, DM2 and DM18 may be suitable candidates for treating neurodegenerative conditions such as Parkinson’s disease.
Background:Nebivolol hydrochloride is a third generation β-blocker with highly selective β1-receptor antagonist with antihypertensive properties having plasma half life of 10 h and 12% oral bioavailability. The aim of the present investigation was to form matrix type transdermal patches containing Nebivolol hydrochloride to avoid its extensive hepatic first pass metabolism, lesser side effect and increase bioavailability of drug.Materials and Methods:Matrix type transdermal patches containing Nebivolol hydrochloride were prepared using EudragitRS100, HPMC K100M (2:8) polymers by solvent evaporation technique. Aluminum foil was used as a backing membrane. Polyethylene glycol (PEG) 400 was used as plasticizer and Dimethyl sulfoxide (DMSO) was used as a penetration enhancer. Drug polymer interactions determined by FTIR and standard calibration curve of Nebivolol hydrochloride were determined by using UV estimation.Result:The systems were evaluated physicochemical parameters and drug present in the patches was determined by scanning electron microscopy. All prepared formulations indicated good physical stability. In vitro drug permeation studies of formulations were performed by using Franz diffusion cells using abdomen skin of Wistar albino rat. Result showed best in vitro skin permeation through rat skin as compared to all other formulations prepared with hydrophilic polymer containing permeation enhancer.Conclusions:It was observed that the formulation containing HPMC: EudragitRS100 (8:2) showed ideal higuchi release kinetics. On the basis of in vitro drug release through skin permeation performance, Formulation F1 was found to be better than other formulations and it was selected as the optimized formulation.
The present work describes a validated reverse phase high performance liquid chromatographic method for simultaneous estimation of Irbesartan chlorthalidone and cilnidipine in tablet dosage form. The quantification was carried out using C18 column (250 x 4.6mm, 5μm) and mobile phase comprised of Buffer, Acetonitrile and TEA in a proportion of 80:20:0.1 %v/v/v. The flow rate was 1.0 ml/min and the eluent was monitored at 222 nm. The selected chromatographic conditions were found to effectively separate Irbesartan Chlorthalidone and cilnidipine were 3.807 min, 4.667 min, and 6.887 min respectively. Linearity was found to be in the range of 30-90 μg/ml, 1.25-3.75 μg/ml and 1-3 μg/ml for Irbesartan Chlorthalidone and cilnidipine respectively. The percentage recoveries of all the drugs were found to be 99.27-99.81%, 99.57-99.99% and 99.22-99.44% for Irbesartan, chlorthalidone, and cilnidipine. The proposed method was found to be fast, accurate, precise, and reproducible and can be used for simultaneous estimation of these drugs in a tablet.
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