RESUMEN

Repaglinide (RPG) is an oral insulin secretagogue used in the treatment of diabetes. In this study, a new RPG analog was synthesized. Its antidiabetic and neuroprotective effects on dorsal root ganglions (DRG) in streptozotocin (STZ)-induced diabetic rats were examined compared to RPG. To assess the effects of 2-methoxy-4-(2-((3-methyl-1-(2-(piperidin-1-yl)phenyl)butyl)amino)-2-oxoethoxy)benzoic acid (OXR), the impact of OXR on oxidative stress biomarkers, motor function, and the expression of the glutamate dehydrogenase 1 (GLUD1), SLC2A2/glucose transporter 2 (GLUT2), and glucokinase (GCK) genes in STZ-induced diabetic rats were assessed. DRGs were examined histologically using hemotoxylin and eosin staining. Molecular docking was used to investigate the interactions between OXR and the binding site of RPG, the ATP-sensitive potassium (KATP) channel. Following 5 weeks of treatment, OXR significantly increased the level of total antioxidant power, decreased reactive oxygen species, and lipid peroxidation in the DRGs of diabetic rats. OXR restored STZ-induced pathophysiological damages in DRG tissues. Administration of OXR improved motor function of rats with diabetic neuropathy. Administration of 0.5 mg/kg OXR reduced blood glucose while promoting insulin, mainly through upregulation of messenger RNA expression of GLUD1, GLUT2, and GCK in the pancreas. Molecular docking revealed a favorable binding mode of OXR to the KATP channel. In conclusion, OXR has neuroprotective effects in diabetic rats by lowering oxidative stress, lowering blood glucose, and stimulating insulin secretion. We report that 0.5 mg/kg OXR administration was the most effective concentration of the compound in this study. OXR may be a promising target for further research on neuroprotective antidiabetic molecules.

Asunto(s)

Diabetes Mellitus Experimental , Fármacos Neuroprotectores , Adenosina Trifosfato/metabolismo , Animales , Antioxidantes/metabolismo , Antioxidantes/farmacología , Ácido Benzoico/farmacología , Biomarcadores/metabolismo , Glucemia/metabolismo , Carbamatos , Diabetes Mellitus Experimental/metabolismo , Eosina Amarillenta-(YS)/farmacología , Glucoquinasa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/metabolismo , Proteínas Facilitadoras del Transporte de la Glucosa/farmacología , Glutamato Deshidrogenasa/metabolismo , Glutamato Deshidrogenasa/farmacología , Hematoxilina/farmacología , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina , Canales KATP/metabolismo , Simulación del Acoplamiento Molecular , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo , Piperidinas , Potasio/metabolismo , Potasio/farmacología , ARN Mensajero/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Secretagogos/farmacología

RESUMEN

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-dibenzo[b,e][1,4]diazepin-1-one, identified as a submicromolar inhibitor of BuChE with IC50 value of 0.2 µM. In addition, the amyloid-ß 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.

Asunto(s)

Benzodiazepinas/química , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/síntesis química , Triazoles/química , Acetilcolinesterasa/metabolismo , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad

RESUMEN

The development of novel leishmanicidal agents that are capable of being replaced by the available therapeutic options has become a priority. In the present study, the synthesis and leishmanicidal activity of a series of 5-(nitroheteroaryl-2-yl)-1,3,4-thiadiazole derivatives are described. All compounds appeared to be potent anti-leishmanial agents against both promastigote and amastigote forms of Leishmania major (L. major). Amongst the synthesized compounds, 2-([1,4'-bipiperidin]-1'-yl)-5-(5-nitrofuran-2-yl)-1,3,4-thiadiazole (IIa) and 1-(5-(1-methyl-5-nitro-1H-imidazole-2-yl)-1,3,4-thiadiazol-2-yl)-4-(piperidine-1-yl) piperidine (IIc) are the most effective. Infection index was statistically declined in the presence of all compounds. The analysis of redox-related factors revealed that exposure of L. major cells to IIa and IIc led to an increase in reactive oxygen species (ROS). Furthermore, two compounds were able to increase ROS and NO levels in infected macrophages in a dose-independent manner. In addition, we showed that these compounds induced cell death in promastigotes. Altogether, our results indicated the anti-leishmanial potential of IIa and IIc is mediated by apoptosis through an imbalance in the redox system resulting in the elevation of ROS. This new class of compound seems to hold great promise for the development of new and useful anti-leishmanial agents.

Asunto(s)

Antiprotozoarios/síntesis química , Antiprotozoarios/uso terapéutico , Leishmania major/efectos de los fármacos , Tiadiazoles/síntesis química , Tiadiazoles/uso terapéutico , Antiprotozoarios/farmacología , Estructura Molecular , Relación Estructura-Actividad , Tiadiazoles/farmacología

RESUMEN

Herein, we describe a simple, four-step process for the preparation of 1,2,3-triazino[1,6- a]quinazolin-13-ones. This method involves ring-opening, quinazoline-forming condensation, reduction, diazotization accompanied by rapid intramolecular cyclization in the last step afforded the desired products with structurally complex heterocyclic core in excellent to high yields.

Asunto(s)

Quinazolinas/síntesis química , Triazinas/síntesis química , Ciclización , Estructura Molecular , Quinazolinas/química , Triazinas/química

RESUMEN

New sulfonamide and amide derivatives containing coumarin moieties; oxo-2H-chromen-sulfamoylphenylacetamides and oxo-2H-chromen-arylacetamides were synthesized starting from diverse 2-chloroacetamide derivatives and a wide range of coumarins. The structures of compounds were elucidated by IR and NMR spectra and also analytical elemental analysis. In the next step, the above mentioned compounds were screened for their antimicrobial and antioxidant activities. Their antimicrobial activity was assigned using the conventional agar dilution method and the antioxidant activity was assessed using two methods, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method and ferric reducing antioxidant power (FRAP) assay. Although the compounds showed no remarkable antimicrobial activities, most of them exhibited good antioxidant activities. Compounds 5b showed the most potent DPPH activity, whereas 8c was the most efficient compound in FRAP assay.