RESUMEN
A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a-o has been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. The synthetic approach started with diazotizing 2-aminobenzoic acids 1 to produce 2-azidobenzoic acids 2. Next, reaction of the latter compounds with propargylamine 3, benzaldehyde 4, and isocyanides 5 led to the formation of the title compounds 6a-o, in good yields. All the synthesized compounds exhibited high anticonvulsant activity in the PTZ test, comparable to or better than the standard drug diazepam. Among the tested compounds, N-(tert-butyl)-2-(9-chloro-6-oxo-4H-[1,2,3]triazolo[1,5-a][1,4]benzodiazepin-5(6H)-yl)-2-(3-bromophenyl)acetamide 6h was the most potent compound in this assay. Moreover, compounds 6i and 6k showed excellent activity in MES test. Loss of the anticonvulsant effect of compound 6h in the presence of flumazenil in the PTZ test and appropriate interaction of this compound in the active site of benzodiazepine (BZD)-binding site of GABAA receptor confirm involvement of BZD receptors in the anticonvulsant activity of compound 6h. A novel series of 1,2,3-triazolo-benzodiazepine derivatives 6a-o have been synthesized and evaluated in vivo for their anticonvulsant activities using by pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced seizures in mice. All the synthesized compounds exhibited high anticonvulsant activity, comparable to or better than the standard drug diazepam in the PTZ test and compounds 6i and 6k showed excellent activity in MES test. Flumazenil test and in silico docking study confirm involvement of benzodiazepine receptors in the anticonvulsant activity of these compounds.
Asunto(s)
Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Benzodiazepinas/química , Benzodiazepinas/farmacología , Triazoles/química , Anticonvulsivantes/síntesis química , Benzodiazepinas/síntesis química , Sitios de Unión , Técnicas de Química Sintética , Diseño de Fármacos , Antagonistas de Receptores de GABA-A/química , Antagonistas de Receptores de GABA-A/farmacología , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Unión Proteica , Relación Estructura-Actividad Cuantitativa , Receptores de GABA-A/química , Convulsiones/tratamiento farmacológico , Convulsiones/etiologíaRESUMEN
A novel series of biscoumarin-1,2,3-triazole hybrids 6a-n was prepared and evaluated for α-glucosidase inhibitory potential. All fourteen derivatives exhibited excellent α-glucosidase inhibitory activity with IC50 values ranging between 13.0⯱â¯1.5 and 75.5⯱â¯7.0⯵M when compared with the acarbose as standard inhibitor (IC50â¯=â¯750.0⯱â¯12.0⯵M). Among the synthesized compounds, compounds 6c (IC50â¯=â¯13.0⯱â¯1.5⯵M) and 6g (IC50â¯=â¯16.4⯱â¯1.7⯵M) exhibited the highest inhibitory activity against α-glucosidase and were non-cytotoxic towards normal fibroblast cells. Kinetic study revealed that compound 6c inhibits the α-glucosidase in a competitive mode. Furthermore, molecular docking investigation was performed to find interaction modes of the biscoumarin-1,2,3-triazole derivatives.
Asunto(s)
Cumarinas/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , Simulación del Acoplamiento Molecular , Triazoles/farmacología , alfa-Glucosidasas/metabolismo , Células Cultivadas , Cumarinas/síntesis química , Cumarinas/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Lactante , Cinética , Estructura Molecular , Saccharomyces cerevisiae/enzimología , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/químicaRESUMEN
AIM AND OBJECTIVE: The importance of Chromeno[4,3-b]pyridines in bioactive compounds, highlighted the ongoing research on developing novel methods for the construction of this heterocyclic scaffold. Regarding the advantageous features of multi-component reactions in organic synthesis, we will try to synthesize pyridocoumarins through this method. MATERIALS AND METHODS: Chromeno[4,3-b]pyridines were conveniently prepared from a threecomponent condensation reaction between 4-hydroxy coumarin, ammonia and ethyl 2,4-dioxo-4- arylbutanoates in refluxing n-propanol. The synthesized compounds were characterized by NMR, IR and Mass spectroscopy. RESULTS: The reaction proceeded through an in situ formed 4-amino coumarin, affording eight new target compounds in good yields. CONCLUSION: This method introduce a novel approach to ethyl 4-aryl-5-oxo-5H-chromeno[4,3- b]pyridine-2-carboxylate derivatives and allow organic chemists to prepare 4-aminocoumarin in reaction medium.
Asunto(s)
Benzopiranos/síntesis química , Piridinas/síntesis química , Aminocumarinas/síntesis química , Amoníaco/química , Ácido Butírico/química , Estructura Molecular , Solventes/química , TemperaturaRESUMEN
A novel series of dihydropyrano[3,2-c]quinoline derivatives 6a-q were synthesized and evaluated for their in vitro α-glucosidase inhibitory activities. All newly synthesized compounds displayed potent α-glucosidase inhibitory activity in the range of 10.3⯱â¯0.3⯵M-172.5⯱â¯0.8⯵M against the yeast α-glucosidase enzyme when compared to the standard drug acarbose (IC50â¯=â¯750.0⯱â¯1.5⯵M). Among these compounds, compounds 6e and 6d displayed the most potent α-glucosidase inhibitory activity (IC50â¯=â¯10.3⯱â¯0.3 and 15.7⯱â¯0.5⯵M, respectively). The kinetic analysis of the most potent compounds 6e and 6d revealed that compound 6e inhibited α-glucosidase in an uncompetitive manner (Kiâ¯=â¯11⯵M) while compound 6d was a non-competitive inhibitor (Kiâ¯=â¯28⯵M) of the enzyme. Then, the cytotoxicity of the most potent compounds (i.e., compounds 6a, 6d, 6e, 6â¯g, 6j, and 6l) were evaluated for toxicity using the breast cancer cell lines MDA-MB231, MCF-7, and T-47D by using a MTT assay, and no toxicity was observed.