RESUMEN
AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aß, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/metabolismo , Animales , HumanosRESUMEN
A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2H)-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c-3e and 4c-4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c-3e and 4c-4e (IC50 0.60-1.11µM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Diseño de Fármacos , Edema/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Triazinas/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Carragenina , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Femenino , Compuestos Heterocíclicos de 4 o más Anillos/química , Humanos , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/química , Úlcera/inducido químicamente , Úlcera/tratamiento farmacológicoRESUMEN
A series of triazin-3(2H)-one derivatives bearing 1,3,4-oxadiazole (4a-4o) were synthesized, characterized and evaluated for anti-inflammatory and analgesic activities. Preliminary in vitro anti-inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub-chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti-inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d, 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e, 4g, 4j, and 4l to inhibit (cyclooxygenase-1) COX-1 and (cyclooxygenase-2) COX-2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX-2 IC50: 3.07 µM) at the COX-2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme.
Asunto(s)
Analgésicos/síntesis química , Analgésicos/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Simulación de Dinámica Molecular , Oxadiazoles/química , Triazinas/farmacología , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/química , Conducta Animal/efectos de los fármacos , Carragenina , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/tratamiento farmacológico , Formaldehído , Cinética , Ratones , Estructura Molecular , Oxadiazoles/farmacología , Dolor/inducido químicamente , Dolor/tratamiento farmacológico , Ratas , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/químicaRESUMEN
Novel N3 aryl/heteroaryl substituted 2-((benzyloxy and phenylthio) methyl) 6,7-dimethoxyquinazolin-4(3H)- ones (8a-8l) were synthesized and evaluated for their anticonvulsant activity using various models of epilepsy, such as maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and intracerebroventricular AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in mice. The rotarod test has been used to determine the acute neurotoxicity. Further, the serum enzymatic activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assessed along with histopathological examination of liver. Among all the derivatives, compound 8f displayed significant activity profile based on the overall magnitude of activity and minimum neurotoxicity.