RESUMEN
Novel N-Benzylpyrrolidine hybrids were designed, synthesized, and tested against multiple in-vitro and in-vivo parameters. Among all the synthesized molecules, 8f and 12f showed extensive inhibition against beta-secretase-1 (hBACE-1), human acetylcholinesterase (hAChE) & human butyrylcholinesterase (hBuChE). These molecules are also endowed with significant AChE-peripheral anionic site (PAS) binding capability, blood-brain barrier permeability, potential disassembly of Aß aggregates along with neuroprotection ability on SHSY-5Y cell lines. Results of the Y-Maze and Morris water maze test concluded that compounds 8f and 12f ameliorated cognitive dysfunction induced by scopolamine and Aß. The ex-vivo activity was executed on rat's brain homogenate indicating a reduction in AChE level and oxidative stress. The pharmacokinetic investigation ascertained considerable oral absorption profile of the lead 12f. The results of the in silico docking studies and molecular dynamics simulations demonstrated stable interactions of compounds 8f and 12f with the target residues of hAChE, hBuChE and hBACE-1.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Fármacos Neuroprotectores/farmacología , Oxadiazoles/farmacología , Pirrolidinas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Oxadiazoles/síntesis química , Oxadiazoles/química , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Multitarget molecular hybrids of N-benzyl pyrrolidine derivatives were designed, synthesized, and biologically evaluated for the treatment of Alzheimer's disease (AD). Among the synthesized compounds, 4k and 4o showed balanced enzyme inhibitions against cholinesterases (AChE and BChE) and BACE-1. Both leads showed considerable PAS-AChE binding capability, excellent brain permeation, potential disassembly of Aß aggregates, and neuroprotective activity against Aß-induced stress. Compounds 4k and 4o also ameliorated cognitive dysfunction against the scopolamine-induced amnesia model in the Y-maze test. The ex vivo study signified attenuated brain AChE activity and antioxidant potential of compounds 4k and 4o. Furthermore, compound 4o also showed improvement in Aß-induced cognitive dysfunction by the Morris water maze test with excellent oral absorption characteristics ascertained by the pharmacokinetic study. In silico molecular docking and dynamics simulation studies of leads suggested their consensual binding affinity toward PAS-AChE in addition to aspartate dyad of BACE-1.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Fármacos Neuroprotectores/farmacología , Pirrolidinas/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Ratas Wistar , Escopolamina , Relación Estructura-ActividadRESUMEN
Thirty ferulic acid-based 1,3,4-oxadiazole molecular hybrids were designed, synthesized, and screened them for multifunctional inhibitory potential against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and beta-secretase-1 (BACE-1). Compound 6j was the most potent inhibitor of AChE (IC50 = 0.068 µM). It also showed equipotent inhibition of BChE and BACE-1 with IC50 values of 0.218 µM and 0.255 µM, respectively. Compound 6k possessed the most significant inhibition of BChE and BACE-1 with IC50 values, 0.163 µM and 0.211 µM, respectively. Compounds 6j and 6k elicited significant displacement of propidium iodide from PAS-AChE, excellent BBB permeability in PAMPA assay, and anti-Aß aggregatory activity in self- and AChE-induced experiments with neuroprotective activity towards neuroblastoma SH-SY5Y cells. The in vivo behavioral studies suggested amelioration of cognitive dysfunction by 6j and 6k in the Y maze test. The ex vivo study signified brain AChE inhibition and antioxidant activity from these compounds. Moreover, 6j showed improvement in learning and memory behavior in the Aß-induced ICV rat model by Morris water maze test with excellent oral absorption characteristics ascertained by pharmacokinetic studies.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Ácidos Cumáricos/farmacología , Diseño de Fármacos , Fármacos Neuroprotectores/farmacología , Oxadiazoles/farmacología , Acetilcolinesterasa/metabolismo , Administración Oral , Enfermedad de Alzheimer/metabolismo , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Amnesia/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Animales , Butirilcolinesterasa/metabolismo , Línea Celular Tumoral , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Ácidos Cumáricos/síntesis química , Ácidos Cumáricos/química , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Oxadiazoles/química , Agregado de Proteínas/efectos de los fármacos , Ratas , Ratas Wistar , Escopolamina , Relación Estructura-ActividadRESUMEN
The diverse nature of Alzheimer's disease (AD) has prompted researchers to develop multi-functional agents. Herein, we have designed and synthesized molecular hybrids of 2-pyridylpiperazine and 5-phenyl-1,3,4-oxadiazoles. Biological activities of synthesized compounds suggested significant and balanced inhibitory potential against target enzymes. In particular, compound 49 containing 2,4-difluoro substitution at terminal phenyl ring considered as most potential lead with inhibition of acetylcholinesterase (hAChE, IC50â¯=â¯0.054⯵M), butyrylcholinesterase (hBChE, IC50â¯=â¯0.787⯵M) and beta-secretase-1 (hBACE-1, IC50â¯=â¯0.098⯵M). The enzyme kinetics study of 49 against hAChE suggested a mixed type of inhibition (Kiâ¯=â¯0.030⯵M). Also, 48 and 49 showed significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE, excellent blood-brain barrier (BBB) permeability in parallel artificial membrane permeation assay (PAMPA), and neuroprotective ability against SH-SY5Y neuroblastoma cell lines. Further, 49 also exhibited anti-Aß aggregation activity in self- and AChE-induced thioflavin T assay, which was ascertained by morphological characterization by atomic force microscopy (AFM). Moreover, in vivo behavioral studies signified learning and memory improvement by compound 49 in scopolamine- and Aß-induced cognitive dysfunctions performed on Y-maze and Morris water maze. The ex vivo studies suggested decreased AChE activity and antioxidant potential of compound 49, with good oral absorption characteristics ascertained by pharmacokinetic studies.