Unveiling new thiazole-clubbed piperazine derivatives as multitarget anti-AD: Design, synthesis, and in silico studies.

Nasr, Eman E; Tawfik, Samar S; Massoud, Mohammed A M; Mostafa, Amany S

Nasr, Eman E; Tawfik, Samar S; Massoud, Mohammed A M; Mostafa, Amany S.

Afiliación

Nasr EE; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Tawfik SS; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Massoud MAM; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.
Mostafa AS; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

Arch Pharm (Weinheim) ; 357(9): e2400044, 2024 Sep.

Article en En | MEDLINE | ID: mdl-38754070

ABSTRACT

ABSTRACT

New thiazole-clubbed piperazine derivatives were designed, synthesized, evaluated for their inhibitory capabilities against human acetylcholinesterase and butyrylcholinesterase (hAChE and/or hBuChE) and ß-amyloid (Aß) aggregation, and investigated for their metal chelating potential as multitarget agents for the treatment of Alzheimer's disease. Compounds 10, 19-21, and 24 showed the highest hAChE inhibitory activity at submicromolar concentrations, of which compound 10 was the most potent with a half-maximal inhibitory concentration (IC50) value of 0.151 µM. Compounds 10 and 20 showed the best hBuChE inhibitory activities (IC50 values of 0.135 and 0.103 µM, respectively), in addition to remarkable Aß1-42 aggregation inhibitory activities and metal chelating capabilities. Both compounds were further evaluated against human neuroblastoma SH-SY5Y and PC12 neuronal cells, where they proved noncytotoxic at their active concentrations against hAChE or hBuChE. They also offered a significant neuroprotective effect against Aß25-35-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. Compound 10 displayed acceptable physicochemical properties and could pass the blood-brain barrier. The molecular docking study revealed the good binding interactions of compound 10 with the key amino acids of both the catalytic active site and the peripheral anionic site of hAChE, explaining its significant potency.

Asunto(s)

Acetilcolinesterasa; Enfermedad de Alzheimer; Péptidos beta-Amiloides; Inhibidores de la Colinesterasa; Diseño de Fármacos; Simulación del Acoplamiento Molecular; Piperazinas; Tiazoles; Humanos; Enfermedad de Alzheimer/tratamiento farmacológico; Inhibidores de la Colinesterasa/farmacología; Inhibidores de la Colinesterasa/síntesis química; Inhibidores de la Colinesterasa/química; Relación Estructura-Actividad; Tiazoles/farmacología; Tiazoles/síntesis química; Tiazoles/química; Piperazinas/farmacología; Piperazinas/síntesis química; Piperazinas/química; Péptidos beta-Amiloides/antagonistas & inhibidores; Péptidos beta-Amiloides/metabolismo; Acetilcolinesterasa/metabolismo; Ratas; Estructura Molecular; Animales; Fármacos Neuroprotectores/farmacología; Fármacos Neuroprotectores/síntesis química; Fármacos Neuroprotectores/química; Células PC12; Butirilcolinesterasa/metabolismo; Relación Dosis-Respuesta a Droga; Línea Celular Tumoral; Fragmentos de Péptidos/antagonistas & inhibidores; Fragmentos de Péptidos/farmacología; Simulación por Computador

Palabras clave

AD; Aß; hAChE; piperazine; thiazole

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperazinas / Acetilcolinesterasa / Tiazoles / Diseño de Fármacos / Inhibidores de la Colinesterasa / Péptidos beta-Amiloides / Enfermedad de Alzheimer / Simulación del Acoplamiento Molecular Límite: Animals / Humans Idioma: En Revista: Arch Pharm (Weinheim) Año: 2024 Tipo del documento: Article País de afiliación: Egipto Pais de publicación: Alemania

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google