RESUMEN
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease that has a heavy social and economic impact on all societies and for which there is still no cure. Multitarget-directed ligands (MTDLs) seem to be a promising therapeutic strategy for finding an effective treatment for this disease. For this purpose, new MTDLs were designed and synthesized in three steps by simple and cost-efficient procedures targeting calcium channel blockade, cholinesterase inhibition, and antioxidant activity. The biological and physicochemical results collected in this study allowed us the identification two sulfonamide-dihydropyridine hybrids showing simultaneous cholinesterase inhibition, calcium channel blockade, antioxidant capacity and Nrf2-ARE activating effect, that deserve to be further investigated for AD therapy.
Asunto(s)
Enfermedad de Alzheimer , Dihidropiridinas , Enfermedades Neurodegenerativas , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/uso terapéutico , Ligandos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Dihidropiridinas/farmacología , Dihidropiridinas/uso terapéutico , Canales de Calcio , Colinesterasas/metabolismo , Acetilcolinesterasa/metabolismoRESUMEN
Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software.
Asunto(s)
Enfermedad de Alzheimer , Antioxidantes , Bloqueadores de los Canales de Calcio , Inhibidores de la Colinesterasa , Terapia Molecular Dirigida , Factor 2 Relacionado con NF-E2 , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Antioxidantes/síntesis química , Inhibidores de la Colinesterasa/síntesis química , Ligandos , Factor 2 Relacionado con NF-E2/metabolismo , Relación Estructura-Actividad , Bloqueadores de los Canales de Calcio/síntesis químicaRESUMEN
This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a-l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities.