ABSTRACT
The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine-N-benzyl-acyl-hydrazone derivatives 5a-l, designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N-benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC50 = 5.9 µM, SI > 5.1), with an additional antioxidant activity (IC50 = 7.45 µM) against neuronal t-BOOH-induced oxidative stress and neuroprotective ability against neurotoxicity elicited by both t-BOOH and OAß1-42, and a moderate ability to interfere in Aß1-42 aggregates, with low cytotoxicity and good predictive druggability properties, suggesting a multifunctional pharmacological profile suitable for further drug development against AD.
Subject(s)
Alzheimer Disease , Neuroblastoma , Neuroprotective Agents , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Amyloid beta-Peptides , Antioxidants/pharmacology , Cholinesterase Inhibitors/chemistry , Drug Design , Humans , Hydrazones/pharmacology , Hydrazones/therapeutic use , Ligands , Molecular Structure , Neuroblastoma/drug therapy , Neuroprotective Agents/chemistry , Piperidines/chemistry , Structure-Activity RelationshipABSTRACT
Over the past 70 years, the understanding of Autism Spectrum Disorder (ASD) improved greatly and is characterized as a heterogeneous neuropsychiatric syndrome. ASD is characterized by difficulties in social communication, restricted and repetitive behavior, interests, or activities. And it is often described as a combination of genetic predisposition and environmental factors. There are many treatments and approaches to ASD, including pharmacological therapies with antipsychotics, antidepressants, mood regulators, stimulants, and behavioral ones. However, no treatment is capable of reverting ASD. This review provides an overview of animal models of autism. We summarized genetic and environmental models and then valproic acid treatment as a useful model for ASD. As well as the main therapies and approaches used in the treatment, relating them to the neurochemical pathways altered in ASD, emphasizing the pharmacological potential of peptides and bioinspired compounds found in animal venoms as a possible future treatment for ASD.
