Curcumin, Resveratrol and Cannabidiol as Natural Key Prototypes in Drug Design for Neuroprotective Agents.

Nowadays, neurodegenerative diseases (NDs), such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), represent a great challenge in different scientific fields, such as neuropharmacology, medicinal chemistry, molecular biology and medicine, as all these pathologies remain incurable, with high socioeconomic impacts and high costs for governmental health services. Due to their severity and multifactorial pathophysiological complexity, the available approved drugs for clinic have not yet shown adequate effectiveness and exhibited very restricted options in the therapeutic arsenal; this highlights the need for continued drug discovery efforts in the academia and industry. In this context, natural products, such as curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) have been recognized as important sources, with promising chemical entities, prototype models and starting materials for medicinal organic chemistry, as their molecular architecture, multifunctional properties and single chemical diversity could facilitate the discovery, optimization and development of innovative drug candidates with improved pharmacodynamics and pharmacokinetics compared to the known drugs and, perhaps, provide a chance for discovering novel effective drugs to combat NDs. In this review, we report the most recent efforts of medicinal chemists worldwide devoted to the exploration of curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) as starting materials or privileged scaffolds in the design of multi-target directed ligands (MTDLs) with potential therapeutic properties against NDs, which have been published in the scientific literature during the last 10 years of research and are available in PubMed, SCOPUS and Web of Science databases.

Cinnamoyl-N-Acylhydrazone-Donepezil Hybrids: Synthesis and Evaluation of Novel Multifunctional Ligands Against Neurodegenerative Diseases.

A new series of ten multifunctional Cinnamoyl-N-acylhydrazone-donepezil hybrids was synthesized and evaluated as multifunctional ligands against neurodegenerative diseases. The molecular hybridization approach was based on the combination of 1-benzyl-4-piperidine fragment from the anti-Alzheimer AChE inhibitor donepezil (1) and the cinnamoyl subunit from curcumin (2), a natural product with remarkable antioxidant, neuroprotective and anti-inflammatory properties, using a N-acylhydrazone fragment as a spacer subunit. Compounds 4a and 4d showed moderate inhibitory activity towards AChE with IC50 values of 13.04 and 9.1 µM, respectively. In addition, compound 4a and 4d showed a similar predicted binding mode to that observed for donepezil in the molecular docking studies. On the other hand, compounds 4a and 4c exhibited significant radical scavenging activity, showing the best effects on the DPPH test and also exhibited a significant protective neuronal cell viability exposed to t-BuOOH and against 6-OHDA insult to prevent the oxidative stress in Parkinson's disease. Similarly, compound 4c was capable to prevent the ROS formation, with indirect antioxidant activity increasing intracellular GSH levels and the ability to counteract the neurotoxicity induced by both OAß1-42 and 3-NP. In addition, ADMET in silico prediction indicated that both compounds 4a and 4c did not show relevant toxic effects. Due to their above-mentioned biological properties, compounds 4a and 4c could be explored as lead compounds in search of more effective and low toxic small molecules with multiple neuroprotective effects for neurodegenerative diseases.

Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases.

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.