A New Series of Aryloxyacetic Acids Endowed with Multi-Target Activity towards Peroxisome Proliferator-Activated Receptors (PPARs), Fatty Acid Amide Hydrolase (FAAH), and Acetylcholinesterase (AChE)

Abstract

A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer’s disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Aβ peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD.

Novel Phenothiazine/Donepezil-like Hybrids Endowed with Antioxidant Activity for a Multi-Target Approach to the Therapy of Alzheimer’s Disease

“…These are the best results obtained so far for multi-target agents synthesized by our group: in a recent study on donepezil-like hybrids [ 13 ] we obtained compounds with very high activities on AChE (IC 50 up to sub-nanomolar), moderate inhibitory abilities on FAAH (in the medium-micromolar range) and no activity on Aβ 1-40 aggregation, except for a few derivatives at very high concentrations (100 µM). In other cases [ 15 ], the good activity on FAAH (low-micromolar range) was not associated with acceptable potencies against AChE and Aβ 1-40 aggregation.…”

“…The crude brown solid was purified by column chromatography (n-hexane/EtOAc 7:3), affording a glassy solid, yield 37%. 1 H-NMR (300 MHz, CDCl 3 ) δ (ppm): 2.21 (s, 3H, NCOCH 3 ), 2.60 (s, 3H, COCH 3 ), 7.22-7.52 (m, 5H, aromatics), 7.81 (dd, J = 8.1 Hz, 1.8 Hz, 1H, aromatic), 8.09 (d, J = 1.5 Hz, 1H, aromatic); 13 (15) [M] + , 241 (100) [26].…”

“…FAAH is involved in the degradation of the important endocannabinoid mediator anandamide and its expression is heightened in inflammatory states and during neurodegenerative processes. Its inhibition may therefore be a feasible route in the search for new therapeutic options for the treatment of AD [ 15 ].…”

A New Antidiabetic Agent Showing Short- and Long-Term Effects Due to Peroxisome Proliferator-Activated Receptor Alpha/Gamma Dual Agonism and Mitochondrial Pyruvate Carrier Inhibition

“…Compounds 6 was prepared starting from phenyl acetone and 4-phenylphenol (Scheme ) according to the Bargellini conditions, using chloroform as a reagent in the presence of NaOH solution as a base …”

“…24 Compounds 6 was prepared starting from phenyl acetone and 4-phenylphenol (Scheme 4) according to the Bargellini conditions, using chloroform as a reagent in the presence of NaOH solution as a base. 25 Scheme 5 describes the synthesis of compound 9, which started from the preparation of 9a from 4-phenylphenol and ethyl bromoacetate. The condensation of 9a with benzaldehyde in the presence of lithium diisopropylamide (LDA) and subsequent treatment with benzenesulfonyl chloride gave the sulfonic intermediate 9b.…”