Multifunctional Small Molecules as Potential Anti-Alzheimer’s Disease Agents

Abstract

Alzheimer’s disease (AD) is a severe multifactorial neurodegenerative disorder characterized by a progressive loss of neurons in the brain. Despite research efforts, the pathogenesis and mechanism of AD progression are not yet completely understood. There are only a few symptomatic drugs approved for the treatment of AD. The multifactorial character of AD suggests that it is important to develop molecules able to target the numerous pathological mechanisms associated with the disease. Thus, in the context of the worldwide recognized interest of multifunctional ligand therapy, we report herein the synthesis, characterization, physicochemical and biological evaluation of a set of five (1a–e) new ferulic acid-based hybrid compounds, namely feroyl-benzyloxyamidic derivatives enclosing different substituent groups, as potential anti-Alzheimer’s disease agents. These hybrids can keep both the radical scavenging activity and metal chelation capacity of the naturally occurring ferulic acid scaffold, presenting also good/mild capacity for inhibition of self-Aβ aggregation and fairly good inhibition of Cu-induced Aβ aggregation. The predicted pharmacokinetic properties point towards good absorption, comparable to known oral drugs.

Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress

“…The synthesis of the target (E)-benzaldehyde O-(benzyl)-oximes 6a-e, 7a-e, 8a-e, 9-11 (Table 1) was carried out as outlined in Scheme 1. The O-(arylmethyl)hydroxylamine hydrochlorides 16a-e were synthetized as pr ously described by a Mitsunobu reaction between the suitably substituted benzyl brom 13a-e and the N-hydroxyphthalimide 14, followed by the removal of the protec phthalimido group from the key intermediates 15a-e, carried out with ammonia solu 7N in MeOH [17,51,52]. Treatment of 16a-e with the opportune aldehydes 17-21, in m anolic solution and at room temperature, afforded the desired (E)-benzaldehyde O-ben oxime derivatives 6a-e, 7a-e, 8a-e, and 9-11 as the only geometric isomers.…”

“…Treatment of 16a-e with the opportune aldehydes 17-21, in m anolic solution and at room temperature, afforded the desired (E)-benzaldehyde O-ben oxime derivatives 6a-e, 7a-e, 8a-e, and 9-11 as the only geometric isomers. The cor configuration of the products was attributed by their 1 HNMR spectra on the basis of chemical shift value of the diagnostic iminic proton, ranging from 8.46 to 8.03 ppm reported by the literature for the E form [52]. The IR spectra of compounds 6a-e, 7a-e, Scheme 1.…”

New Hybrid Compounds Incorporating Natural Products as Multifunctional Agents against Alzheimer’s Disease

“…A solution of commercially available acids 7-11, (1 eq) in anhydrous DMF (2 mL) under inert nitrogen atmosphere, was added by hydroxybenzotriazole (HOBt) (1.2 eq), Nmethylmorpholine (3 eq), the opportune benzylhydroxylamine hydrochloride 6a-c (3.1 eq) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCI) (1.4 eq) [56]. The mixture obtained was stirred at room temperature (r.t.) and monitored by TLC.…”

“…The studied trifluoromethyl benzyloxyamidic compounds 1a-c, 2a-c, 3a-c, 4a-c, 5a-c (Figure S1) were synthesized according to the synthetic procedure reported in Scheme 1, following the method previously described [56]. The O-arylmethylhydroxylamine hydrochloride 6a-c were prepared applying the synthetic route already described [70,71].…”

“…In a previous work, we synthesized ferulic acid (FA) hybrids as potential multifunctional compounds suitable in the context of multifactorial diseases like AD. Among the FA hybrids, we have identified the good ability of the trifluoromethyl benzyloxyamidic moiety to reduce the Aβ 1-40 fibrillization especially in presence of Cu 2+ [56]. In this context, the conjugation of natural acids with the trifluoromethyl benzyloxyaminic bioactive group has led to a series of new benzyloxyamidic derivatives 1a-c, 2a-c, 3a-c, 4a-c, 5a-c, which were characterized and studied as potential multifunctional agents for the treatment of AD, Figure 1.…”