Donepezil-based hybrids as multifunctional anti-Alzheimer's disease chelating agents: Effect of positional isomerization

Abstract

The intricate and multifactorial nature of Alzheimer´s disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid-β peptide (Aβ) and metal dyshomeostasis.In order to continue the search for new anti-AD drugs, a design strategy was followed based on repositioning donepezil (DNP), by attaching a benzylpiperidine mimetic of DNP moiety at different (ortho, para) attachment points of a hydroxyphenyl-benzimidazole (BIM) chelating unit. Herein, two compounds (1 and 2) are compared in terms of their potential multiple properties: both present good AChE inhibition (low micromolar range) and are moderate/good inhibitors of Aβ self-and Cu-mediated aggregation; although compound 1 has a higher chelating capacity towards Cu 2+ (pCu = 14.3, pZn = 6.4, pH 7.4, CL/CM = 10, CM = 10 −6 M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Aβ-induced cell toxicity.

Design, Synthesis, and In Vitro Evaluation of Hydroxybenzimidazole-Donepezil Analogues as Multitarget-Directed Ligands for the Treatment of Alzheimer’s Disease

“…(log K3 = 2.86−3.37) and O-phenol (log K1 = 6.99−9.09), when compared with equivalent standard groups (e.g., imidazole 6.95 [30] and phenol 9.98 [27]), reflects the existence of intramolecular hydrogen bond interactions involving these atoms in the BIM moiety. Regarding compound 5 (see Table 1), previously studied [31], its three protonation constants and sequence of protonation were found to be similar to those of compound 1. Table 1.…”

“…12.58 4 and sequence of protonation were found to be similar to those of compound 1. Regarding compound 5 (see Table 1), previously studied [31], its three protonation constants and sequence of protonation were found to be similar to those of compound 1.…”

Importance of Biometals as Targets in Medicinal Chemistry: An Overview about the Role of Zinc (II) Chelating Agents

“…Importantly, the moderate Zn 2+ chelation does not lead to its depletion in synaptic keys, according to the requested selectivity profile [25]. Meanwhile, 6a-6c and derivatives showed numerous additional properties that candidate them for future development on the road of multitarget therapy for AD [36][37][38][39]. Among bifunctional molecules (metal chelation, Figure 7, and Aβ interactions), compound 7a (Figure 7) reduced metal-Aβ neurotoxicity via the modulation of ROS production and of metal-induced Aβ aggregation.…”

Development of new donepezil analogs: synthesis, biological screening and in silico study rational

“…In fact, AChEI may inhibit AChE via a competitive mechanism, by interacting with the CAS of the enzyme, via a non-competitive mechanism, by binding PAS, or via both mechanisms, by exerting a dual binding AChE inhibition [16]. In particular, the indanone moiety of donepezil stacks against Trp279 residue in PAS, while the benzyl ring moiety interacts with Trp 84 residue in CAS [17,18]. Nevertheless, the multifactorial hitting strategy in Alzheimer disease necessitates adapting the multitargeting drug design one [19,20].…”