Insights into the Drug Repositioning Applied to the Alzheimer's Disease Treatment and Future Perspectives

Abstract

Alzheimer's disease is known to be a chronic disease, with an estimated prevalence of about 10-30%, considering the population over 60 years of age. Most patients with this disorder (> 95%) present the sporadic form, being characterized by a late onset (80-90 years of age), and it is the consequence of the failure to clear the amyloid-β (Aβ) peptide from the interstices of the brain. Significant numbers of genetic risk factors for the sporadic disease have been researched. Some existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease- modifying therapies. In this line, a complementary strategy based on repositioning drugs which are approved for the treatment of other disorders could be interesting. It is noteworthy the fact that some clinical trials indicate that several classes of drugs own potent and beneficial effects on the Alzheimer's disease treatment. In this present work, we present the details and evaluation of these alternative treatments. It has highlighted several compounds with relevant evidence for this purpose, which deserves further investigation to clarify optimal treatment conditions in the clinical trials of patients with Alzheimer's disease.

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

“…The inhibition of AChE by the DNP-BIM hybrids herein studied was assayed by using a variation of Ellman´s test [23,34] and the IC 50 values obtained are included in Table 2. All the inhibitors, but the benzyl-pyridinium derivative (12), present IC 50 values in low micromolar range. Among the piperidine (PP) series (PP-BIM), the best results were obtained with compounds 1, 3, and 6, while for the piperazine (PZ) series (PZ-BIM), the most potent were compounds 8, 9, and 10.…”

“…In particular, all the compounds have the first pharmacophore moieties, namely the benzyl-piperidinium (3-6), -piperazinium (7)(8)(9)(10)(11), or -pyridinium (12), anchored to the CAS of AChE (bottom of the gorge), through binding interactions via aromatic π-π stacking with the phenyl ring from Trp 84A; at the middle of the gorge, the charged nitrogen atom can establish a cation-π binding interaction with the phenyl group of Phe330. Noteworthy is the observation that the benzyl-piperidinium moieties of positional isomers (3)(4)(5) present some bending relative to that of DNP, though no significant effect appeared on the complexes with the benzyl-piperazinium substituted (10,11) or the benzyl-pyridinium (12) moieties. Regarding the BIM moieties, similar to the DNP indanone ring, these moieties are at the entrance of the gorge interacting via π-π stacking with the peripheral anionic residue Trp279.…”

“…Molecules 2020, 24, x 4 of 26 DNP, though no significant effect appeared on the complexes with the benzyl-piperazinium substituted (10,11) or the benzyl-pyridinium (12) moieties. Regarding the BIM moieties, similar to the DNP indanone ring, these moieties are at the entrance of the gorge interacting via π-π stacking with the peripheral anionic residue Trp279.…”

“…Twelve hybrid compounds resulted from the conjugation of a hydroxyphenylbenzimidazole (BIM) moiety with benzylpiperidine (PP, 1, 3−6), benzylpiperazine (PZ, 2, 7−11), and also benzylpyridine (12). The hybrids were obtained by following the convergent synthetic approach depicted in Scheme 1.…”

“…Therefore, it seems that there is no competition for copper between these BIM hybrids and Aβ peptide, and so the inhibition Concerning the inhibition of Cu-induced Aβ aggregation, all the compounds induce an increase when comparing with their corresponding capacity for self-inhibition, in accordance with their good chelating capacity towards copper. Nevertheless, these chelators have conditional dissociation constants (K´d) for the copper complexes at pH 7.4 of 34 nanomolar (1), 24 nanomolar (2), 254 picomolar (5), 80 nanomolar (7), and 365 picomolar (12). These values are outside the proposed range K´d = 1−10 picomolar corresponding to chelators eventually able to retrieve copper from Aβ peptide (K´d = 10 picomolar-100 nanomolar for Cu(Aβ) complexes) [41].…”