Novel Tacrine-Hydroxyphenylbenzimidazole hybrids as potential multitarget drug candidates for Alzheimer's disease

• Published in: European journal of medicinal chemistry Vol. 148; no. C; pp. 255 - 267
• Main Authors: Hiremathad, Asha, Keri, Rangappa S., Esteves, A. Raquel, Cardoso, Sandra M., Chaves, Sílvia, Santos, M. Amélia
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 25.03.2018; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid beta-Peptides - antagonists & inhibitors; Anti amyloid aggregation; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Chemistry, Medicinal; Cholinesterase Inhibitors - pharmacology; Dual binding site AChE inhibitors; Humans; Life Sciences & Biomedicine; Multitarget compounds; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - prevention & control; Pharmacology & Pharmacy; Protein Aggregation, Pathological - prevention & control; Science & Technology; Tacrine - chemistry; Tacrine - pharmacology; Tacrine hybrids; Anti amyloid aggregation; Dual binding site AChE inhibitors; Alzheimer's disease; Multitarget compounds; Tacrine hybrids; DESIGN; ACETYLCHOLINESTERASE; AMYLOID-BETA; VALIDATION; INHIBITORS; BINDING
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.02.023

Alzheimer's disease (AD) is a severe age-dependent neurodegenerative disorder affecting millions of people, with no cure so far. The current treatments only achieve some temporary amelioration of the cognition symptoms. The main characteristics of the patient brains include the accumulation of amyloid plaques and neurofibrillary tangles (outside and inside the neurons) but also cholinergic deficit, increased oxidative stress and dyshomeostasis of transition metal ions. Considering the multi-factorial nature of AD, we report herein the development of a novel series of potential multi-target directed drugs which, besides the capacity to recover the cholinergic neurons, can also target other AD hallmarks. The novel series of tacrine-hydroxyphenylbenzimidazole (TAC-BIM) hybrid molecules has been designed, synthesized and studied for their multiple biological activities. These agents showed improved AChE inhibitory activity (IC50 in nanomolar range), as compared with the single drug tacrine (TAC), and also a high inhibition of self-induced- and Cu-induced-Aβ aggregation (up to 75%). They also present moderate radical scavenging activity and metal chelating ability. In addition, neuroprotective studies revealed that all these tested compounds are able to inhibit the neurotoxicity induced by Aβ and Fe/AscH(-) in neuronal cells. Hence, for this set of hybrids, structure-activity relationships are discussed and finally it is highlighted their real promising interest as potential anti-AD drugs. [Display omitted] •A novel series of TAC-BIM hybrids as potential anti-AD agents.•Excellent AChE inhibitors in nanomolar range.•Good inhibition of self- and Cu-induced Aβ aggregation (up to 75%).•Radical scavenging and metal chelating capacity.•Neuroprotection of cell toxicity induced by AD stressors (Aβ and Fe/AscH(-)).