Novel tacrine–benzofuran hybrids as potential multi-target drug candidates for the treatment of Alzheimer’s Disease

Abstract

Pursuing the widespread interest on multi-target drugs to combat Alzheimer s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self-and Cu-mediated Ab aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Ab 1-42 induced toxicity. Structure-activity relationship analysis provides insights on the best structural parameters, to take in consideration for future studies in view of potential applications in AD therapy.

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.…”

Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer’s disease

“…Tacrine is a widely used scaffold in the AD therapy research 40 . It provides compounds with reliable inhibitory activity against cholinesterases, its derivatives are repeatedly reported as Aβ aggregation inhibitors 18 , 22 , 41 , 42 and dual inhibitors of self-induced Aβ and tau aggregation potent in in vitro assays and living cells 43 . On the downside of the tacrine-based multifunctional ligands is the fact that very often they lack drug-likeness, mostly due to their high molecular weight, exceeded of limits logP values or potential toxicity.…”

“…Escherichia coli E. coli competent cells BL21 (DE3) were transformed with the pET28a vector (Novagen, Inc., Madison, WI) carrying the DNA sequence of Ab 42 or with pTARA containing the RNA polymerase gene of T7 phage (T7RP) under the control of the promoter pBAD, then with pRKT42 vector encoding four repeats of tau protein in two inserts. For overnight culture preparation, 10 ml of M9 minimal medium containing 50 lg/mL of kanamycin (Ab 42 ) or 50 lg/ mL of ampicillin and 12.5 lg/mL of chloramphenicol (tau) were inoculated with a colony of BL21 (DE3) bearing the plasmid Ab 42 or tau plasmids to be expressed at 37 C and 180 rpm using an incubator shaker (Ovan, Barcelona, Spain). After overnight growth, the OD 600 was usually 2 À 2.5.…”

Natural Compounds for the Prevention and Treatment of Cardiovascular and Neurodegenerative Diseases

“…The prevention and treatment of neurodegenerative diseases (NDs), such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), is an important avenue of research due to the increasing occurrence of these pathologies in the rapidly aging world population. Their multifactorial nature complicates their diagnostic and therapeutic profile and only few drugs are available [ 16 , 17 , 18 ]. Lifestyle factors, including dietary habits, influence the development of NDs, further cementing the role of food-derived compounds such as plant SMs in the long-term physiological balance of the nervous system [ 19 ].…”