Dual-target compounds for Alzheimer's disease: Natural and synthetic AChE and BACE-1 dual-inhibitors and their structure-activity relationship (SAR)

Alzheimer's disease (AD) is a chronic neurodegenerative disease and represents the major cause of dementia worldwide. Currently, there are no available treatments capable to deliver disease-modifying effects, and the available drugs can only alleviate the symptoms. The exact pathology of AD is not yet fully understood and several hallmarks such as the presence of amyloid-β (Aβ) senile plaques, neurofibrillary tangles (NFTs) as well as the loss of cholinergic function have been associated to AD. Distinct pharmacological targets have been validated to address AD, with acetylcholinesterase (AChE) and β-secretase-1 (BACE-1) being two of the most explored ones. A great deal of research has been devoted to the development of new AChE and BACE-1 effective inhibitors, tackled separately or in combination of both. The multi-factorial nature of AD conducted to the development of multi-target directed ligands (MTDLs), defined as single molecules capable to modulate more than one biological target, as an alternative approach to the old paradigm one-target one-drug. In this context, this review describes a collection of natural and synthetic compounds with dual-inhibitory properties towards both AChE and BACE-1 in the MTDLs context. Furthermore, this review also provides a critical comprehensive analysis of structure-activity relationships (SAR) of the synthetic compounds. [Display omitted] •AChE and BACE-1 are the most interesting AD related targets.•Single target AChE or BACE-1 inhibitors do not provide disease modifying effects.•Combining pharmacophores for AChE and BACE-1 inhibition results in well-balanced dual-inhibitors.•AChE and BACE-1 dual-inhibitors can be of both natural or synthetic origin.•BBB permeability should not be disregarded from the very beginning of any design strategy.