Design, Synthesis and Multitarget Biological Profiling of Second-Generation Anti-Alzheimer Rhein–Huprine Hybrids

Abstract

Aim: Simultaneous modulation of several key targets of the pathological network of Alzheimer's disease (AD) is being increasingly pursued as a promising option to fill the critical gap of efficacious drugs against this condition. Materials & Methods: A short series of compounds purported to hit multiple targets of relevance in AD has been designed, on the basis of their distinct basicities estimated from high-level quantum mechanical computations, synthesized, and subjected to assays of inhibition of cholinesterases, BACE-1, and Aβ42 and tau aggregation, of antioxidant activity, and of brain permeation. Results: Using, as a template, a lead rhein–huprine hybrid with an interesting multitarget profile, we have developed second-generation compounds, designed by the modification of the huprine aromatic ring. Replacement by [1,8]-naphthyridine or thieno[3,2-e]pyridine systems resulted in decreased, although still potent, acetylcholinesterase or BACE-1 inhibitory activities, which are more balanced relative to their Aβ42 and tau antiaggregating and antioxidant activities. Conclusion: Second-generation naphthyridine- and thienopyridine-based rhein–huprine hybrids emerge as interesting brain permeable compounds that hit several crucial pathogenic factors of AD.

A walk through tau therapeutic strategies

“…Derivatives of 2,4-thiazolidinedione showed activity against GSK-3β (at micromolar IC 50 values) and were also found to inhibit tau aggregation. Other examples of multifunctional compounds include rhein-huprine hybrids, which showed AChE and BACE1 inhibitory activity, as well as Aβ 1-42 and tau anti-aggregating properties [259]. A 1-benzylamino-2-hydroxyalkyl derivative with a diphenylpiperazine fragment, selected form a series of compounds, showed balanced inhibitory activity against both disease-modifying targets, inhibition of BACE1, inhibition of Aβ, inhibition of tau aggregation, as well as inhibition of BuChE as a symptomatic target [254].…”

Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy

“…The presented hybrid protects transgenic mice from cognitive deficits and, thereby, can be considered a multifunctional disease-modifying anti-Alzheimer agent. Additionally, the group has reported on second-generation anti-AD rhein-huprine hybrids with potent inhibitory activities against human AChE and BACE-1 and Aβ42 anti-aggregating activity [ 139 ]. The most potent compound ( 7e , Figure 5 ), after intraperitoneal administration in APP-PS1 transgenic mice, showed a central effect in lowering soluble Aβ [ 140 ].…”

A novel class of multitarget anti-Alzheimer benzohomoadamantane‒chlorotacrine hybrids modulating cholinesterases and glutamate NMDA receptors

“…Aβ and tau [52]. Additionally, other families of hybrid compounds featuring a huprine moiety, closely related to 6chlorotacrine, as AChE inhibitor pharmacophore, have been shown to inhibit in vitro BACE-1, the enzyme that catalyzes the first and rate-limiting step of Aβ production from the amyloid precursor protein (APP) [53,63,64], with IC50 values ranging from nanomolar to low micromolar.…”