ASS234, As a New Multi-Target Directed Propargylamine for Alzheimer's Disease Therapy

Abstract

Highlights: ASS2324 is a hybrid compound resulting from the juxtaposition of donepezil and the propargylamine PF9601N ASS2324 is a multi-target directed propargylamine able to bind to all the AChE/BuChE and MAO A/B enzymes ASS2324 shows antioxidant, neuroprotective and suitable permeability properties ASS2324 restores the scopolamine-induced cognitive impairment to the same extent as donepezil, and is less toxic ASS2324 prevents β-amyloid induced aggregation in the cortex of double transgenic mice ASS2324 is the most advanced anti-Alzheimer agent for pre-clinical studies that we have identified in our laboratories The complex nature of Alzheimer's disease (AD) has prompted the design of Multi-Target-Directed Ligands (MTDL) able to bind to diverse biochemical targets involved in the progress and development of the disease. In this context, we have designed a number of MTD propargylamines (MTDP) showing antioxidant, anti-beta-amyloid, anti-inflammatory, as well as cholinesterase and monoamine oxidase (MAO) inhibition capacities. Here, we describe these properties in the MTDL ASS234 , our lead-compound ready to enter in pre-clinical studies for AD, as a new multipotent, permeable cholinesterase/monoamine oxidase inhibitor, able to inhibit Aβ-aggregation, and possessing antioxidant and neuroprotective properties.

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

“…236 In addition, it possessed the desirable properties of both donepezil and PF9601N (237) being capable of simultaneously enhancing both cholinergic and monoaminergic transmission as well as possessing neuroprotective effects. [237][238][239][240] Ultraviolet-visible spectrophotometry analyses showed an irreversible modification of the MAO flavin group by ASS234 (238). The crystal structure of hMAO-B in complex with ASS234 (238) revealed the formation of a covalent adduct with the N5 atom of the flavin cofactor.…”

“…The compound ASS234 ( 238 ) was found to be a potent inhibitor of MAO‐B with IC 50 of 39 ± 4 nM . In addition, it possessed the desirable properties of both donepezil and PF9601N ( 237 ) being capable of simultaneously enhancing both cholinergic and monoaminergic transmission as well as possessing neuroprotective effects . Ultraviolet–visible spectrophotometry analyses showed an irreversible modification of the MAO flavin group by ASS234 ( 238 ).…”

“…Donepezil‐linked hybrids ( 237‐242 ) . hMAO, human monoamine oxidase; IC 50 , half maximal inhibitory concentration…”

“…Donepezil-linked hybrids(237)(238)(239)(240)(241)(242) [234][235][236][237][238][239][240][241][242][243][244][245]. hMAO, human monoamine oxidase; IC50 , half maximal inhibitory concentration as a combined increase in 5-HT and NE levels in the cortex, which was distinct from those induced by the typicalMAOIs clorgyline and deprenyl.…”

Caffeine gold complex supported on magnetic nanoparticles as a green and high turnover frequency catalyst for room temperature A3 coupling reaction in water

“…Propargylamines are useful synthetic intermediates in organic synthesis, and are important building blocks in natural products and therapeutic drug molecules . Some examples of pharmaceutically active compounds having diverse propargylamine moieties are shown in Scheme …”