Design, synthesis, evaluation of novel compounds to treat Alzheimer's

Alzheimer's disease (AD) is a chronic, irreversible, and progressive neurodegenerative disorder that produces severe cognitive impairment in the elderly.

At the molecular level, AD is characterized by the presynaptic decrease of acetylcholine (ACh), extracellular deposition of amyloid-b (Ab) plaques, and intracellular accumulation of hyper-phosphorylated tau protein and neurofibrillary tangles (NFTs).

Carbazoles are naturally occurring phytochemicals which possess a wide range of biological activities including beneficial effect in AD; Studies show that carbazole derivatives have the capacity of inhibiting Ab aggregation.

Moreover, the substituted carbazole derivative carvedilol is an effective inhibitor of Ab fibril formation.

Based on pharmacophoric role of both carbazole and 1,2,3-triazole scaffold, designing triazole containing carbazole derivatives for pharmacological studies in the field of AD therapy seems to be desirable.

In this study, synthesis and biological evaluation of 9-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-9H-carbazole derivatives were analyzed as new AChE inhibitors.

To implement the study, target compounds 6a–q were easily synthesized in two steps. At first, 9-(prop-2-yn-1-yl)-9Hcarbazole was synthesized via the reaction between carbazole and propargyl bromide.

Several bases and solvents were screened for this reaction, but the best result was obtained in the presence of sodium hydride (NaH) as a base and a mixture of DMF and THF as solvent at ambient temperature.

Finally, copper-catalyzed azide–alkyne cycloaddition (CuAAC) was used to prepare the novel carbazole derivatives 6 bearing N-benzyl triazole moiety via one-pot three-component click reaction of alkyne 3, sodium azide (4), and benzyl halides 5.

All of target compounds were obtained as pure 1,4-substituted regioisomers and isolated by simple crystallization from ethanol without the need for chromatography. 

According to the results, the best media were achieved by using mixture of DMSO/water as solvent and sodium ascorbate/CuSO4.5H2O as catalyst.

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