From BACE1 Inhibitor to Multifunctionality of Tryptoline and Tryptamine Triazole Derivatives for Alzheimer’s Disease

Abstract

Efforts to discover new drugs for Alzheimer’s disease emphasizing multiple targets was conducted seeking to inhibit amyloid oligomer formation and to prevent radical formation. The tryptoline and tryptamine cores of BACE1 inhibitors previously identified by virtual screening were modified in silico for additional modes of action. These core structures were readily linked to different side chains using 1,2,3-triazole rings as bridges by copper catalyzed azide-alkyne cycloaddition reactions. Three compounds among the sixteen designed compounds exerted multifunctional activities including β-secretase inhibitory action, anti-amyloid aggregation, metal chelating and antioxidant effects at micromolar levels. The neuroprotective effects of the multifunctional compounds 6h, 12c and 12h on Aβ1-42 induced neuronal cell death at 1 μM were significantly greater than those of the potent single target compound, BACE1 inhibitor IV and were comparable to curcumin. The observed synergistic effect resulting from the reduction of the Aβ1-42 neurotoxicity cascade substantiates the validity of our multifunctional strategy in drug discovery for Alzheimer’s disease.

Melatonin ameliorates Aβ42‐induced alteration of βAPP‐processing secretases via the melatonin receptor through the Pin1/GSK3β/NF‐κB pathway in SH‐SY5Y cells

“…Aggregated Aβ 42 was prepared as described previously . The lyophilized powder of Aβ 42 was dissolved in PBS at a concentration of 2 mmol/L and stored at −80°C.…”

Benzofuran and Indole: Promising Scaffolds for Drug Development in Alzheimer's Disease

“…Jiaranaikulwanitch et al report tryptoline and tryptamine triazole derivatives as multifunctional agents to treat AD. [135] Of the 16 derivatives prepared, compounds 65, 66,a nd 67 ( Figure 49) show multifunctional activities, including b-secretase inhibitory action, antiamyloid aggregation,a nd metal chelating and antioxidant effects at micromolar levels. Compounds 65, 66,a nd 67 show neuroprotective effects against Ab42-induced neuronal cell death at 1 mm concentration, which is comparable to curcumin.…”

“…Structures of compounds 65, 66,a nd 67. [135] ChemMedChem 2018, 13,1275 -1299 www.chemmedchem.org radicals cavenging and lipid peroxidation inhibition in vitro is expressed by most of the studied compounds;h owever,J L40 and JL432 presentt he highest lipoxygenase inhibitory activities.…”

Combining BACE1 Inhibition with Metal Chelation as Possible Therapy for Alzheimer’s Disease

“…10 [51]. Among the compounds prepared, 27 showed good activity with the anti-Aβ aggregation by inhibiting the BACE1 and removing high oxidation potential through iron chelation to form complex 28 as presented in Fig.…”