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.

A series of prenylated resveratrol derivatives were designed, semisynthesized and biologically evaluated for inhibition of β-secretase (BACE1) and amyloid-β (Aβ) aggregation as well as free radical scavenging and neuroprotective and neuritogenic activities, as potential novel multifunctional agents against Alzheimer's disease (AD). The results showed that compound 4b exhibited good anti-Aβ aggregation (IC = 4.78 µM) and antioxidant activity (IC = 41.22 µM) and moderate anti-BACE1 inhibitory activity (23.70% at 50 µM), and could be a lead compound. Moreover, this compound showed no neurotoxicity along with a greater ability to inhibit oxidative stress on P19-derived neuronal cells (50.59% cell viability at 1 nM). The neuritogenic activity presented more branching numbers (9.33) and longer neurites (109.74 µm) than the control, and was comparable to the quercetin positive control. Taken together, these results suggest compound 4b had the greatest multifunctional activities and might be a very promising lead compound for the further development of drugs for AD.

Tryptoline, a core structure of ochrolifuanine E, which is a hit compound from virtual screening of the Thai herbal database against BACE1 was used as a scaffold for the design of BACE1 inhibitors. The tryptoline was linked with different side chains by 1,2,3-triazole ring readily synthesized by catalytic azide-alkyne cycloaddition reactions. Twenty two triazolyl tryptoline derivatives were synthesized and screened for the inhibitory action against BACE1. JJCA-140 was the most potent inhibitor (IC 50 = 1.49 μM) and was 100 times more selective for BACE1 than for Cat-D. KeywordsBACE1; BACE1 inhibitor; JJCA-140; Tryptoline; Docking; Binding mode; Enzyme assay; Cathepsin-D Alzheimer's disease (AD) is a common neuro-degenerative disorder which affects 20-30 million individuals worldwide. 1 The patients' cognitive function slowly declines, leading to end-stage disease and death with-in 9 years after the diagnosis. 1,2 The deposition of aggregated β-amyloid peptides (Aβ 40,42 ) as plaques in brain is a hallmark of AD. Inhibition of the formation of amyloid plaques has been targeted in the new drug development. β-Secretase (BACE1) and γ-secretase are the key enzymes to generate these peptides from amyloid precursor protein (APP). The cleavage of APP by BACE1 is the initial step in Aβ formation; also, BACE1-knockout mice are deficient in Aβ production with no compensatory mechanism. Thus, inhibition of BACE1 activity becomes the promising target is an attractive target for AD drug development. 2,3 BACE1 inhibitor was studied for more than a decade. Most of them were developed from nonhydrolyzable hydroxyethylene dipeptide isostere, 4-6 high-throughput screening (HTS), 7,8 and fragment-base screening. [9][10][11] In this study, new core structures of BACE1 inhibitors were identified via virtual screening of the Thai medicinal database. Ochrolifuanine E and its tryptoline core have not previously been described pharmacophores for BACE1 inhibition, and this discovery represents another direction in the design of BACE1 inhibitors. Thai medicinal database (Chemiebase 12,13 ) compounds were the source of various scaffolds for virtual screening (AutoDock 4.0) 14 and pharmacokinetic and toxicity filtering (Discovery Studio, Accelrys). 15 The Chemiebase covers the herbs in Thai Traditional Pharmacopoeias and the herbs used by the local practitioners for the preparation of traditional medicines. The flora in the database ranges from common to scarce and some plants are in danger of extinction in Thailand. Most of the plants are also common in neighboring countries or countries in other part of the world with the same climate. All identified compounds from the herbs reported under the same botanical names were collected and compiled. Currently, there are 2048 compounds in the database. Based on Thai traditional knowledge and the reduced search space, this database considered a knowledgebased database, and virtual screening of a knowledge-based database or focus library is recognized as an efficient strategy for lead identi...

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