Triazolyl tryptoline derivatives as β-secretase inhibitors

Abstract

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...

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

“…The tryptoline azide ( S )-3-(azidomethyl)-2,3,4,9-tetrahydro-1 H -pyrido[3,4-b]indole ( 5 ) was synthesized as described previously [8]. The synthetic pathway to the tryptamine core, (S) -3-(-2-amino-3-(1 H -1,2,3-triazol-1-yl)propyl)indole, is shown in Scheme 1.…”

“…The BACE1 template 2IRZ-F was constructed from two crystal structures of β-secretase (BACE1) bound to inhibitors (Protein Data Bank code: 2IRZ [26] and 1FKN [27]) as previously described [8]. Docking parameters in the docking studies were as follows: the number of genetic algorithm (GA) runs was 100; the population size was 150; the maximum number of energy evaluations was increased to 15,000,000 per run; and the maximum number of generations was 27,000.…”

“…In a previous report, we discovered the core BACE1 inhibitor structure (tryptoline) from virtual screening of Thai medicinal plants [8]. To increase the efficacy, modification of a core structure and multifunctional design were performed.…”

Recent Development of Multifunctional Agents as Potential Drug Candidates for the Treatment of Alzheimer’s Disease

“…A new series of tryptoline and tryptamine triazole derivatives was designed and synthesized by Jiaranaikulwanitch et al [ 119 ] as multifunctional agents. In a previous report [ 120 ], the authors discovered the structure of tryptoline as responsible for BACE1 inhibition. In the development of new multifunctional ligands the tryptamine moiety was introduced as a bioisostere of tryptoline.…”

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

“…Jiaranaikulwanitch et al used tryptoline, a core structure of ochrolifuanine E 25, which is a hit compound from virtual screening of the Thai herbal database against BACE1 was used for the design of BACE1 inhibitors [50]. The tryptoline was linked with different side chains by 1,2,3-triazole ring readily synthesized by catalytic azide-alkyne cycloaddition reactions.…”