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...
Alzheimer’s disease (AD) is a common neurodegenerative disorder. The number of patients with AD is projected to reach 152 million by 2050. Donepezil, rivastigmine, galantamine, and memantine are the only four drugs currently approved by the United States Food and Drug Administration for AD treatment. However, these drugs can only alleviate AD symptoms. Thus, this research focuses on the discovery of novel lead compounds that possess multitarget regulation of AD etiopathology relating to amyloid cascade. The ascorbic acid structure has been designated as a core functional domain due to several characteristics, including antioxidant activities, amyloid aggregation inhibition, and the ability to be transported to the brain and neurons. Multifunctional ascorbic derivatives were synthesized by copper (I)-catalyzed azide–alkyne cycloaddition reaction (click chemistry). The in vitro and cell-based assays showed that compounds 2c and 5c exhibited prominent multifunctional activities as beta-secretase 1 inhibitors, amyloid aggregation inhibitors, and antioxidant, neuroprotectant, and anti-inflammatory agents. Significant changes in activities promoting neuroprotection and anti-inflammation were observed at a considerably low concentration at a nanomolar level. Moreover, an in silico study showed that compounds 2c and 5c were capable of being permeated across the blood–brain barrier by sodium-dependent vitamin C transporter-2.
Since the pandemic of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in December 2019, the infection cases have quickly increased by more than 511 million people. The long epidemic outbreak over 28 months has affected health and economies worldwide. An alternative medicine appears to be one choice to alleviate symptoms and reduce mortality during drug shortages. Dendrobium extract is one of the traditional medicines used for COVID-19 infection. Several compounds in Dendrobium sp. had been reported to exert pharmacological activities to treat common COVID-19-related symptoms. Herein, in silico screening of 83 compounds from Dendrobium sp. by using the SARS-CoV-2 spike protein receptor-binding domain (RBD) as a drug target was performed in searching for a new lead compound against SARS-CoV-2 infection. Four hit compounds showing good binding affinity were evaluated for antiviral infection activity. The new lead compound DB36, 5-methoxy-7-hydroxy-9,10-dihydro-1,4-phenanthrenequinone, was identified with the IC50 value of 6.87 ± 3.07 µM. The binding mode revealed that DB36 bound with the spike protein at the host receptor, angiotensin-converting enzyme 2 (ACE2) binding motif, resulted in antiviral activity. This study substantiated the use of Dendrobium extract for the treatment of SARS-CoV-2 infection and has identified new potential chemical scaffolds for further drug development of SARS-CoV-2 entry inhibitors.
Miang, a Thai traditional fermented tea (Camellia sinensis var. assamica), is exploited as nutraceutical and cosmeceutical ingredients despite limited standardization studies. Thus, this research aimed to develop a simple and rapid method for miang quality control using catechin and high‐performance thin‐layer chromatography (HPTLC) validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the Association of Official Analytical Collaboration (AOAC). The developing solvent consisting of toluene: ethyl acetate: acetone: formic acid (6:6:6:1 v/v/v/v) showed acceptable specificity with Rf value of 0.54 ± 0.02 and linearity with correlation coefficient of 0.9951. The recovery was 98.84%–103.53%, and the RSD of intra‐ and inter‐day precision was 0.70%–3.00% and 1.93%–4.94%, respectively. Miang ethyl acetate fraction is suggested to be attractive ingredient due to rich catechin (25.78 ± 0.53%), prolonged stability at 40 ◦C, and strong antioxidants determined by the assays of ABTS (IC50 = 3.32 ± 0.74 mg/ml), FRAP (89.05 ± 15.49 mg equivalent of FeSO4/g), and inhibition of lipid peroxidation (IC50 = 4.36 ± 0.67 mg/ml).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.