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Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity.

ABSTRACT: Acetylcholinesterase (AChE) and ?-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer's disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35-85%). Six of the synthetic flavones (B4, B5, B6, B8, D6 and D7) had completely new structures. The AChE and BACE-1 inhibitory activities were tested, giving pIC50 3.47-4.59 (AChE) and 4.15-5.80 (BACE-1). Three compounds (B3, D5 and D6) exhibited the highest biological effects on both AChE and BACE-1. A molecular docking investigation was conducted to explain the experimental results. These molecules could be employed for further studies to discover new structures with dual action on both AChE and BACE-1 that could serve as novel therapies for AD.

SUBMITTER: Tran TS

PROVIDER: S-EPMC7570966 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity.

Tran Thai-Son TS Tran Thanh-Dao TD Tran The-Huan TH Mai Thanh-Tan TT Nguyen Ngoc-Le NL Thai Khac-Minh KM Le Minh-Tri MT Le Minh-Tri MT

Molecules (Basel, Switzerland) 20200905 18

Acetylcholinesterase (AChE) and β-secretase (BACE-1) have become attractive therapeutic targets for Alzheimer's disease (AD). Flavones are flavonoid derivatives with various bioactive effects, including AChE and BACE-1 inhibition. In the present work, a series of 14 flavone derivatives was synthesized in relatively high yields (35-85%). Six of the synthetic flavones (B4, B5, B6, B8, D6 and D7) had completely new structures. The AChE and BACE-1 inhibitory ...[more]

PMID: 32899576

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Project description:The quinoxaline core is a promising scaffold in medicinal chemistry. Multiple quinoxaline derivatives, such as the topoisomerase IIβ inhibitor XK-469 and the tissue transglutaminase 2 inhibitor GK-13, have been evaluated for their antiproliferative activity. Previous work reported that quinoxaline derivatives bearing an oxirane ring present antiproliferative properties against neuroblastoma cell lines SK-N-SH and IMR-32. Likewise, quinoxalines with an arylethynyl group displayed promising antineoplastic properties against glioblastoma and lung cancer cell lines, U87-MG and A549 respectively. Here, 40 new quinoxaline derivatives bearing an oxirane ring were synthesized using a tetrakis(dimethylamino)ethylene (TDAE) strategy and a Sonogashira cross-coupling reaction. Each reaction with TDAE furnished a pair of diastereoisomers cis and trans. These new compounds formed two series according to the substitution of position 2 on the quinoxaline core, with chlorine or phenylacetylene respectively. Each of these isomers was evaluated for antiproliferative activity against neuroblastoma cell lines SK-N-SH and IMR-32 by MTT assay. All cell viability assay results were analyzed using R programming, as well as a statistical comparison between groups of compounds. Our evaluation showed no difference in drug sensitivity between the two neuroblastoma cell lines. Moreover, trans derivatives were observed to display better activities than cis derivatives, leading us to conclude that stereochemistry plays an important role in the antiproliferative activity of these compounds. Further support for this hypothesis is provided by the lack of improvement in antineoplastic activity following the addition of the phenylacetylene moiety, probably due to steric hindrance. As a result, compounds with nitrofuran substituents from the TDAE series demonstrated the highest antiproliferative activity with IC50 = 2.49 ± 1.33 μM and IC50 = 3.96 ± 2.03 μM for compound 11a and IC50 = 5.3 ± 2.12 μM and IC50 = 7.12 ± 1.59 μM for compound 11b against SK-N-SH and IMR-32, respectively. Furthermore, an in silico study was carried out to evaluate the mechanism of action of our lead compounds and predict their pharmacokinetic properties.

Dataset Information

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity.

Publications

Synthesis, In Silico and In Vitro Evaluation of Some Flavone Derivatives for Acetylcholinesterase and BACE-1 Inhibitory Activity.

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