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Fulltext Triazoloquinazolines as a new class of potent α-glucosidase inhibitors: in vitro evaluation and docking study

Abuelizz HA, Anouar EH, Ahmad R, Azman NIIN, Marzouk M, Al-Salahi R

PLoS One, 2019;14(8):e0220379.
PMID: 31412050 DOI: 10.1371/journal.pone.0220379

Previously, we synthesized triazoloquinazolines 1-14 and characterized their structure. In this study, we aimed to evaluate the in vitro activity of the targets 1-14 as α-glucosidase inhibitors using α-glucosidase enzyme from Saccharomyces cerevisiae type 1. Among the tested compounds, triazoloquinazolines 14, 8, 4, 5, and 3 showed the highest inhibitory activity (IC50 = 12.70 ± 1.87, 28.54 ± 1.22, 45.65 ± 4.28, 72.28 ± 4.67, and 83.87 ± 5.12 μM, respectively) in relation to that of acarbose (IC50 = 143.54 ± 2.08 μM) as a reference drug. Triazoloquinazolines were identified herein as a new class of potent α-glucosidase inhibitors. Molecular docking results envisaged the plausible binding interaction between the target triazoloquinazolines and α-glucosidase enzyme and indicated considerable interaction with the active site residues.
Fulltext Synthesis, biological activity and molecular docking of new tricyclic series as α-glucosidase inhibitors

Abuelizz HA, Iwana NANI, Ahmad R, Anouar EH, Marzouk M, Al-Salahi R

BMC Chem, 2019 Dec;13(1):52.
PMID: 31384800 DOI: 10.1186/s13065-019-0560-4

Diabetes is an emerging metabolic disorder. α-Glucosidase inhibitors, such as acarbose, delay the hydrolysis of carbohydrates by interfering with the digestive enzymes. This action decreases the glucose absorption and the postprandial glucose level. We have synthesized 25 tricyclic 2-phenoxypyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones hybrids and evaluated their α-glucosidase inhibitory activity. Compounds 6h and 6d have shown stronger activity than that of acarbose. Compound 6h exhibited the highest inhibition with an IC50 of 104.07 µM. Molecular modelling studies revealed that compound 6h inhibits α-glucosidase due to the formation of a stable ligand-α-glucosidase complex and extra hydrogen bond interactions, and directed in the binding site by Trp329.25 tricyclic 2-phenoxypyrido[3,2-e][1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-ones hybrids have been synthesized and evaluated their α-glucosidase inhibitory activity. Compounds 6h have shown stronger activity than that of acarbose.
3-Benzyl(phenethyl)-2-thioxobenzo[g]quinazolines as a new class of potent α-glucosidase inhibitors: synthesis and molecular docking study

Al-Salahi R, Ahmad R, Anouar E, Iwana Nor Azman NI, Marzouk M, Abuelizz HA

Future Med Chem, 2018 08 01;10(16):1889-1905.
PMID: 29882426 DOI: 10.4155/fmc-2018-0141

AIM: Using a simple modification on a previously reported synthetic route, 3-benzyl(phenethyl)-2-thioxobenzo[g]quinazolin-4(3H)-ones (1 and 2) were synthesized with high yields. Further transformation of 1 and 2 produced derivatives 3-26, which were structurally characterized based on NMR and MS data, and their in vitro α-glucosidase inhibitory activity was evaluated using Baker's yeast α-glucosidase enzyme.
RESULTS: Compounds 2, 4, 8, 12 and 20 exhibited the highest activity (IC50 = 69.20, 59.60, 49.40, 50.20 and 83.20 μM, respectively) compared with the standard acarbose (IC50 = 143.54 μM).
CONCLUSION: A new class of potent α-glucosidase inhibitors was identified, and the molecular docking predicted plausible binding interaction of the targets in the binding pocket of α-glucosidase and rationalized the structure-activity relationship (SARs) of the target compounds.
Evaluation of Cytotoxic and Tyrosinase Inhibitory Activities of 2-phenoxy(thiomethyl) pyridotriazolopyrimidines: In Vitro and Molecular Docking Studies

Abuelizz HA, Anouar EH, Marzouk M, Hasan MH, Saleh SR, Ahudhaif A, et al.

Anticancer Agents Med Chem, 2020;20(14):1714-1721.
PMID: 32593283 DOI: 10.2174/1871520620666200627212128

BACKGROUND: The use of tyrosinase has confirmed to be the best means of recognizing safe, effective, and potent tyrosinase inhibitors for whitening skin. Twenty-four 2-phenoxy(thiomethyl)pyridotriazolopyrimidines were synthesized and characterized in our previous studies.
OBJECTIVE: The present work aimed to evaluate their cytotoxicity against HepG2 (hepatocellular carcinoma), A549 (pulmonary adenocarcinoma), MCF-7 (breast adenocarcinoma) and WRL 68 (embryonic liver) cell lines.
METHODS: MTT assay was employed to investigate the cytotoxicity, and a tyrosinase inhibitor screening kit was used to evaluate the Tyrosinase (TYR) inhibitory activity of the targets.
RESULTS: The tested compounds exhibited no considerable cytotoxicity, and nine of them were selected for a tyrosinase inhibitory test. Compounds 2b, 2m, and 5a showed good inhibitory percentages against TYR compared to that of kojic acid (reference substance). Molecular docking was performed to rationalize the Structure-Activity Relationship (SAR) of the target pyridotriazolopyrimidines and analyze the binding between the docked-selected compounds and the amino acid residues in the active site of tyrosinase.
CONCLUSION: The target pyridotriazolopyrimidines were identified as a new class of tyrosinase inhibitors.