In Vitro α-Glucosidase and α-Amylase Inhibition, Cytotoxicity and Free Radical Scavenging Profiling of the 6-Halogeno and Mixed 6,8-Dihalogenated 2-Aryl-4-methyl-1,2-dihydroquinazoline 3-Oxides

Nontokozo M Magwaza; Garland K More; Samantha Gildenhuys; Malose J Mphahlele

doi:10.3390/antiox12111971

In Vitro α-Glucosidase and α-Amylase Inhibition, Cytotoxicity and Free Radical Scavenging Profiling of the 6-Halogeno and Mixed 6,8-Dihalogenated 2-Aryl-4-methyl-1,2-dihydroquinazoline 3-Oxides

Antioxidants (Basel). 2023 Nov 6;12(11):1971. doi: 10.3390/antiox12111971.

Authors

Nontokozo M Magwaza¹, Garland K More², Samantha Gildenhuys³, Malose J Mphahlele¹

Affiliations

¹ Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa.
² College of Agriculture and Environmental Sciences Laboratories, University of South Africa, Private Bag X06, Florida 1710, South Africa.
³ Department of Life & Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa.

Abstract

Series of the 6-bromo/iodo substituted 2-aryl-4-methyl-1,2-dihydroquinazoline-3-oxides and their mixed 6,8-dihalogenated (Br/I and I/Br) derivatives were evaluated for inhibitory properties against α-glucosidase and/or α-amylase activities and for cytotoxicity against breast (MCF-7) and lung (A549) cancer cell lines. The 6-bromo-2-phenyl substituted 3a and its corresponding 6-bromo-8-iodo-2-phenyl-substituted derivative 3i exhibited dual activity against α-glucosidase (IC₅₀ = 1.08 ± 0.02 μM and 1.01 ± 0.05 μM, respectively) and α-amylase (IC₅₀ = 5.33 ± 0.01 μM and 1.18 ± 0.06 μM, respectively) compared to acarbose (IC₅₀ = 4.40 ± 0.05 μM and 2.92 ± 0.02 μM, respectively). The 6-iodo-2-(4-fluorophenyl)-substituted derivative 3f, on the other hand, exhibited strong activity against α-amylase and significant inhibitory effect against α-glucosidase with IC₅₀ values of 0.64 ± 0.01 μM and 9.27 ± 0.02 μM, respectively. Compounds 3c, 3l and 3p exhibited the highest activity against α-glucosidase with IC₅₀ values of 1.04 ± 0.03, 0.92 ± 0.01 and 0.78 ± 0.05 μM, respectively. Moderate cytotoxicity against the MCF-7 and A549 cell lines was observed for these compounds compared to the anticancer drugs doxorubicin (IC₅₀ = 0.25 ± 0.05 μM and 0.36 ± 0.07 μM, respectively) and gefitinib (IC₅₀ = 0.19 ± 0.04 μM and 0.25 ± 0.03 μM, respectively), and their IC₅₀ values are in the range of 10.38 ± 0.08-25.48 ± 0.08 μM and 11.39 ± 0.12-20.00 ± 0.05 μM, respectively. The test compounds generally exhibited moderate to strong antioxidant capabilities, as demonstrated via robust free radical scavenging activity assays, viz., DPPH and NO. The potential of selected derivatives to inhibit superoxide dismutase (SOD) was also investigated via enzymatic assay in vitro. Molecular docking revealed the N-O moiety as essential to facilitate electrostatic interactions of the test compounds with the protein residues in the active site of α-glucosidase and α-amylase. The presence of bromine and/or iodine atoms resulted in increased hydrophobic (alkyl and/or π-alkyl) interactions and therefore increased inhibitory effect against both enzymes.

Keywords: antioxidant activity; cytotoxicity; diabetes; halogenated 1,2-dihydroquinazoline 3-oxides; molecular docking.

Grants and funding

SRUG2204203861/National Research Foundation