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

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 (IC(50) = 1.08 ± 0.02 μM and 1.01 ± 0.05 μM, respectively) and α-amylase (IC(50) = 5.33 ± 0.01 μM and 1.18 ± 0.06 μM, respectively) compared to acarbose (IC(50) = 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 IC(50) 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 IC(50) 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 (IC(50) = 0.25 ± 0.05 μM and 0.36 ± 0.07 μM, respectively) and gefitinib (IC(50) = 0.19 ± 0.04 μM and 0.25 ± 0.03 μM, respectively), and their IC(50) 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.