Magwaza Nontokozo M, More Garland K, Gildenhuys Samantha, Mphahlele Malose J
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, Private Bag X06, Florida 1710, South Africa.
College of Agriculture and Environmental Sciences Laboratories, University of South Africa, Private Bag X06, Florida 1710, South Africa.
Antioxidants (Basel). 2023 Nov 6;12(11):1971. doi: 10.3390/antiox12111971.
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 and its corresponding 6-bromo-8-iodo-2-phenyl-substituted derivative exhibited dual activity against α-glucosidase (IC = 1.08 ± 0.02 μM and 1.01 ± 0.05 μM, respectively) and α-amylase (IC = 5.33 ± 0.01 μM and 1.18 ± 0.06 μM, respectively) compared to acarbose (IC = 4.40 ± 0.05 μM and 2.92 ± 0.02 μM, respectively). The 6-iodo-2-(4-fluorophenyl)-substituted derivative , on the other hand, exhibited strong activity against α-amylase and significant inhibitory effect against α-glucosidase with IC values of 0.64 ± 0.01 μM and 9.27 ± 0.02 μM, respectively. Compounds , and exhibited the highest activity against α-glucosidase with IC 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 = 0.25 ± 0.05 μM and 0.36 ± 0.07 μM, respectively) and gefitinib (IC = 0.19 ± 0.04 μM and 0.25 ± 0.03 μM, respectively), and their IC 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.
对一系列6-溴/碘取代的2-芳基-4-甲基-1,2-二氢喹唑啉-3-氧化物及其6,8-二卤代（溴/碘和碘/溴）混合衍生物进行了评估，以检测它们对α-葡萄糖苷酶和/或α-淀粉酶活性的抑制特性，以及对乳腺癌（MCF-7）和肺癌（A549）细胞系的细胞毒性。与阿卡波糖（IC分别为4.40±0.05 μM和2.92±0.02 μM）相比，6-溴-2-苯基取代物及其相应的6-溴-8-碘-2-苯基取代衍生物对α-葡萄糖苷酶（IC分别为1.08±0.02 μM和1.01±0.05 μM）和α-淀粉酶（IC分别为5.33±0.01 μM和1.18±0.06 μM）均表现出双重活性。另一方面，6-碘-2-（4-氟苯基）取代衍生物对α-淀粉酶表现出强活性，对α-葡萄糖苷酶有显著抑制作用，IC值分别为0.64±0.01 μM和9.27±0.02 μM。化合物、和对α-葡萄糖苷酶表现出最高活性，IC值分别为1.04±0.03、0.92±0.01和0.78±0.05 μM。与抗癌药物多柔比星（IC分别为0.25±0.05 μM和0.36±0.07 μM）和吉非替尼（IC分别为0.19±0.04 μM和0.25±0.03 μM）相比，这些化合物对MCF-7和A549细胞系表现出中等细胞毒性，其IC值分别在10.38±0.08 - 25.48±0.08 μM和11.39±0.12 - 20.00±0.0 MU范围内。通过强大的自由基清除活性测定，即DPPH和NO测定，测试化合物总体上表现出中等至强的抗氧化能力。还通过体外酶促测定研究了所选衍生物抑制超氧化物歧化酶（SOD）的潜力。分子对接显示，N - O部分对于促进测试化合物与α-葡萄糖苷酶和α-淀粉酶活性位点中的蛋白质残基的静电相互作用至关重要。溴和/或碘原子的存在导致疏水（烷基和/或π-烷基）相互作用增加，因此对两种酶的抑制作用增强。
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