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The indazole scaffold and sulfonamide moiety have evoked high interest in medicinal chemistry especially in the context of antidiabetic drug development. A series of the C-5 unsubstituted (2a–f), 5‑bromo (2g–l) and 5-iodo (2m–r) substituted 1-(alkyl/arylsulfonyl)-3-methylindazoles were prepared, characterized and then evaluated through enzymatic assay in vitro for anti-α-glucosidase activity and for potential free radical scavenging properties. Compounds 2b, 2d, 2f–h, 2k, 2p and 2q exhibited strong activity against α-glucosidase compared to acarbose (IC50 = 1.30 ± 0.02 µM) with IC50 values in the range of 0.72 ± 0.03 – 1.20 ± 0.01 µM. These compounds exhibited increased or strong 2,2-diphenyl-1-picrylhydrazyl (DPPH) and/or nitric oxide (NO) free radical scavenging activities. The compounds were, in turn, evaluated through enzymatic assays in vitro for the potential to inhibit or activate superoxide dismutase (SOD), lipoxygenase-15 (LOX-15) and/or vascular endothelial growth factor receptor-2 (VEGFR-2) activities. An in vitro cell-based antioxidant activity assay involving lipopolysaccharide induced reactive oxygen species (ROS) production in the human breast (MCF-7) cancer cell line revealed that compounds 2d, 2f and 2h exhibit moderate activity (35.5 %, 47 % and 28 %, respectively) compared to staurosporine (24 %). Compounds 2d, 2f and 2h significantly reduced the ROS level in the human embryonic kidney (HEK293-T) cells (65.5 %, 58 % and 48 %, respectively) compared to staurosporine (34 %). The planar benzo-fused heterocyclic scaffold and the distorted tetrahedral geometry of the N-sulfonyl moiety are predicted to facilitate hydrophobic and/or hydrogen bonding interactions to stabilize protein-ligand interaction in the receptors. The ADME analysis predicted that the test compounds have drug-like properties, a safe toxicity profile in silico without any carcinogenic and mutagenicity side effect. Molecular modelling was also used to attempt to rationalize the biological activity of these compounds and to correlate the results of in vitro and in silico studies.
Mphahlele et al. (Mon,) studied this question.