New sulfonamide derivatives based on 1,2,3-triazoles: synthesis, in vitro biological activities and in silico studies

Eight new hybrid constructs containing a series of sulfonamide and 1,2,3-triazole units were designed and synthesized. Anticancer, antioxidant and cholinesterase activities of these hybrid structures were investigated. In our design, the Cu(I)-catalyzed click reaction between N,4-dimethyl-N-(prop-2-yn-1-yl)benzenesulfonamide (6) and aryl azides 8a-h was used. Antioxidant activity values of 9f (IC₅₀: 229.46 ± 0.001 μg/mL) and 9h (IC₅₀: 254.32 ± 0.002 μg/mL) hybrid structures were higher than BHT (IC₅₀: 286.04 ± 0.003 μg/mL) and lower than Ascorbic acid (IC₅₀: 63.53 ± 0.001 μg/mL) and α-Tocopherol (IC₅₀: 203.21 ± 0.002 μg/mL). We determined that the cytotoxic effects of hybrid constructs 9d (IC₅₀: 3.81 ± 0.1084 µM) and 9g (IC₅₀: 4.317 ± 0.0367 µM) against A549 and healthy cell line (HDF) are much better than standard cisplatin (IC₅₀: 6.202 ± 0.0705 µM). It was determined that the AChE inhibitory activities of all synthesized compounds were much better than Galantamine used as a standard. In particular, 9c (IC₅₀: 13.81 ± 0.0026 mM) had ten times better activity than the standard Galantamine (IC₅₀: 136 ± 0.008 mM). The ADMET properties of the molecules have been thoroughly examined and met the criteria for drug-like substances. They also have a high oral absorption rate, as they can effectively cross the blood-brain barrier and are easily absorbed in the gastrointestinal tract. In vitro experiments were confirmed by in silico molecular docking studies.Communicated by Ramaswamy H. Sarma.