Synthesis of novel benzene bissulfonamides with carbonic anhydrase and choline esterase inhibitory properties

Compounds that possess a benzene sulfonamide structure are utilized in a wide range of fields. Benzene bissulfonamides are also important compounds in the field of organic and medicinal chemistry. Based on these features, a series of benzene bissulfonamides were synthesized in moderate yields starting from 3-methylanisole. The in vitro effects of novel benzene bissulfonamide derivatives on several significant metabolic enzymes, including human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE), were systematically evaluated. The title compounds exhibited IC₅₀ values ranging from 2.76 ± 0.40 to 265.48 ± 7.33 μM against hCA I and from 2.98 ± 0.49 to 313.92 ± 11.48 μM against hCA II, whereas the reference compound AZA demonstrated inhibition at the nanomolar level for both enzymes. On the other hand, the synthesized compounds exhibited IC₅₀ values ranging from 6.67 ± 1.88 to 192.26 ± 10.42 μM against AChE, and from 76.50 ± 3.76 nM to 211.10 ± 14.62 μM against BChE. In contrast, the reference inhibitor Tacrine displayed markedly higher potency, with IC₅₀ values of 123.65 ± 4.41 nM for AChE and 8.39 ± 0.28 nM for BChE. Notably, compounds 20 and 21 demonstrated significant BChE inhibitory activity, with IC₅₀ values of 76.50 ± 3.76 nM and 112.53 ± 4.83 nM, respectively, suggesting that these compounds may serve as promising lead molecules for the development of selective BChE inhibitors. In this study, it was determined that compound 20 was 2301-fold BChE selective, compound 16 was 111-fold BChE selective and 21 was 64-fold BChE selective. In addition, 12 was determined to be 27-fold AChE selective than BChE. Furthermore, ADME and Induced-Fit Docking (IFD) simulations were conducted to elucidate the similarities of the drugs and the mechanisms of inhibition exhibited by the synthesized compounds. The synthesized species may significantly contribute to discovering new pharmaceutical agents for treating diseases such as Alzheimer's and glaucoma, which represent significant chronic global health concerns.