New 4-methanesulfonyloxy benzohydrazide derivatives as potential antioxidant and carbonic anhydrase I and II inhibitors: synthesis, characterization, molecular docking, dynamics & ADME studies

As an archetypal molecule, hydrazides have a crucial vital role in numerous applications, so hydrazide-related inhibitors, especially sulfur-enriched, are favored. In the present work, we designed, synthesized and characterized fifteen novel benzohydrazide derivatives containing 4-methanesulfonyloxy and arylidene building blocks with a four-step synthesis pathway. The inhibitory potential of the compounds was assessed using human carbonic anhydrases I and II (hCA I and II) isozymes and the results were compared to those of the standard inhibitor, acetazolamide (AZA). The antioxidant activity profiles for all compounds were also examined using various bioanalytical methods and the results were compared with the standards. The hCA I and II were the best inhibited by compounds 5f, 5g, and 5i with inhibition constants IC50 in the range 20.45-51.43 nM (AZA: IC50=218.38) for hCA I and 33.54-42.45 nM (AZA: IC50=44.39) for hCA II. Structure-activity relationships were also discussed and discovered that hCA I and II inhibition was unaffected by the presence of an electronwithdrawing or releasing group. This effectiveness was the only result of the sort of substituted group(s), which was located at the reagent. Molecular docking and dynamics simulations showed that compounds 5f, 5g, and 5i have strong and stable interactions with key amino acids and zinc ions in the active sites of enzymes, which supports their ability to block enzyme activity. In silico ADME studies predicted favorable drug-like properties and high human oral absorption for all synthesized compounds. In silico ADME studies predicted favorable drug-like properties and high human oral absorption for all synthesized compounds. These findings highlight the multifunctional potential of the synthesized benzohydrazide derivatives as hCA I and II inhibitors and antioxidants, paving the way for their further development and optimization for therapeutic applications.