Novel beta-lactam substituted benzenesulfonamides: in vitro enzyme inhibition, cytotoxic activity and in silico interactions.

In this study, a library of twelve beta-lactam-substituted benzenesulfonamides ( 5a-l ) was synthesized using the tail-approach method. The compounds were characterized using IR, 1 H NMR, 13 C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases ( h CA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro . The results showed that the synthesized compounds were potent inhibitors of h CA I, with K I s in the low nanomolar range (66.60-278.40 nM) than the reference drug acetazolamide (AAZ), which had a K I of 439.17 nM. The h CA II was potently inhibited by compounds 5a , 5d-g and 5l , with K I s of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, K I of 98.28 nM). Notably, compound 5a selectively inhibited h CA II with a selectivity of > 4-fold over h CA I. In terms of inhibition of AChE, the synthesized compounds had K I s ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a K I of 159.61 nM. Compounds 5f , 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of h CAs and interacts with the Zn 2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski's and Jorgensen's rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of h CAs and AChE and could be lead agents.Communicated by Ramaswamy H. Sarma.