Novel beta-lactam substituted benzenesulfonamides: <i>in vitro</i> enzyme inhibition, cytotoxic activity and <i>in silico</i> interactions

Abstract

In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (<b>5a-l</b>) was synthesized using the tail-approach method. The compounds were characterized using IR, ¹H NMR, ¹³C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (<i>h</i>CA) isoforms, I and II, and acetylcholinesterase (AChE) <i>in vitro</i>. The results showed that the synthesized compounds were potent inhibitors of <i>h</i>CA I, with <i>K</i>_Is in the low nanomolar range (66.60-278.40 nM) than the reference drug acetazolamide (AAZ), which had a <i>K</i>_I of 439.17 nM. The <i>h</i>CA II was potently inhibited by compounds <b>5a</b>, <b>5d-g</b> and <b>5l</b>, with <i>K</i>_Is of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, <i>K</i>_I of 98.28 nM). Notably, compound <b>5a</b> selectively inhibited <i>h</i>CA II with a selectivity of > 4-fold over <i>h</i>CA I. In terms of inhibition of AChE, the synthesized compounds had <i>K</i>_Is ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a <i>K</i>_I of 159.61 nM. Compounds <b>5f</b>, <b>5h</b> and <b>5l</b> 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 <i>h</i>CAs and interacts with the Zn²⁺ 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 <i>h</i>CAs and AChE and could be lead agents.Communicated by Ramaswamy H. Sarma.