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

AbstractIn 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, 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 (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with KIs in the low nanomolar range (66.60–278.40 nM) than the reference drug acetazolamide (AAZ), which had a KI of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d–g and 5l, with KIs of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, KI of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had KIs ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a KI 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 hCAs 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 hCAs and AChE and could be lead agents.Communicated by Ramaswamy H. SarmaKeywords: Carbonic anhydraseacetylcholinesterasebeta-lactamMCF-7in silico study Disclosure statementNo potential conflict of interest was reported by the authors.Data availability statementData will be made available on request. All spectra that support the characterization of the compounds is provided in the Supporting Information.AcknowledgementsAuthor Özcan Güleç is a 100/2000 The Council of Higher Education (CoHE) Ph.D. Scholar in the Organic Smart and Innovative Materials Subsection.Correction StatementThis article has been corrected with minor changes. These changes do not impact the academic content of the article.Additional informationFundingThis work was supported by the Research Fund of Sakarya University (grant number 2021-7-24-56), the Research Fund of Erzincan Binali Yıldırım University (grant number TSA-2020-729), and the Research Fund of Anadolu University (grant number 2102S003).