Sulfonamide‐Bearing Pyrazolone Derivatives as Multitarget Therapeutic Agents: Design, Synthesis, Characterization, Biological Evaluation, In Silico <scp>ADME</scp>/T Profiling and Molecular Docking Study
Nebih Lolak, Süleyman Akocak, Meryem Topal, Ümit M. Koçyiğit, Mesut Işık, Cüneyt Türkeş, Fevzi Topal, Mustafa Durgun, Şükrü Beydemir
Abstract
ABSTRACT The research and design of new inhibitors for the treatment of diseases such as Alzheimer's disease and glaucoma through inhibition of cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and carbonic anhydrase enzymes are among the important targets. Here, a series of novel sulfonamide‐bearing pyrazolone derivatives ( 1a–f and 2a–f ) were successfully synthesized and characterized by using spectroscopic and analytical methods. The inhibitory activities of these newly synthesized compounds were evaluated both in vitro and in silico for their effect on carbonic anhydrases ( h CA I and h CA II isoenzymes) and ChEs. The in vitro studies showed that these novel compounds demonstrated potential inhibitory activity, with K I values covering the following ranges: 18.03 ± 2.86–75.54 ± 4.91 nM for h CA I, 24.84 ± 1.57–85.42 ± 6.60 nM for h CA II, 7.45 ± 0.98–16.04 ± 1.60 nM for AChE, and 34.78 ± 5.88–135.70 ± 17.39 nM for BChE. Additionally, many of these compounds showed promising inhibitory activity, and some showed higher potency than reference compounds. While the in silico studies have also identified the potential binding positions of these compounds, using the crystal structures of h CA I, II, AChE and BChE receptors. The varying affinities demonstrated by these designed compounds for ChEs and h CA isoenzymes show that these compounds could hold promise as potential alternative agents for selectively inhibiting ChEs and h CAs in the treatment of diseases such as Alzheimer's disease and glaucoma.