Bioactivity, cytotoxicity, and molecular modeling studies of novel sulfonamides as dual inhibitors of carbonic anhydrases and acetylcholinesterase

In the present medical epoch, the prevailing approach of drug discovery, which focuses on inhibiting a single target, has been superseded by the concept of designing drugs that target more than one specific site. Herein, we present the design and synthesis of a novel series of 1-oxo-3,4-dihydronaphthalene substituted sulfonamides (5a-j) with human carbonic anhydrase (hCA) and acetylcholinesterase (AChE) inhibitory activities as potential dual-target agents. The design of target compounds 5a-j incorporated two key elements: i) The sulfonamide group, which is widely recognized for its high affinity for the active site of hCAs, and ii) the effectiveness of 2-benzylidene-1-tetralone class compounds in some neurodegenerative disorders. All reported sulfonamides were evaluated for their inhibitory effect against hCA I, II isoforms, and AChE. Both hCAs, and AChE were potently inhibited by 5a-j with KI constants in the nanomolar range; 47.71–113.20 nM, 28.05–206.60 nM, and 87.38–136.60 nM, respectively, compared to standard inhibitors, acetazolamide (KIs of 439.17 and 98.28 nM for hCA I and hCA II, respectively) and tacrine (KI of 159.61 nM). 5i exhibited the best multi-target inhibitory activity against hCA I (KI of 47.71 nM), hCA II (KI of 30.75 nM), and AChE (KI of 88.97 nM), while 5b showed a selectivity index (hCA I/II) of 3.61. Moreover, a cytotoxic activity assay for sulfonamides 5a-j was applied on the human breast adenocarcinoma MCF-7 cell line as well as on the non-tumoral mouse fibroblast L929 cell. Thereafter, extensive molecular dynamics simulations revealed the dynamic behavior of ligand/enzyme complex and predicted vital ligand contacts in the binding pocket. © 2024 Elsevier B.V.