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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, memory impairment, cognitive dysfunction, and speech impairment. The utility of cholinergic replacement by acetylcholinesterase (AChE) inhibitors in AD treatment has been well documented so far. Recently, studies have also evidenced that human carbonic anhydrases (hCAs) serve as an important target for AD treatment. In this direction, the improvement of new multitarget drugs, which can simultaneously modulate several mechanisms or targets included in the AD pathway, may be a potent strategy to treat AD. In light of these data for understanding and developing AD‐related multitarget AChE and hCAs inhibitors, in this study, novel methylene‐aminobenzoic acid and tetrahydroisoquinolynyl‐benzoic acid derivatives (4a–g and 6a–g) were designed. The synthesized analogs were experimentally validated for their effects by in vitro and direct enzymatic tests. Also, the compounds were subjected to in silico monitoring with Schrödinger Suite software to assign binding affinities of potential derivatives based on Glide XP scoring, molecular mechanics‐generalized Born surface area computing, and validation by molecular docking. The results revealed that 6c (1,3‐dimethyldihydropyrimidine‐2,4‐(1H,3H)‐dione‐substituted, KI value of 33.00 ± 0.29 nM), 6e (cyclohexanone‐substituted, KI value of 18.78 ± 0.09 nM), and 6f (2,2‐dimethyl‐1,3‐dioxan‐4‐one‐substituted, KI value of 13.62 ± 0.21 nM) from the benzoic acid derivatives in this series were the most promising derivatives, as they exhibited a good multifunctional inhibition at all experimental levels and in the in silico validation against hCA I, hCA II, and AChE, respectively, for the treatment of AD.

In this study, 15 novel compounds in a series of sulfonamide-based ketenes (7a-o) were synthesized and characterized using Fourier-transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and mass spectrometry. All compounds were tested for their ability to inhibit the human carbonic anhydrase (hCA) isoforms I and II, and acetylcholinesterase (AChE). The halogen-appended compounds, 7g, 7o, and 7i, exhibited the highest hCA I/II and AChE inhibition, with the K I values in the low nanomolar range (K I = 9.01 ± 0.08, 7.41 ± 0.03, and 7.37 ± 0.31 nM, respectively), as compared with their corresponding parent 2-[2,2-dicyano-1-(phenylamino) vinylthio]-N-(4-sulfamoylphenyl)acetamide analogs 7a-o. Besides, derivatives 7c and 7e selectively inhibited the isoform hCA I, whereas compounds 7m and 7n selectively inhibited isoform hCA II. These findings indicated that all compounds can inhibit metabolic dysfunctions, such as edema, epilepsy, glaucoma, and Alzheimer's disease, by specifically targeting both the hCA isoforms and AChE expression.Herein, also the interactions between ligands and receptors were highlighted through in silico molecular docking studies. The molecular mechanics-generalized Born surface area method was utilized to compute the binding free energy and the energy contribution of the critical residues in the active site was estimated. All these results would help us to perfectly understand the relationship between activity and structural characteristics of derivatives and to further improve newly and highly effective analogs targeting hCA and AChE.

Herein, a series of isoindole‐1,3‐dione substituted sulfonamide derivatives (3, 4 a–k) were designed, synthesized, and biologically evaluated, as inhibitors of carbonic anhydrase (CA) and acetylcholinesterase (AChE). CA and AChE inhibitory activities of newly synthesized isoindole‐1,3‐dione substituted sulfonamides compounds (3, 4 a–k) towards the hCA I, II, and AChE were evaluated utilizing the Verpoorte's and Ellman's assays and checked against that of standard inhibitors, acetazolamide (AAZ) and tacrine (TAC). The developed compounds (3, 4 a–k) showed the potent hCA isoenzyme inhibitory effect with Ki constants ranging from 7.96 to 48.34 nM, compared to AAZ (Kis; 436.20 nM for hCA I and 93.53 nM for hCA II). Among these derivatives; 1,3‐dioxo‐1,3‐dihydroisobenzofuran‐5‐carbocyclic acid (3) and benzyl‐1,3‐dioxo‐2‐(4‐sulfomophenyl)isoindoline‐5‐carboxylate (4 i) determined to be effective AChE inhibitors (Kis, 103.51 and 108.92 nM, respectively); these compounds were almost as potent to TAC (Ki, 109.75 nM). Furthermore, molecular docking studies of derivatives 3 and 4 i were carried out utilizing the crystal structures of hCA I (PDB Code: 4WR7), II (PDB Code: 4HT0) isozymes and AChE (PDB Code: 4EY7) receptors to study their binding interactions.