Novel benzoic acid derivatives: Synthesis and biological evaluation as multitarget acetylcholinesterase and carbonic anhydrase inhibitors

Abstract

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.

Synthesis, Characterization, and Inhibition Study of Novel Substituted Phenylureido Sulfaguanidine Derivatives as α‐Glycosidase and Cholinesterase Inhibitors

“…Physicochemical and ADME‐Tox properties of novel substituted phenylureido sulfaguanidine derivatives ( 2a – 2f ) including lipophilicity, solubility, metabolic liabilities, drug‐likeness, and pan‐assay interference compounds alert were calculated using the QikProp tool [56] of Schrödinger Suite 2020‐3 for Mac (Schrödinger, LLC, NY, USA) and SwissADME platform [57,58] …”

Transition‐Metal Complexes of Bidentate Schiff‐Base Ligands: In Vitro and In Silico Evaluation as Non‐Classical Carbonic Anhydrase and Potential Acetylcholinesterase Inhibitors

“…In this study, the procedures applied in synthesis, biological assay, and in silico analyses were provided in the Supporting Information [25–64] …”

The Effects of P‐glycoprotein Modulators on the Transition of Levofloxacin to Rat Brain, Testicle, and Plasma: In Vivo and In Silico Studies

“…In silico molecular docking studies were conducted to elucidate interactions between P‐gp and drugs. In this study, the procedures applied in HPLC and chromatographic conditions, method validation, and in silico analyses were provided in the Supporting Information [39–67] …”