ABSTRACT
A series of benzene sulfonamides 15-26 were synthesized and determined for their in vitro and in silico inhibitory profiles toward acetylcholinesterase (AChE) and carbonic anhydrases (CAs). Commercially available 3,4-dimethoxytoluene was reacted with chlorosulfonic acid to furnish benzene sulfonyl chloride derivatives. The reaction of substituted benzene sulfonyl chloride with some amines also including (±)-α-amino acid methyl esters afforded a series of novel benzene sulfonamides. In this study, the enzyme inhibition abilities of these compounds were evaluated against AChE and CAs. They exhibited a highly potent inhibition ability on AChE and -CAs (Ki values are in the range of 28.11 ± 4.55 nM and 145.52 ± 28.68 nM for AChE, 39.20 ± 2.10 nM to 131.54 ± 12.82 nM for CA I, and 50.96 ± 9.83 nM and 147.94 ± 18.75 nM for CA II). The present newly synthesized novel benzene sulfonamides displayed efficient inhibitory profiles against AChE and CAs, and it is anticipated that they may emerge as lead molecules for some diseases including glaucoma, epilepsy, and Alzheimer's disease.
Subject(s)
Acetylcholinesterase , Carbonic Anhydrase Inhibitors , Cholinesterase Inhibitors , Sulfonamides , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Sulfonamides/pharmacology , Sulfonamides/chemistry , Sulfonamides/chemical synthesis , Acetylcholinesterase/metabolism , Structure-Activity Relationship , Molecular Structure , Molecular Docking Simulation , Humans , Carbonic Anhydrases/metabolism , Dose-Response Relationship, Drug , Benzenesulfonamides , Benzene/chemistryABSTRACT
Due to the important biological properties of dopamine, phenethylamine, and tyramine derivatives in the central nervous system, herein the synthesis of novel α-benzyl dopamine, phenethylamine, and tyramine derivatives is described. The title compounds were synthesized starting from 3-phenylpropanoic acids and methoxybenzenes in six or seven steps. Firstly, 3-(2,3-dimethoxyphenyl)propanoic acid (11) and 3-(3,4-dimethoxyphenyl)propanoic acid (12) were selectively brominated with N-bromosuccinimide (NBS). The Friedel-Crafts acylation of methoxylated benzenes with these brominated acids or commercially available 3-phenylpropanoic acid in polyphosphoric acid gave the desired dihydrochalcones. α-Carboxylation of dihydrochalcones, reduction of benzylic carbonyl groups, hydrolysis of esters to acid derivatives, and the Curtius rearrangement reaction of acids followed by in situ synthesis of carbamates from alkyl isocyanates and hydrogenolysis of the carbamates afforded the title compounds in good total yields. Alzheimer's disease (AD) and Parkinson's disease (PD) are chronic neurodegenerative diseases that become serious over time. However, the exact pathophysiology of both diseases has not been revealed yet. There have been many different approaches to the treatment of patients for many years, especially studies on the cholinergic system cover a wide area. Within the scope of this study, the inhibition effects of dopamine-derived carbamates and amine salts on the cholinergic enzymes AChE and BChE were examined. Dopamine-derived carbamate 24a-i showed inhibition in the micro-nanomolar range; compound 24d showed a Ki value of 26.79 nM against AChE and 3.33 nM against BChE, while another molecule, 24i, showed a Ki range of 27.24 nM and 0.92 nM against AChE and BChE, respectively. AChE and BChE were effectively inhibited by dopamine-derived amine salts 25j-s, with Ki values in the range of 17.70 to 468.57 µM and 0.76-211.23 µM, respectively. Additionally, 24c, 24e and 25m were determined to be 60, 276 and 90 times more selective against BChE than AChE, respectively.
