Novel inhibitors with sulfamethazine backbone: synthesis and biological study of multi-target cholinesterases and α-glucosidase inhibitors

The underlying cause of many metabolic diseases is abnormal changes in enzyme activity in metabolism. Inhibition of metabolic enzymes such as cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and a-glucosidase (alpha-GLY) is one of the accepted approaches in the treatment of Alzheimer's disease (AD) and diabetes mellitus (DM). Here we reported an investigation of a new series of novel ureido-substituted derivatives with sulfamethazine backbone (2a-f) for the inhibition of AChE, BChE, and alpha-GLY. All the derivatives demonstrated activity in nanomolar levels as AChE, BChE, and alpha-GLY inhibitors with K-I values in the range of 56.07-204.95 nM, 38.05-147.04 nM, and 12.80-79.22 nM, respectively. Among the many strong N-(4,6-dimethylpyrimidin-2-yl)-4-(3-substituted-phenylureido) benzenesulfonamide derivatives (2a-f) detected against ChEs, compound 2c, the 4-fluorophenylureido derivative, demonstrated the most potent inhibition profile towards AChE and BChE. A comprehensive ligand/receptor interaction prediction was performed in silico for the three metabolic enzymes providing molecular docking investigation using Glide XP, MM-GBSA, and ADME-Tox modules. The present research reinforces the rationale behind utilizing inhibitors with sulfamethazine backbone as innovative anticholinergic and antidiabetic agents with a new mechanism of action, submitting propositions for the rational design and synthesis of novel strong inhibitors targeting ChEs and alpha-GLY.

Automated summary

A series of novel ureido-substituted derivatives with sulfamethazine backbone were investigated for the inhibition of AChE, BChE, and alpha-GLY. Among these derivatives, compound 2c showed the most potent inhibition profile towards AChE and BChE. The study suggests the potential use of inhibitors with sulfamethazine backbone as innovative anticholinergic and antidiabetic agents.