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

Abstract

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 α-glucosidase (α-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 α-GLY. All the derivatives demonstrated activity in nanomolar levels as AChE, BChE, and α-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-substitutedphenylureido) 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 α-GLY.

Communicated by Ramaswamy H. Sarma

Keywords:

• Acetylcholinesterase
• butyrylcholinesterase
• α-glucosidase
• sulfamethazine
• in silico study

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Research Fund of Anadolu University (grant number 1610S681).