Novel bis-ureido-substituted sulfaguanidines and sulfisoxazoles as carbonic anhydrase and acetylcholinesterase inhibitors

Abstract

To discover alternative substances to compounds used to treat many diseases, especially treating Alzheimer’s disease (AD) and Parkinson’s disease targeting carbonic anhydrase (hCA) and acetylcholinesterase (AChE) enzymes, is important. For this purpose, a series of novel bis-ureido-substituted sulfaguanidine (SG1–4) and sulfsoxazole (SO1–4) derivatives were synthesized, and their inhibitory capacities were screened against hCA isoenzymes (hCA I and II) and AChE. Possible binding mechanisms of inhibitors to the active site were elucidated by in silico studies, and the results were supported by in vitro results. Moreover, the percent radical scavenging capacities of the derivatives were also evaluated. The derivatives (SG1–4 and SO1–4) were more efective against hCAs compared to standard drug acetazolamide (KI values of 98.28–439.17 nM for hCA I and II, respectively) and exhibited the highest inhibition with the KI s in the ranges of 2.54±0.50–41.02±7.52 nM for hCA I, 11.20±2.97–67.14±13.58 nM for hCA II, and 257.60±27.84–442.60±52.13 nM for AChE. Also, compounds SG1 and SO1 also showed ABTS radical scavenging activity at the rate of 70% and 78%, respectively. These results will contribute to the literature for the rational design and synthesis of new potent and selective inhibitors targeting hCAs and AChE with multifunctional efects such as radical scavenging as well as inhibition