Sulfonamide-Linked Ciprofloxacin, Sulfadiazine and Amantadine Derivatives as a Novel Class of Inhibitors of Jack Bean Urease; Synthesis, Kinetic Mechanism and Molecular Docking

Abstract

Sulfonamide derivatives serve as an important building blocks in the drug design discovery and development (4D) process. Ciprofloxacin-, sulfadiazine- and amantadine-based sulfonamides were synthesized as potent inhibitors of jack bean urease and free radical scavengers. Molecular diversity was explored and electronic factors were also examined. All 24 synthesized compounds exhibited excellent potential against urease enzyme. Compound <b>3e</b> (IC₅₀ = 0.081 ± 0.003 µM), <b>6a</b> (IC₅₀ = 0.0022 ± 0.0002 µM), <b>9e</b> (IC₅₀ = 0.0250 ± 0.0007 µM) and <b>12d</b> (IC₅₀ = 0.0266 ± 0.0021 µM) were found to be the lead compounds compared to standard (thiourea, IC₅₀ = 17.814 ± 0.096 µM). Molecular docking studies were performed to delineate the binding affinity of the molecules and a kinetic mechanism of enzyme inhibition was propounded. Compounds <b>3e</b>, <b>6a</b> and <b>12d</b> exhibited a mixed type of inhibition, while derivative <b>9e</b> revealed a non-competitive mode of inhibition. Compounds <b>12a</b>, <b>12b</b>, <b>12d</b>, <b>12e</b> and <b>12f</b> showed excellent radical scavenging potency in comparison to the reference drug vitamin C.