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 3e (IC50 = 0.081 ± 0.003 µM), 6a (IC50 = 0.0022 ± 0.0002 µM), 9e (IC50 = 0.0250 ± 0.0007 µM) and 12d (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 3e, 6a and 12d exhibited a mixed type of inhibition, while derivative 9e revealed a non-competitive mode of inhibition. Compounds 12a, 12b, 12d, 12e and 12f showed excellent radical scavenging potency in comparison to the reference drug vitamin C.

Synthesis, Antioxidant and In-Silico Studies of Potent Urease Inhibitors: N-(4-{[(4-Methoxyphenethyl)-(substituted)amino]sulfonyl}phenyl)acetamides

“…The other residues which are in close contact with the ligand structure are Glu642, Gly641, Arg639, Gln635 and His585. Literature data also ensured the importance of these residues in bonding with other urease inhibitors which strengthen our docking results [36,37]. The comparative binding energy and SAR analysis showed the significance of 5 f may consider as potent inhibitors by targeting jack bean urease.…”

“…The Jack bean urease activity was determined by measuring the amount of ammonia produced with indophenols method described [22][23][24]. The reaction mixtures, comprising 20 µL of enzyme (Jack bean urease, 5 U/mL) and 20 μL of compounds in 50 μL potassium phosphate buffer (100 mM urea, 10 mM K 2 HPO 4 , 1 mM EDTA and 10 mMLiCl, pH 8.2), were incubated for 30 min at 37 ºC in 96-well plate.…”

Novel indole based hybrid oxadiazole scaffolds with N-(substituted-phenyl)butanamides: synthesis, lineweaver–burk plot evaluation and binding analysis of potent urease inhibitors

“…The urease activity was determined by measuring ammonia production using the indophenol method, as reported previously. 17,18 The results (change in absorbance per min) were processed by using the SoMaxPro soware.…”

“…The jack bean urease was used only as a surrogate because the human urease is highly expensive and is not feasible for such in vitro investigations. [16][17][18] Although the observed activity is the resultant of the whole molecule, a limited structure-activity relationship (SAR) was rationalized by analyzing the effect of different aryl moieties on the inhibitory potential. Fig.…”

“…Literature reports also favor our docking results which strengthen our discussions on the ligand binding and conformational position within the active region of the target protein. [25][26][27][28][29][30]…”