Rational Design, Synthesis, Docking Simulation, and ADMET Prediction of Novel Barbituric‐hydrazine‐phenoxy‐1,2,3‐triazole‐acetamide Derivatives as Potent Urease Inhibitors

Abstract

Urease is an important target for the treatment of Helicobacter pylori infection. In this study, several pharmacophores for the inhibition of urease were considered and coupled to design new molecules capable of acting as potent urease inhibitors. Literature review reveals that barbituric-hydrazine, phenoxy-1,2,3-triazole, and acetamide moieties are pharmacophores for urease inhibition. Therefore, in this study, the barbiturichydrazine-phenoxy-1,2,3-triazole-acetamide scaffold was designed and twelve derivatives 9 a-l of it were synthesized and evaluated. The urease inhibition assay of these compounds revealed that all new title compounds, except for one compound, with IC 50 values of 0.73 to 5.27 μM were more potent than standard inhibitor thiourea. The most potent compound inhibited urease in a mixed-type inhibition mode and interacted as well with the urease active site. In silico druglikeness and toxicity studies of the most potent compounds predicted that these compounds passed successfully Lipinski's rule of five and had no carcinogenicity on the rat.

Triazolothiadiazoles and Triazolothiadiazines as New and Potent Urease Inhibitors: Insights from In Vitro Assay, Kinetics Data, and In Silico Assessment

“…29,31−333435 Similarly, 1 H NMR spectra of both compounds (3a,b) showed resonances for the −NH 2 protons as singlets at 5.77 and 5.80 ppm (integrating two protons) and the −SH proton as singlets at 13.83 and 14.03 ppm. The 1 H NMR data of thione form (reported previously) indicate the presence of NH protons of triazole rings at 11.30−8.87 ppm and 13 C NMR spectra showed the corresponding (C�S) resonance at ca. 170 ppm.…”

“…IR spectra were recorded using the FTS 3000 MX, Bio-Rad Merlin (Excalibur type) spectrophotometer. 1 H and 13 C NMR spectral data were obtained by using a Bruker Avance (300 MHz) spectrometer. Chemical shifts (δ) are quoted in parts per million (ppm), with the residual solvent serving as an internal standard (DMSO-d 6 at 2.50 ppm for 1 H NMR and 39.52 ppm for 13 C NMR).…”

“…1 H and 13 C NMR spectral data were obtained by using a Bruker Avance (300 MHz) spectrometer. Chemical shifts (δ) are quoted in parts per million (ppm), with the residual solvent serving as an internal standard (DMSO-d 6 at 2.50 ppm for 1 H NMR and 39.52 ppm for 13 C NMR). Resonances are denoted by the letters s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and Ar (aromatic).…”

“…Urease is a popular enzyme in living organisms, responsible for the hydrolysis of urea into carbon dioxide and ammonia. , The high concentrations of ammonia are caused by urease hyperactivity, which leads to a rise in the pH of the stomach, thus resulting in complications like peptic and gastric ulcers, hepatic coma, pyelonephritis, and kidney stones. , This condition of clinical complications demands such inhibitors that can regulate urease activity. ,− Various studies have revealed the diverse variety of compounds such as Schiff base hydrazones, triazole-(thio) barbituric acids, N -thioacylated ciprofloxacin derivatives, and barbituric-hydrazine-phenoxy-1,2,3-triazole-acetamides which possess urease inhibitory effects. − Urease inhibitors have revealed amplification of the urea N uptake in plants and reduction of environmental issues. ,− Additionally, they play a role as strong antiulcer drugs. , …”

“… 2 , 6 − 8 Various studies have revealed the diverse variety of compounds such as Schiff base hydrazones, triazole-(thio) barbituric acids, N -thioacylated ciprofloxacin derivatives, and barbituric-hydrazine-phenoxy-1,2,3-triazole-acetamides which possess urease inhibitory effects. 9 − 11 12 13 Urease inhibitors have revealed amplification of the urea N uptake in plants 14 and reduction of environmental issues. 6 , 15 − 17 Additionally, they play a role as strong antiulcer drugs.…”