Abstract
The present article describes the design, synthesis, in vitro urease inhibition, and in silico molecular docking studies of a novel series of nitrothiazolacetamide conjugated to different thioquinazolinones. Fourteen nitrothiazolacetamide bearing thioquinazolinones derivatives (8a-n) were synthesized through the reaction of isatoic anhydride with different amine, followed by reaction with carbon disulfide and KOH in ethanol. The intermediates were then converted into final products by treating them with 2-chloro-N-(5-nitrothiazol-2-yl)acetamide in DMF. All derivatives were then characterized through different spectroscopic techniques (1H, 13C-NMR, MS, and FTIR). In vitro screening of these molecules against urease demonstrated the potent urease inhibitory potential of derivatives with IC50 values ranging between 2.22 ± 0.09 and 8.43 ± 0.61 μM when compared with the standard thiourea (IC50 = 22.50 ± 0.44 μM). Compound 8h as the most potent derivative exhibited an uncompetitive inhibition pattern against urease in the kinetic study. The high anti-ureolytic activity of 8h was confirmed against two urease-positive microorganisms. According to molecular docking study, 8h exhibited several hydrophobic interactions with Lys10, Leu11, Met44, Ala47, Ala85, Phe87, and Pro88 residues plus two hydrogen bound interactions with Thr86. According to the in silico assessment, the ADME-Toxicity and drug-likeness profile of synthesized compounds were in the acceptable range.
Highlights
The present article describes the design, synthesis, in vitro urease inhibition, and in silico molecular docking studies of a novel series of nitrothiazolacetamide conjugated to different thioquinazolinones
Mustafa and co-workers identified another set of quinazolinone-coumarin derivatives and the most potent compound (Fig. 1B) exhibited the IC50 values of 1.26 ± 0.07 μg/mL
In vitro results showed that the heterocyclic group substituted on N-3 position of quinazolinone ring plays an important role in the inhibitory activity[39]
Summary
The present article describes the design, synthesis, in vitro urease inhibition, and in silico molecular docking studies of a novel series of nitrothiazolacetamide conjugated to different thioquinazolinones. Compound 8h as the most potent derivative exhibited an uncompetitive inhibition pattern against urease in the kinetic study. The possible reaction mechanism for urease activities at neutral pH involves the coordination of H 2O–Ni plus hydroxyl groups to other Ni. the substrate (urea) is activated toward nucleophilic attack by O-coordination of Ni2+ ions, and a nickel-coordinated hydroxide ion attacks the carbonyl carbon of the coordinated substrate to form a tetrahedral intermediate. Urease of H. pylori as a virulence factor neutralizes the acidic pH of the stomach, leading to alteration of the properties of the gastric mucous layer[8] as well as providing ammonia for bacterial protein synthesis. To design effective urease inhibitors, the structure and active site of the aforementioned enzyme should be discussed. The structures of potent inhibitors displayed the critical role of interaction with Ni (I) and Ni (II) as well as the residues of the binding site
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