Synthesis, structure-activity relationships, and mechanistic studies of 5-arylazo-tropolone derivatives as novel xanthine oxidase (XO) inhibitors

Integrated in silico – in vitro strategy for the discovery of potential xanthine oxidase inhibitors from Egyptian propolis and their synergistic effect with allopurinol and febuxostat

“…Despite the imperfect overlay between C-3 and C-4′ of febuxostat and techtochrysin, respectively, introducing a nitrile group at techtochrysin's C-4′ would still be a valid strategy to enhance the XO binding affinity due to the dynamic flexibility of active site. 57 To mimic this, a second possible direction for future optimization of techtochrysin as a novel XO inhibitor can be implemented by introducing a small hydrophobic angular substituent, such as methoxy group, at C-4′ to efficiently fill the XO hydrophobic subpocket, where the nitrile group resides, whilst retaining the hydrogen bond acceptor property to engage in a hydrogen bond with ASN768. The small lipophilic subpocket could still be able to accommodate this methoxy group with a small conformational shift due to the plasticity of the protein in molding the Mo-pt center to the shape of the ligand in the binding site, 58 and yet the XO inhibitory effect might be improved by fine-tuning modifications at 4′-position.…”

“… 57 To mimic this, a second possible direction for future optimization of techtochrysin as a novel XO inhibitor can be implemented by introducing a small hydrophobic angular substituent, such as methoxy group, at C-4′ to efficiently fill the XO hydrophobic subpocket, where the nitrile group resides, whilst retaining the hydrogen bond acceptor property to engage in a hydrogen bond with ASN768. The small lipophilic subpocket could still be able to accommodate this methoxy group with a small conformational shift due to the plasticity of the protein in molding the Mo-pt center to the shape of the ligand in the binding site, 58 and yet the XO inhibitory effect might be improved by fine-tuning modifications at 4′-position. Future optimization in the aforementioned directions is predicted to improve the techtochrysin's binding affinity, drug-likeness, and its subsequent XO inhibitory potential.…”

Past, present and future of xanthine oxidase inhibitors: design strategies, structural and pharmacological insights, patents and clinical trials

“…The compound having a nitro group on the meta position of the phenyl ring significantly increases the activity profile. 113 Figueiredo et al prepared trisubstituted barbiturates and thiobarbiturates and investigated their xanthine oxidase inhibitory activity. The test results highlighted that compound 50 with an IC 50 value of 24.3 μM was the most energetic molecule in the series.…”

Synthetic heterocyclic derivatives as promising xanthine oxidase inhibitors: An overview

“…Compound 47 with NO 2 (electron-withdrawing group) on the meta position of benzene ring was found to be most potent. Molecular docking study suggested that the most potent compound 47 showed hydrogen bonds between the carbonyl group of the tropolone ring, a hydroxyl group bound to the molybdenum ion, and the NH group of Ala1079 as a backbone; (ii) a hydrogen bond between the acidic hydroxyl group of the tropolone ring and the guanidine group of Arg880, an electrostatic interaction between the nitro group on the benzene ring and the amino acid residue of Lys771 (Sato et al, 2018). Figueiredo et al synthesized a series of trisubstituted barbiturates and thiobarbiturates and evaluated them for their XO (bovine) inhibitory potential.…”