Design, synthesis and bioevaluation of 2-mercapto-6-phenylpyrimidine-4-carboxylic acid derivatives as potent xanthine oxidase inhibitors

Inhibitors of Xanthine Oxidase: Scaffold Diversity and Structure‐Based Drug Design

“…[97] Cyano and nitrog roups at position 4a nd/orp osition5 gave compounds with activity similar to that of the compound with at rifluoromethyl group. Hydrogen, methyl, or carbomethoxy substituents at the same position instead negatively affected the activityo ft he inhibitor.B ulky substituents at positions 4 and 5s eemed also to decrease the activity of the resulting compound, while double substitution with small substituents increased activity.M ore acidic amidine hydrogen was preferred, as evidenced by the IC 50 values obtained for chloro-sub-stituted2 -(4-pyridyl)benzimidazoles.C ompound 117 was demonstrated to be inactive, compound 118 exhibited only 11 % inhibition at 20 mm,a nd compound 119 had an IC 50 value of 15 mm,r elative to allopurinol with an IC 50 value of 3 mm.T he most potent compound obtained was 4,5-dicyano-2-(4-pyridy-l)imidazole (120), with an IC 50 value 150 times (IC 50 = 20 nm) better than that of allopurinol.…”

“…XO inhibitors bearing as ix-membered heterocycle instead of af ive-membered ring as al inker betweent he aryl substituent and the carboxylic acid group were investigated by Shi et al [120] Moleculard ocking simulations performed by the authors identified the 2-mercaptopyrimidine structure as ap ossible scaffold to improvei nteraction between the enzyme and the inhibitor inside the active site. Among the 18 derivatives synthesized and tested, compound 168 showedt he best in vitro activity,b ut it was still approximately 10 times weakert han febuxostat.…”

“…XO inhibitors bearing a six‐membered heterocycle instead of a five‐membered ring as a linker between the aryl substituent and the carboxylic acid group were investigated by Shi et al . Molecular docking simulations performed by the authors identified the 2‐mercaptopyrimidine structure as a possible scaffold to improve interaction between the enzyme and the inhibitor inside the active site.…”

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

“…Branched alkoxy group inhibition was more effective than that with linear alkoxy groups. 63 Continuing with the lead and to improve the potency of the molecule, Zhang et al screened the potential of 3-oxo-6-aryl-2, 3-dihydropyridazine-4-carbohydrazide derivatives. In this series, compound 14 emerged as a potent candidate with an IC 50 value of 1.03 μM.…”

Synthetic heterocyclic derivatives as promising xanthine oxidase inhibitors: An overview

“…Furthermore, compounds with branched alkoxy groups inhibited more effectively than those with linear alkoxy groups. Molecular docking study suggested that the most potent compound 29 showed that carboxylate group binds by hydrogen bonds with Glu802, Arg880 and Thr1010 (Shi et al, 2018). Mao et al synthesized a series of 2‐(4‐alkoxy‐3‐cyano)phenyl‐6‐oxo‐1,6‐dihydropyrimidine‐5‐carboxylic acid derivatives and evaluated them for their XO (bovine) inhibitory potential.…”