Novel organophosphorus scaffolds of urease inhibitors obtained by substitution of Morita-Baylis-Hillman adducts with phosphorus nucleophiles

作者：Ntatsopoulos Vassilis; Vassiliou Stamatia^*; Macegoniuk Katarzyna; Berlicki Lukasz; Mucha Artur^*

来源：European Journal of Medicinal Chemistry, 2017, 133: 107-120.

DOI：10.1016/j.ejmech.2017.03.070

• Phosphonic and phosphinic acids
• Substitution of allyl acetates
• Enzyme inhibitors
• Structure-activity relationship
• Binding mode

The reactivity of Morita-Baylis-Hillman allyl acetates was employed to introduce phosphorus-containing functionalities to the side chain of the cinnamic acid conjugated system by nucleophilic displacement. The proximity of two acidic groups, the carboxylate and phosphonate/phosphinate groups, was necessary to form interactions in the active site of urease by recently described inhibitor frameworks. Several organophosphorus scaffolds were obtained and screened for inhibition of the bacterial urease, an enzyme that is essential for survival of urinary and gastrointestinal tract pathogens. alpha-Substituted phosphonomethyl- and 2-phosphonoethyl-cinnamate appeared to be the most potent and were further optimized. As a result, one of the most potent organophosphorus inhibitors of urease, alpha-phosphonomethyl-p-methylcinnamic acid, was identified, with K-i = 0.6 mu M for Sporosarcina pasteurii urease. High complementarity to the enzyme active site was achieved with this structure, as any further modifications significantly decreased its affinity. Finally, this work describes the challenges faced in developing ligands for urease.

• 出版日期2017-6-16