Synthesis of Phosphonate Derivatives of Benzisoselenazolones and Their Remarkable Antiureolytic Activity in Helicobacter pylori Cells

Abstract

The attachment of a nickel-ion-complexing functionality to the structures of covalent inhibitors of ureases has been considered an effective method for enhancing binding to these pivotal virulence factors of various microbial pathogens. Following this approach, we envisioned a structural combination of 1,2-benzisoselenazol-3(2H)-one, a scaffold that produced the most significant antiureolytic effect achieved, with a phosphonic acid group intended to block the function of nickel ions in the catalytic mechanism. The multistep preparation of hybrid compounds involved aminolysis of 2-(chloroseleno)benzoyl chloride with the key diethyl aminophosphonate intermediates, followed by hydrolysis of the final phosphonate esters. Although not entirely consistent with the rationale of the design idea, the esters themselves, rather than the corresponding acids, demonstrated more substantial inactivation of the model Sporosarcina pasteurii urease and inhibition of ureolysis in Helicobacter pylori. In particular, IC50values in pathogen cells reached an unprecedented range of 30–40 nM for some compounds.