Probing of the cis-5-phenyl proline scaffold as a platform for the synthesis of mechanism-based inhibitors of the Staphylococcus aureus sortase SrtA isoform

Abstract

Abstractcis-5-Phenyl prolinates with electrophilic substituents at the fourth position of a pyrrolidine ring were synthesized by 1,3-dipolar cycloaddition of arylimino esters with divinyl sulfone and acrylonitrile. 4-Vinylsulfonyl 5-phenyl prolinates inhibit S. aureus sortase SrtA irreversibly by modification of the enzyme Cys184 and could be used as hits for the development of antibacterials and antivirulence agents.

Sortase A: An ideal target for anti-virulence drug development

“…Beginning with the results of this study concerning the role of the nitrile group in the inhibition of the enzyme, and considering the activity showed by some vinyl sulfones, which will be described in the paragraph 6 of this review, as cysteine protease inhibitors [42,43], Kudryavtsev et al described the synthesis of novel 5-phenyl proline functionalizated with these two groups. Ultimately, however, they resulted weak inhibitors in the order of mM [44].…”

Inhibition of the procoagulant activity of blood platelets by vinylsulfonyl derivatives of pyrrolidine-2-carboxylic acid

“…The residue was chromatographed on silica gel us ing CHCl 3 (m, 5 Н arom ); 7.71-7.75 (m, 1 Н arom ). 13 (2S*,4S*,5S*) Methyl 1 (4 fluorobenzoyl) 2 methyl 5 phe nyl 4 (vinylsulfonyl)pyrrolidine 2 carboxylate (8). Vinyl sulfone 6b (0.272 g, 0.88 mmol) was dissolved in THF (20 mL) and Et 3 N (0.135 mL, 0.098 g, 0.97 mmol) was added.…”

“…15 Pyrrolidinyl vinyl sulfones 2-4 inhibit also irreversibly sortase A of S. aureus, compound 4 showing the highest activity (see Ref. 13). …”

“…In previous studies, one of the co authors of the present work has obtained 4 (vinylsulfonyl)pyrrolidine 2 carboxylic acid derivatives and assessed their inhibiting abilities with respect to sor tase A of Staphylococcus aureus, which is a cysteine transpeptidase. 12, 13 Mass spectrometry of the fragment with the established sequences has revealed the covalent modification of the Cys184 amino acid residue of the sortase A active site by one of inhibitors. 13 In the present work, we studied the influence of known 13 and novel pyr rolidinyl vinyl sulfones on exposing of phosphatidylserine by platelets.…”

“…12, 13 Mass spectrometry of the fragment with the established sequences has revealed the covalent modification of the Cys184 amino acid residue of the sortase A active site by one of inhibitors. 13 In the present work, we studied the influence of known 13 and novel pyr rolidinyl vinyl sulfones on exposing of phosphatidylserine by platelets.…”