ABSTRACT
Identification of allosteric inhibitors of PTPs has attracted great interest as a new strategy to overcome the challenge of discover potent and selective molecules for therapeutic intervention. YopH is a virulence factor of the genus Yersinia, validated as an antimicrobial target. The finding of a second substrate binding site in YopH has revealed a putative allosteric site that could be further exploited. Novel chalcone compounds that inhibit PTPs activity were designed and synthesized. Compound 3j was the most potent inhibitor, interestingly, with different mechanisms of inhibition for the panel of enzymes evaluated. Further, our results showed that compound 3j is an irreversible non-competitive inhibitor of YopH that binds to a site different than the catalytic site, but close to the well-known second binding site of YopH.
Subject(s)
Bacterial Outer Membrane Proteins/antagonists & inhibitors , Chalcone/pharmacology , Enzyme Inhibitors/pharmacology , Protein Tyrosine Phosphatases/antagonists & inhibitors , Virulence Factors/antagonists & inhibitors , Allosteric Site/drug effects , Bacterial Outer Membrane Proteins/metabolism , Chalcone/chemical synthesis , Chalcone/chemistry , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Molecular Structure , Protein Tyrosine Phosphatases/metabolism , Structure-Activity Relationship , Virulence Factors/metabolismABSTRACT
BACKGROUND: Bacterial resistance to antibiotics is a growing problem in all countries and has been discussed worldwide. In this sense, the development of new drugs with antibiotic properties is highly desirable in the context of medicinal chemistry. METHODOLOGY: In this paper we investigate the antioxidant and antibacterial potential of sulfonamides derived from carvacrol, a small molecule with drug-like properties. Most sulfonamides had antioxidant and antibacterial potential, especially compound S-6, derived from beta-naphthylamine. RESULTS: To understand the possible mechanisms of action involved in biological activity, the experimental results were compared with molecular docking data. CONCLUSION: This research allows appropriate discussion on the identified structure activity relationships.
