1. Phosphonamidates are the first phosphorus-based zinc binding motif to show inhibition of β-class carbonic anhydrases from bacteria, fungi, and protozoa.
- Author
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Alissa SA, Alghulikah HA, Alothman ZA, Osman SM, Del Prete S, Capasso C, Nocentini A, and Supuran CT
- Subjects
- Amides chemistry, Anti-Infective Agents chemical synthesis, Anti-Infective Agents chemistry, Bacteria drug effects, Bacteria enzymology, Carbonic Anhydrase Inhibitors chemical synthesis, Carbonic Anhydrase Inhibitors chemistry, Dose-Response Relationship, Drug, Fungi drug effects, Fungi enzymology, Humans, Leishmania donovani drug effects, Leishmania donovani enzymology, Molecular Structure, Organometallic Compounds chemical synthesis, Organometallic Compounds chemistry, Phosphoric Acids chemistry, Phosphorus chemistry, Phosphorus pharmacology, Structure-Activity Relationship, Zinc chemistry, Zinc pharmacology, Amides pharmacology, Anti-Infective Agents pharmacology, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases metabolism, Organometallic Compounds pharmacology, Phosphoric Acids pharmacology
- Abstract
A primary strategy to combat antimicrobial resistance is the identification of novel therapeutic targets and anti-infectives with alternative mechanisms of action. The inhibition of the metalloenzymes carbonic anhydrases (CAs, EC 4.2.1.1) from pathogens (bacteria, fungi, and protozoa) was shown to produce an impairment of the microorganism growth and virulence. As phosphonamidates have been recently validated as human α-CA inhibitors (CAIs) and no phosphorus-based zinc-binding group have been assessed to date against β-class CAs, herein we report an inhibition study with this class of compounds against β-CAs from pathogenic bacteria, fungi, and protozoa. Our data suggest that phosphonamidates are among the CAIs with the best selectivity for β-class over human isozymes, making them interesting leads for the development of new anti-infectives.
- Published
- 2020
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