2. Academic Validation
  3. Inhibition of Pseudomonas aeruginosa Carbonic Anhydrases, Exploring Ciprofloxacin Functionalization Toward New Antibacterial Agents: An In-Depth Multidisciplinary Study

Inhibition of Pseudomonas aeruginosa Carbonic Anhydrases, Exploring Ciprofloxacin Functionalization Toward New Antibacterial Agents: An In-Depth Multidisciplinary Study

  • J Med Chem. 2024 Nov 14;67(21):19077-19102. doi: 10.1021/acs.jmedchem.4c01555.
Beatrice Marinacci 1,  Ilaria D'Agostino 2,  Andrea Angeli 3,  Simone Carradori 1,  Francesco Melfi 1,  Rossella Grande 1,  Micol Corsiani 3,  Marta Ferraroni 4,  Mariangela Agamennone 1,  Anna Rita Tondo 5,  Susi Zara 1,  Valentina Puca 1,  Benedetta Pellegrini 1,  Chiara Vagaggini 6,  Elena Dreassi 6,  Marianna A Patrauchan 7,  Clemente Capasso 8,  Orazio Nicolotti 5,  Fabrizio Carta 3,  Claudiu T Supuran 3
Affiliations

Affiliations

  • 1 Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.
  • 2 Department of Pharmacy, University of Pisa, via Bonanno 6, 56126 Pisa, Italy.
  • 3 NEUROFARBA Department, University of Florence, 50019 Sesto Fiorentino, Florence, Italy.
  • 4 Department of Chemistry ″Ugo Schiff″, University of Florence, Via Della Lastruccia 3-13, 50019 Sesto Fiorentino, Italy.
  • 5 Department of Pharmacy - Pharmaceutical Sciences, University of Bari Aldo Moro, 70121 Bari, Italy.
  • 6 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy.
  • 7 Department of Microbiology and Molecular Genetics, Oklahoma State University, Stillwater, Oklahoma 74078, United States.
  • 8 Department of Biology, Agriculture and Food Sciences, CNR, Institute of Biosciences and Bioresources, 80131 Napoli, Italy.
PMID: 39453626 DOI: 10.1021/acs.jmedchem.4c01555
Abstract

Ciprofloxacin (CPX) is one of the most employed Antibiotics in clinics to date. However, the rise of drug-resistant bacteria is dramatically impairing its efficacy, especially against life-threatening pathogens, such as Pseudomonas aeruginosa. This Gram-negative bacterium is an opportunistic pathogen, often infecting immuno-compromised patients with severe or fatal outcomes. The evidence of the possibility of exploiting Carbonic Anhydrase (CA, EC: 4.2.1.1) Enzymes as pharmacological targets along with their role in P. aeruginosa virulence inspired the derivatization of CPX with peculiar CA-inhibiting chemotypes. Thus, a large library of CPX derivatives was synthesized and tested on a panel of Bacterial CAs and human isoenzymes I and II. Selected derivatives were evaluated for Antibacterial activity, revealing bactericidal and antibiofilm properties for some compounds. Importantly, promising preliminary absorption, distribution, metabolism, and excretion (ADME) properties in vitro were found and no cytotoxicity was detected for some representative compounds when tested in Galleria mellonella larvae.

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