Exploration of piperazine-derived thioureas as antibacterial and anti-inflammatory agents. In vitro evaluation against clinical isolates of colistin-resistant Acinetobacter baumannii

Sarah Mazzotta; Tania Cebrero-Cangueiro; Luca Frattaruolo; Margarita Vega-Holm; Marta Carretero-Ledesma; Javier Sánchez-Céspedes; Anna Rita Cappello; Francesca Aiello; Jerónimo Pachón; José Manuel Vega-Pérez; Fernando Iglesias-Guerra; María Eugenia Pachón-Ibáñez

doi:10.1016/j.bmcl.2020.127411

Exploration of piperazine-derived thioureas as antibacterial and anti-inflammatory agents. In vitro evaluation against clinical isolates of colistin-resistant Acinetobacter baumannii

Bioorg Med Chem Lett. 2020 Sep 15;30(18):127411. doi: 10.1016/j.bmcl.2020.127411. Epub 2020 Jul 15.

Affiliations

¹ Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
² Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain; Institute of Biomedicine of Seville, University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain.
³ Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy.
⁴ Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain. Electronic address: mvegaholm@us.es.
⁵ Institute of Biomedicine of Seville, University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain; Department of Medicine, University of Seville, Seville, Spain.
⁶ Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain. Electronic address: vega@us.es.
⁷ Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain.

PMID: 32717617
DOI: 10.1016/j.bmcl.2020.127411

Abstract

A. baumannii is one of the most important multidrug-resistant microorganisms in hospital units. It is resistant to many classes of antibiotics and the development of new therapeutic strategies is necessary. The aim of this study was to evaluate the antibacterial activity of a set of piperazine-derived thioureas against 13 clinical strains of colistin-resistant A. baumannii. Six derivatives were identified to inhibit bacterial growth of 46% of the A. baumannii strains at low micromolar concentrations (Minimum Inhibitory Concentration from 1.56 to 6.25 μM). A common structural feature in most active compounds was the presence of a 3,5-bis-trifluoromethyl phenyl ring at the thiourea function. In addition, the ability of the compounds to inhibit production of nitric oxide (NO) was examined in RAW 264.7 murine macrophages, highlighting the potential of piperazine-derived thioureas as promising scaffolds for the design of new combined anti-bacterial/anti-inflammatory agents.

Keywords: Acinetobacter baumannii; Anti-inflammatory; Antibacterial agents; Multidrug-resistant; Piperazine thiourea derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acinetobacter Infections / drug therapy*
Acinetobacter baumannii / drug effects*
Animals
Anti-Bacterial Agents / chemical synthesis*
Anti-Bacterial Agents / pharmacology
Anti-Inflammatory Agents / chemical synthesis*
Anti-Inflammatory Agents / pharmacology
Colistin / pharmacology*
Drug Evaluation, Preclinical
Drug Resistance, Bacterial
Drug Resistance, Multiple, Bacterial
Humans
Mice
Microbial Sensitivity Tests
Nitric Oxide / metabolism
Piperazines / chemistry*
RAW 264.7 Cells
Structure-Activity Relationship
Thiourea / chemical synthesis*
Thiourea / pharmacology

Substances

Anti-Bacterial Agents
Anti-Inflammatory Agents
Piperazines
Nitric Oxide
Thiourea
Colistin