{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:02:04Z","timestamp":1790128924532,"version":"4.0.1"},"reference-count":41,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T00:00:00Z","timestamp":1710460800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>To meet the urgent need for new antibacterial molecules, a small library of pyrazolyl thioureas (PTUs) was designed, synthesized and tested against difficult-to-treat human pathogens. The prepared derivatives are characterized by a carboxyethyl functionality on C4 and different hydroxyalkyl chains on N1. Compounds 1a\u2013o were first evaluated against a large panel of Gram-positive and Gram-negative pathogens. In particular, the majority of PTUs proved to be active against different species of the Staphylococcus genus, with MIC values ranging from 32 to 128 \u00b5g\/mL on methicillin-resistant Staphylococcus strains, often responsible for severe pulmonary disease in cystic fibrosis patients. Time-killing experiments were also performed for the most active compounds, evidencing a bacteriostatic mechanism of action. For most active derivatives, cytotoxicity was evaluated in Vero cells, and at the tested concentrations and at the experimental exposure time of 24 h, none of the compounds analysed showed significant toxicity. In addition, favourable drug-like, pharmacokinetic and toxicity properties were predicted for all new synthesized derivatives. Overall, the collected data confirmed the PTU scaffold as a promising chemotype for the development of novel antibacterial agents active against Gram-positive multi-resistant strains frequently isolated from cystic fibrosis patients.<\/jats:p>","DOI":"10.3390\/ph17030376","type":"journal-article","created":{"date-parts":[[2024,3,15]],"date-time":"2024-03-15T12:02:39Z","timestamp":1710504159000},"page":"376","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["New Pyrazolyl Thioureas Active against the Staphylococcus Genus"],"prefix":"10.3390","volume":"17","author":[{"given":"Anna Maria","family":"Schito","sequence":"first","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debora","family":"Caviglia","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Viale Benedetto XV, 6, 16132 Genoa, Italy"},{"name":"Department of Pharmacy (DIFAR), Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Penco","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DIMES), University of Genoa, Via L.B. Alberti, 2, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-7146","authenticated-orcid":false,"given":"Andrea","family":"Spallarossa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cichero","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5636-5645","authenticated-orcid":false,"given":"Bruno","family":"Tasso","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-7726","authenticated-orcid":false,"given":"Chiara","family":"Brullo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), Section of Medicinal Chemistry, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Breijyeh, Z., and Karaman, R. (2023). Design and Synthesis of Novel Antimicrobial Agents. Antibiotics, 12.","DOI":"10.3390\/antibiotics12030628"},{"key":"ref_2","first-page":"269","article-title":"Vancomycin Resistance in Staphylococcus aureus","volume":"90","author":"McGuinness","year":"2017","journal-title":"YJBM"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e01542-18","DOI":"10.1128\/AAC.01542-18","article-title":"Daptomycin Resistance and Tolerance Due to Loss of Function in Staphylococcus aureus dsp1 and asp23","volume":"63","author":"Barros","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.1093\/jac\/dkaa075","article-title":"Linezolid resistance in Enterococcus faecium and Enterococcus faecalis from hospitalized patients in Ireland: High prevalence of the MDR genes optrA and poxtA in isolates with diverse genetic backgrounds","volume":"75","author":"Egan","year":"2020","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1001\/jama.2010.791","article-title":"Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis","volume":"303","author":"Dasenbrook","year":"2010","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/ppul.20604","article-title":"Presence of methicillin resistant Staphylococcus Aureus in respiratory cultures from cystic fibrosis patients is associated with lower lung function","volume":"42","author":"Ren","year":"2007","journal-title":"Pediatr. Pulmonol."},{"key":"ref_7","unstructured":"Xu, X., Zhang, X., Zhang, G., and Tadi, D.A. (2013). Prevalence of antibiotic resistance of Staphylococcus aureus in cystic fibrosis infection: A systematic review and meta-analysis. JGAR, in press."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"S64","DOI":"10.1002\/ppul.24139","article-title":"Biology and management of methicillin resistant Staphylococcus aureus in cystic fibrosis","volume":"53","author":"Akil","year":"2018","journal-title":"Pediatr. Pulmonol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1093\/jac\/dkn302","article-title":"High prevalence in cystic fibrosis patients of multiresistant hospital-acquired methicillin-resistant Staphylococcus aureus ST228-SCCmecI capable of biofilm formation","volume":"62","author":"Molina","year":"2008","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Lusardi, M., Spallarossa, A., and Brullo, C. (2023). Amino-Pyrazoles in Medicinal Chemistry: A Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24097834"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113134","DOI":"10.1016\/j.ejmech.2020.113134","article-title":"Pyrazole-based analogs as potential antibacterial agents against methicillin-resistance staphylococcus aureus (MRSA) and its SAR elucidation","volume":"212","author":"Verma","year":"2021","journal-title":"Eur. J. Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1007\/s00706-017-1960-6","article-title":"Synthesis of quinoxaline, pyrimidine, and pyrazole furochromone derivatives as cytotoxic agents","volume":"148","year":"2017","journal-title":"Monatsh. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/s12272-012-0306-5","article-title":"Synthesis of New Pyrazole, Triazole, Thiazolidine, -Pyrimido[4,5-b] quinoline derivatives with Potential Antitumor Activity","volume":"35","author":"Aly","year":"2012","journal-title":"Arch. Pharm. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1002\/jhet.2576","article-title":"Synthesis and Antimicrobial Activity of Some Novel Quinoline, Chromene, Pyrazole Derivatives Bearing Triazolopyrimidine Moiety","volume":"54","author":"Gouda","year":"2017","journal-title":"J. Heter. Chem."},{"key":"ref_15","first-page":"59","article-title":"Synthesis, and biological activity of pyrimidines, quinolines, thiazines and pyrazoles bearing a common thieno moiety","volume":"75","year":"2018","journal-title":"Acta Pol. Pharm.-Drug Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1002\/jhet.4216","article-title":"Synthesis of new pyrazoles, oxadiazoles, triazoles, pyrrolotriazines and pyrrolotriazepines as potential cytotoxic agents","volume":"58","year":"2021","journal-title":"J. Heter. Chem."},{"key":"ref_17","first-page":"1217","article-title":"Identification of the new progress on Pyrazole Derivatives Molecules as Antimicrobial and Antifungal Agents","volume":"39","author":"Bennani","year":"2022","journal-title":"West Afr. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.4155\/fmc-2023-0207","article-title":"Pyrazole: An emerging privileged scaffold in drug discovery","volume":"15","author":"Alam","year":"2023","journal-title":"Future Med. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ambade, S.S., Gupta, V.K., Bhole, R.P., Khedekar, P.B., and Chikhale, R.V. (2023). A Review on Five and Six-Membered Heterocyclic Compounds Targeting the Penicillin-Binding Protein 2 (PBP2A) of Methicillin-Resistant Staphylococcus aureus (MRSA). Molecules, 28.","DOI":"10.20944\/preprints202309.0856.v1"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Brullo, C., Caviglia, D., Spallarossa, A., Alfei, S., Franzblau, S.G., Tasso, B., and Schito, A.M. (2022). Microbiological Screening of 5-Functionalized Pyrazoles for the Future Development of Optimized Pyrazole-Based Delivery Systems. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14091770"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.1016\/j.bmc.2009.03.035","article-title":"1-Methyl and 1-(2-hydroxyalkyl)-5-(3-alkyl\/cycloalkyl\/phenyl\/naphthylureido)-1H-pyrazole-4-carboxylic acid ethyl esters as potent human neutrophil chemotaxis inhibitors","volume":"17","author":"Bruno","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6523","DOI":"10.1021\/jm3005866","article-title":"The discovery and optimization of a novel class of potent, selective, and orally bioavailable anaplastic lymphoma kinase (ALK) inhibitors with potential utility for the treatment of cancer","volume":"55","author":"Lewis","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1002\/cmdc.200700139","article-title":"Lessons learnt from assembling screening libraries for drug discovery for neglected diseases","volume":"3","author":"Brenk","year":"2008","journal-title":"ChemMedChem"},{"key":"ref_25","first-page":"1000","article-title":"ESOL: Estimating Aqueous Solubility Directly from Molecular Structure","volume":"44","author":"Delaney","year":"2004","journal-title":"J. Chem. Inf. Model."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"115727","DOI":"10.1016\/j.ejmech.2023.115727","article-title":"Novel 5-aminopyrazoles endowed with anti-angiogenetic properties: Design, synthesis and biological evaluation","volume":"260","author":"Lusardi","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_27","unstructured":"EUCAST (2023, June 23). European Committee on Antimicrobial Susceptibility Testing. Available online: https:\/\/www.eucast.org\/ast_of_bacteria."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Schito, A.M., Piatti, G., Caviglia, D., Zuccari, G., Zorzoli, A., Marimpietri, D., and Alfei, S. (2021). Bactericidal Activity of Non-Cytotoxic Cationic Nanoparticles against Clinically and Environmentally Relevant Pseudomonas spp. Isolates. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091411"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Meth."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/BF03256660","article-title":"Antibiotic treatment of multidrug-resistant organisms in cystic fibrosis","volume":"2","author":"Conway","year":"2003","journal-title":"Am. J. Respir. Med."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Chen, H., Zhang, J., He, Y., Lv, Z., Liang, Z., Chen, J., Li, P., Liu, J., Yang, H., and Tao, A. (2022). Exploring the Role of Staphylococcus aureus in Inflammatory Diseases. Toxins, 14.","DOI":"10.3390\/toxins14070464"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Biswas, L., and G\u00f6tz, F. (2022). Molecular Mechanisms of Staphylococcus and Pseudomonas Interactions in Cystic Fibrosis. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.824042"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1093\/jac\/dkq245","article-title":"Newer antibacterial agents and their potential role in cystic fibrosis pulmonary exacerbation management","volume":"65","author":"Parkins","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Rusnati, M., D\u2019Ursi, P., Pedemonte, N., Urbinati, C., Ford, R.C., Cichero, E., Uggeri, M., Orro, A., and Fossa, P. (2020). Recent Strategic Advances in CFTR Drug Discovery: An Overview. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072407"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Raslan, M.A., Raslan, S.A., Shehata, E.M., Mahmoud, A.S., and Sabri, N.A. (2023). Advances in the Applications of Bioinformatics and Chemoinformatics. Pharmaceuticals, 16.","DOI":"10.3390\/ph16071050"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5293","DOI":"10.1016\/j.ejmech.2011.08.014","article-title":"Synthesis and biological evaluation of novel pyrazole derivatives with anticancer activity","volume":"46","author":"Balbi","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6088","DOI":"10.1021\/acsomega.0c04513","article-title":"Pyrazolyl Thioureas and Carbothioamides with an NNSN Motif against MSSA and MRSA","volume":"6","author":"Zhang","year":"2021","journal-title":"ACS Omega"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1039\/D3MD00079F","article-title":"Synthesis and pharmacological evaluation of 1,3-diaryl substituted pyrazole based (thio)urea derivatives as potent antimicrobial agents against multi-drug resistant Staphylococcus aureus and Mycobacterium tuberculosis","volume":"14","author":"Ommi","year":"2023","journal-title":"RSC Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/s41467-023-36244-2","article-title":"Future therapies for cystic fibrosis","volume":"14","author":"Allen","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Esposito, C., Kamper, M., Trentacoste, J., Galvin, S., Pfister, H., and Wang, J. (2023). Advances in the Cystic Fibrosis Drug Development Pipeline. Life, 13.","DOI":"10.3390\/life13091835"},{"key":"ref_41","first-page":"3","article-title":"A systematic review on the use of bacteriophage in treating Staphylococcus aureus and Pseudomonas aeruginosa infections in cystic fibrosis","volume":"48","author":"Singh","year":"2023","journal-title":"Paediatr. Respir. Rev."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/3\/376\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:14:06Z","timestamp":1760105646000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/3\/376"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,15]]},"references-count":41,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ph17030376"],"URL":"https:\/\/doi.org\/10.3390\/ph17030376","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,15]]}}}