{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T21:44:36Z","timestamp":1791236676903,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2013,6,25]],"date-time":"2013-06-25T00:00:00Z","timestamp":1372118400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The aptitude of cyclodextrins (CDs) to form host-guest complexes has prompted an increase in the development of new drug formulations. In this study, the inclusion complexes of pipemidic acid (HPPA), a therapeutic agent for urinary tract infections, with native \u03b2-CD were prepared in solid state by kneading method and confirmed by FT-IR and 1H NMR. The inclusion complex formation was also characterized in aqueous solution at different pH via UV-Vis titration and phase solubility studies obtaining the stability constant. The 1:1 stoichiometry was established by a Job plot and the inclusion mechanism was clarified using docking experiments. Finally, the antibacterial activity of HPPA and its inclusion complex was tested on P. aeruginosa, E. coli and S. aureus to determine the respective EC50s and EC90s. The results showed that the antibacterial activity of  HPPA:\u03b2-CD against E. coli and S. aureus is higher than that of HPPA. Furthermore, HPPA and HPPA:\u03b2-CD, tested on human hepatoblastoma HepG2 and MCF-7 cell lines by MTT assay, exhibited, for the first time, antitumor activities, and the complex revealed a higher activity than that of HPPA. The use of \u03b2-CD allows an increase in the aqueous solubility of the drug, its bioavailability and then its bioactivity.<\/jats:p>","DOI":"10.3390\/ijms140713022","type":"journal-article","created":{"date-parts":[[2013,6,25]],"date-time":"2013-06-25T12:43:50Z","timestamp":1372164230000},"page":"13022-13041","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["\u03b2-Cyclodextrin Inclusion Complex to Improve Physicochemical Properties of Pipemidic Acid: Characterization and  Bioactivity Evaluation"],"prefix":"10.3390","volume":"14","author":[{"given":"Rosa","family":"Iacovino","sequence":"first","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filomena","family":"Rapuano","sequence":"additional","affiliation":[{"name":"Department of Biological and Environmental Science, University of Sannio, Via Port'Arsa 11, 82100 Benevento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolanda","family":"Caso","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostino","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Lavorgna","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Isidori","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Russo","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaetano","family":"Malgieri","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Isernia","sequence":"additional","affiliation":[{"name":"Department of Environmental, Biological and Pharmaceutical Sciences and Technologies,  Second University of Naples, Via A. Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2013,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1021\/jm00235a017","article-title":"Pyrido[2,3-dipyrimidine antibacterial agents. 3,8-Alkyl-and 8-vinyl-5,8-dihydro-5-oxo-2-(1-piperazinyl)pyrido[2,3-d]-pyrimidine-6-carboxylic acids and their derivatives","volume":"18","author":"Matsumoto","year":"1975","journal-title":"J. Med. Chem"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1107\/S0108270186091266","article-title":"Structure of pipemidic acid","volume":"42","author":"Fonseca","year":"1986","journal-title":"Acta Crystallogr. Sect. C"},{"key":"ref_3","first-page":"257","article-title":"The use of pipemidic acid in urinary infections","volume":"34","author":"Toscano","year":"1982","journal-title":"Miner. Urol"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1128\/AAC.19.1.188","article-title":"Comparative activities of AM-715 and pipemidic and nalidixic acids against experimentally induced systemic and urinary tract infections","volume":"19","author":"Hirai","year":"1981","journal-title":"Antimicrob. Agents Chemother"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.trac.2007.09.004","article-title":"Determination of pKa values of active pharmaceutical ingredients","volume":"26","author":"Horvat","year":"2007","journal-title":"Trends Anal. Chem"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1128\/AAC.9.4.569","article-title":"Pipemidic acid: Its activities against various experimental infections","volume":"9","author":"Shimizu","year":"1976","journal-title":"Antimicrob. Agents Chemother"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1128\/AAC.29.4.598","article-title":"Inhibition of micrococcus luteus DNA gyrase by norfloxacin and 10 other quinolone carboxylic acids","volume":"29","author":"Zweerink","year":"1986","journal-title":"Antimicrob. Agents Chemother"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1016\/j.poly.2006.10.017","article-title":"Transition metal complexes with the quinolone antibacterial agent pipemidic acid: Synthesis, characterization and biological activity","volume":"26","author":"Efthimiadou","year":"2007","journal-title":"Polyhedron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1021\/je7007044","article-title":"Aqueous solubilities for ofloxacin, norfloxacin, lomefloxacin, ciprofloxacin, pefloxacin, and pipemidic acid from (293.15 to 323.15) K","volume":"53","author":"Zhang","year":"2008","journal-title":"J. Chem. Eng. Data"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.jpba.2004.02.006","article-title":"Influence of solvent composition on the solid phase at equilibrium with saturated solutions of quinolones in different solvent mixtures","volume":"35","author":"Romero","year":"2004","journal-title":"J. Pharm. Biomed. Anal"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Szejtli, J. (1989). Cyclodextrin Technology, Kluwer Academic.","DOI":"10.1007\/978-94-015-7797-7"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.3109\/03639048609042630","article-title":"Cyclodextrin, their value in pharmaceutical technology","volume":"12","author":"Duchene","year":"1988","journal-title":"Drug Dev. Ind. Pharm"},{"key":"ref_13","first-page":"171","article-title":"Characterization of cyclodextrin inclusion complexes\u2014A review","volume":"2","author":"Singh","year":"2010","journal-title":"J. Pharm. Sci. Technol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4482","DOI":"10.3390\/molecules16064482","article-title":"Pharmaceutical composition of hydrochlorothiazide:\u03b2-cyclodextrin: Preparation by three different methods, physico-chemical characterization and in vivo diuretic activity evaluation","volume":"16","author":"Pires","year":"2011","journal-title":"Molecules"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1158\/1535-7163.MCT-07-2000","article-title":"CHM-1, a novel synthetic quinolone with potent and selective antimitotic antitumor activity against human hepatocellular carcinoma in vitro and in vivo","volume":"7","author":"Wang","year":"2008","journal-title":"Mol. Cancer Ther"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bcp.2007.03.015","article-title":"Quinolone analogue inhibits tubulin polymerization and induces apoptosis via Cdk1-involved signaling pathways","volume":"74","author":"Chen","year":"2007","journal-title":"Biochem. Pharmacol"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Menezes, P.P., Serafini, M.R., Santana, B.V., Nunes, R.S., Quintans, L.J., Silva, G.F., Medeiros, I.A., Marchioro, M., Fraga, B.P., and Santos, M.R.V. (2012). Acta, 548, 45\u201350.","DOI":"10.1016\/j.tca.2012.08.023"},{"key":"ref_18","first-page":"125","article-title":"FTIR and Raman spectroscopic investigations of a controlled release Ciprofloxacin\/Carbopol940 mucoadhesive suspension","volume":"5","author":"Sahoo","year":"2012","journal-title":"Asian J. Pharm. Clin. Res"},{"key":"ref_19","first-page":"451","article-title":"Physicochemical study of ciprofloxacin with \u03b2-cyclodextrin","volume":"2","author":"Aithal","year":"1996","journal-title":"Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s10847-008-9474-9","article-title":"Investigation on the inclusion behavior of Norfloxacin with 2-methyl-\u03b2-cyclodextrin","volume":"62","author":"Li","year":"2008","journal-title":"J. Inclusion Phenom. Macrocyclic Chem"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.ejpb.2003.10.020","article-title":"Solubility enhancement of celecoxib using \u03b2-cyclodextrin inclusion complexes","volume":"57","author":"Rawat","year":"2004","journal-title":"Eur. J. Pharm. Biopharm"},{"key":"ref_22","first-page":"113","article-title":"Formation and stability of inorganic complexes in solution","volume":"9","author":"Job","year":"1928","journal-title":"Annal. Chim. Fr"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S0076-6879(82)87029-8","article-title":"Determination of binding stoichiometry by the continuous variation method: The Job plot","volume":"87","author":"Huang","year":"1982","journal-title":"Methods Enzymol"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1021\/cr960371r","article-title":"The stability of cyclodextrin complexes in solution","volume":"97","author":"Connors","year":"1997","journal-title":"Chem. Rev"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2703","DOI":"10.1021\/ja01176a030","article-title":"A spectrophotometric investigation of the interaction of iodine with aromatic hydrocarbons","volume":"71","author":"Benesi","year":"1949","journal-title":"J. Am. Chem. Soc"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6056","DOI":"10.3390\/molecules17056056","article-title":"Physicochemical characterization and cytotoxic activity evaluation of hydroxymethylferrocene:\u03b2-Cyclodextrin inclusion complex","volume":"17","author":"Iacovino","year":"2012","journal-title":"Molecules"},{"key":"ref_27","first-page":"117","article-title":"Phase solubility techniques","volume":"4","author":"Higuchi","year":"1965","journal-title":"Anal. Chem. Instrum"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s10847-006-9244-5","article-title":"Rigorous nonlinear regression analysis of phase solubility diagrams to obtain complex stoichiometry and true thermodynamic drug-cyclodextrin complexation parameters","volume":"57","author":"Zughul","year":"2007","journal-title":"J. Incl. Phenom. Macrocyclic Chem"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1111\/j.2042-7158.2011.01279.x","article-title":"Pharmaceutical applications of cyclodextrins: Effects on drug permeation through biological membranes","volume":"63","author":"Loftsson","year":"2011","journal-title":"J. Pharm. Pharmacol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1007\/s10847-004-4271-6","article-title":"Complexation study and spectrofluorimetric determination of pipemidic acid with \u03b3-cyclodextrin","volume":"51","year":"2005","journal-title":"J. Incl. Phenom. Macrocycl. Chem"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1128\/AAC.8.2.132","article-title":"Pipemidic acid, a new antibacterial agent active against pseudomonas aeruginosa: In vitro properties","volume":"8","author":"Shimizu","year":"1975","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1128\/AAC.25.3.319","article-title":"Ciprofloxacin, a quinolone carboxylic acid compound active against aerobic and anaerobic bacteria","volume":"25","author":"Chin","year":"1984","journal-title":"Antimicrob. Agents Chemother"},{"key":"ref_33","first-page":"263","article-title":"Experimental and clinical studies on fluoroquinolone-insusceptible Escherichia coli isolated from patients with urinary tract infections from 1994 to 2007","volume":"63","author":"Wada","year":"2009","journal-title":"Acta Med. Okayama"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1248\/cpb.51.494","article-title":"Synthesis, characterization, and antibacterial activities of some rare earth metal complexes of Pipemidic Acid","volume":"51","author":"Yang","year":"2003","journal-title":"Chem. Pharm. Bull"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1016\/j.poly.2011.03.044","article-title":"Ligation of the quinolone antibacterial agent pipemidic acid to Keggin polyoxotungstates","volume":"30","author":"Sha","year":"2011","journal-title":"Polyhedron"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.poly.2011.09.029","article-title":"Study on ligation of copper complexes of the quinolone antibacterial drugs and octamolybdates POMs","volume":"31","author":"Sha","year":"2012","journal-title":"Polyhedron"},{"key":"ref_37","unstructured":"Cavanagh, J., Fairbrother, W., Palmer, A.G., and Skelton, N.J. (1996). Protein NMR Spectroscopy, Principles, and Practice, Academic Press, Inc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1006\/jmra.1995.1047","article-title":"Water suppression that works. Excitation sculpting using arbitrary wave-forms and pulsed-field gradients","volume":"112","author":"Hwang","year":"1995","journal-title":"J. Magn. Reson. A"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00417486","article-title":"The program XEASY for computer-supported NMR spectral analysis of biological macromolecules","volume":"6","author":"Bartels","year":"1995","journal-title":"J. Biomol. NMR"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2398","DOI":"10.1093\/bioinformatics\/btq444","article-title":"Ultra-fast FFT protein docking on graphics processors","volume":"26","author":"Ritchie","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1590\/S0104-66322008000200005","article-title":"Enhancement of solubility of albendazole by complexation with \u03b2-Cyclodextrin","volume":"25","author":"Moriwaki","year":"2008","journal-title":"Braz. J. Chem. Eng."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.mimet.2010.11.008","article-title":"Optimal methods for evaluating antimicrobial activities from plant extracts","volume":"84","author":"Othman","year":"2011","journal-title":"J. Microbiol. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2944","DOI":"10.3390\/molecules16042944","article-title":"Selective Cytotoxicity of goniothalamin against hepatoblastoma HepG2 cells","volume":"16","author":"Mothanna","year":"2011","journal-title":"Molecules"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/7\/13022\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:47:33Z","timestamp":1760219253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/14\/7\/13022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,25]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2013,7]]}},"alternative-id":["ijms140713022"],"URL":"https:\/\/doi.org\/10.3390\/ijms140713022","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,25]]}}}