{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T09:22:22Z","timestamp":1774430542425,"version":"3.50.1"},"reference-count":170,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T00:00:00Z","timestamp":1732579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures","award":["164\/21\/10.01.2023"],"award-info":[{"award-number":["164\/21\/10.01.2023"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Fluoroquinolones (FQs) are topoisomerase II inhibitors with antibacterial activity, repositioned recently as anti-cancer agents. Glutamic acid (GLA) is an amino acid that affects human metabolism. Since an anti-cancer mechanism of FQs is human topoisomerase II inhibition, it is expected that FQ-GLA hybrids can act similarly. Methods: We designed 27 hypothetical hybrids of 6 FQs and GLA through amide bonds at the 3- and 7-position groups of FQs or via ethylenediamine\/ethanolamine linkers at the carboxyl group of the FQ. Hydroxamic acid derivatives were also theoretically formulated. Computational methods were used to predict their physicochemical, pharmacokinetic, or toxicological properties and their anti-cancer activity. For comparison, etoposide was used as an anti-cancer agent inhibiting topoisomerase II. Molecular docking assessed whether the hybrids could interact with the human topoisomerase II beta in the same binding site and interaction sites as etoposide. Results: All the hybrids acted as potential topoisomerase II inhibitors, demonstrating possible anti-cancer activity on several cancer cell lines. Among all the proposed hybrids, MF-7-GLA would be the ideal candidate as a lead compound. The hybrid OF-3-EDA-GLA and the hydroxamic acid derivatives also stood out. Conclusions: Both FQs and GLA have advantageous structures for obtaining hybrids with favourable properties. Improvements in the hybrids\u2019 structure could lead to promising results.<\/jats:p>","DOI":"10.3390\/ph17121593","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T10:00:58Z","timestamp":1732615258000},"page":"1593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["In Silico Evaluation of Some Computer-Designed Fluoroquinolone\u2013Glutamic Acid Hybrids as Potential Topoisomerase II Inhibitors with Anti-Cancer Effect"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9333-4063","authenticated-orcid":false,"given":"Octavia-Laura","family":"Oancea","sequence":"first","affiliation":[{"name":"Organic Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2486-3391","authenticated-orcid":false,"given":"\u0218erban Andrei","family":"G\u00e2z","sequence":"additional","affiliation":[{"name":"Organic Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9397-0388","authenticated-orcid":false,"given":"Gabriel","family":"Marc","sequence":"additional","affiliation":[{"name":"Organic Chemistry Department, Faculty of Pharmacy, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 41 Victor Babe\u0219 Street, 400012 Cluj-Napoca, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0909-0762","authenticated-orcid":false,"given":"Ioana-Andreea","family":"Lungu","sequence":"additional","affiliation":[{"name":"Medicine and Pharmacy Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4979-6903","authenticated-orcid":false,"given":"Aura","family":"Rusu","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Therapeutic Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.biopha.2018.12.119","article-title":"Repositioning of Fluoroquinolones from Antibiotic to Anti-Cancer Agents: An Underestimated Truth","volume":"111","author":"Yadav","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_2","first-page":"787","article-title":"Suppression of Human Prostate Cancer Cell Growth by Ciprofloxacin Is Associated with Cell Cycle Arrest and Apoptosis","volume":"22","author":"Aranha","year":"2003","journal-title":"Int. J. Oncol."},{"key":"ref_3","first-page":"891","article-title":"Ciprofloxacin Mediated Cell Growth Inhibition, S\/G2-M Cell Cycle Arrest, and Apoptosis in a Human Transitional Cell Carcinoma of the Bladder Cell Line","volume":"6","author":"Aranha","year":"2000","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jphotobiol.2014.07.006","article-title":"Structure\u2013Activity Relationship and Role of Oxygen in the Potential Antitumour Activity of Fluoroquinolones in Human Epithelial Cancer Cells","volume":"140","author":"Perucca","year":"2014","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/374131a0","article-title":"Principles of CDK Regulation","volume":"374","author":"Morgan","year":"1995","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1387\/ijdb.041794hp","article-title":"Transcriptional Regulation of Cadherins during Development and Carcinogenesis","volume":"48","author":"Peinado","year":"2004","journal-title":"Int. J. Dev. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1111\/j.1349-7006.2009.01419.x","article-title":"Epithelial-Mesenchymal Transition in Cancer Development and Its Clinical Significance","volume":"101","author":"Iwatsuki","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_8","first-page":"1747","article-title":"HERG K+ Channel Related Chemosensitivity to Sparfloxacin in Colon Cancer Cells","volume":"23","author":"Gong","year":"2010","journal-title":"Oncol. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1007\/s00109-013-1083-4","article-title":"Gemifloxacin Inhibits Migration and Invasion and Induces Mesenchymal\u2013Epithelial Transition in Human Breast Adenocarcinoma Cells","volume":"92","author":"Chen","year":"2014","journal-title":"J. Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4","DOI":"10.21608\/jmr.2022.166535.1094","article-title":"The Prospective Potential of Fluoroquinolones as Anticancer Agents","volume":"5","author":"AbuBaih","year":"2023","journal-title":"J. Mod. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1038\/nbt.1481","article-title":"A Small Molecule Enhances RNA Interference and Promotes MicroRNA Processing","volume":"26","author":"Shan","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Valianatos, G., Valcikova, B., Growkova, K., Verlande, A., Mlcochova, J., Radova, L., Stetkova, M., Vyhnakova, M., Slaby, O., and Uldrijan, S. (2017). A Small Molecule Drug Promoting MiRNA Processing Induces Alternative Splicing of MdmX Transcript and Rescues P53 Activity in Human Cancer Cells Overexpressing MdmX Protein. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0185801"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"439","DOI":"10.2174\/1568011033482279","article-title":"The Quinolone Family: From Antibacterial to Anticancer Agents","volume":"3","author":"Sissi","year":"2003","journal-title":"CMCACA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1111\/j.1476-5381.2009.00161.x","article-title":"Ciprofloxacin Decreases Survival in HT-29 Cells via the Induction of TGF-\u03921 Secretion and Enhances the Anti-Proliferative Effect of 5-Fluorouracil","volume":"157","author":"Bourikas","year":"2009","journal-title":"Br. J. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1038\/sj.bjc.6600079","article-title":"Ciprofloxacin Induces Apoptosis and Inhibits Proliferation of Human Colorectal Carcinoma Cells","volume":"86","author":"Herold","year":"2002","journal-title":"Br. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1186\/1475-2867-13-67","article-title":"Trimethoxy-Benzaldehyde Levofloxacin Hydrazone Inducing the Growth Arrest and Apoptosis of Human Hepatocarcinoma Cells","volume":"13","author":"Sun","year":"2013","journal-title":"Cancer Cell Int."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Abdel-Aal, M.A.A., Abdel-Aziz, S.A., Shaykoon, M.S.A., and Abuo-Rahma, G.E.A. (2019). Towards Anticancer Fluoroquinolones: A Review Article. Arch. Pharm. Chem. Life Sci., 352.","DOI":"10.1002\/ardp.201800376"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Herrero-Ruiz, A., Mart\u00ednez-Garc\u00eda, P.M., Terr\u00f3n-Bautista, J., Mill\u00e1n-Zambrano, G., Lieberman, J.A., Jimeno-Gonz\u00e1lez, S., and Cort\u00e9s-Ledesma, F. (2021). Topoisomerase II\u03b1 Represses Transcription by Enforcing Promoter-Proximal Pausing. Cell Rep., 35.","DOI":"10.1016\/j.celrep.2021.108977"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Matias-Barrios, V.M., and Dong, X. (2023). The Implication of Topoisomerase II Inhibitors in Synthetic Lethality for Cancer Therapy. Pharmaceuticals, 16.","DOI":"10.3390\/ph16010094"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1080\/14756366.2022.2136172","article-title":"Design, Synthesis, and Biological Evaluation of Novel Ciprofloxacin Derivatives as Potential Anticancer Agents Targeting Topoisomerase II Enzyme","volume":"38","author":"Swedan","year":"2023","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Swedan, H.K., Kassab, A.E., Gedawy, E.M., and Elmeligie, S.E. (2023). Topoisomerase II Inhibitors Design: Early Studies and New Perspectives. Bioorg. Chem., 136.","DOI":"10.1016\/j.bioorg.2023.106548"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5135","DOI":"10.7150\/jca.47470","article-title":"Antibiotics for Cancer Treatment: A Double-Edged Sword","volume":"11","author":"Gao","year":"2020","journal-title":"J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Elanany, M.A., Osman, E.E.A., Gedawy, E.M., and Abou-Seri, S.M. (2023). Design and Synthesis of Novel Cytotoxic Fluoroquinolone Analogs through Topoisomerase Inhibition, Cell Cycle Arrest, and Apoptosis. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-30885-5"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.plaphy.2015.07.016","article-title":"The Effects of Anti-DNA Topoisomerase II Drugs, Etoposide and Ellipticine, Are Modified in Root Meristem Cells of Allium Cepa by MG132, an Inhibitor of 26S Proteasomes","volume":"96","author":"Winnicki","year":"2015","journal-title":"Plant Physiol. Biochem."},{"key":"ref_25","unstructured":"DrugBank Online (2024, May 10). Mitoxantrone. Available online: https:\/\/go.drugbank.com\/drugs\/DB01204."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Christowitz, C., Davis, T., Isaacs, A., Van Niekerk, G., Hattingh, S., and Engelbrecht, A.-M. (2019). Mechanisms of Doxorubicin-Induced Drug Resistance and Drug Resistant Tumour Growth in a Murine Breast Tumour Model. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5939-z"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1097\/FPC.0b013e32833ffb56","article-title":"Doxorubicin Pathways: Pharmacodynamics and Adverse Effects","volume":"21","author":"Thorn","year":"2011","journal-title":"Pharmacogenet. Genom."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.breast.2011.12.012","article-title":"Epirubicin: Is It like Doxorubicin in Breast Cancer? A Clinical Review","volume":"21","author":"Khasraw","year":"2012","journal-title":"Breast"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.21037\/gs-20-647","article-title":"Standard-Dose Epirubicin Increases the Pathological Complete Response Rate in Neoadjuvant Chemotherapy for Breast Cancer: A Multicenter Retrospective Study","volume":"9","author":"Shan","year":"2020","journal-title":"Gland Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.31557\/APJCP.2022.23.5.1529","article-title":"Antiproliferative Activities of Lipophililic Fluoroquinolones- Based Scaffold Against a Panel of Solid and Liquid Cancer Cell Lines","volume":"23","author":"Qashou","year":"2022","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.31557\/APJCP.2022.23.7.2507","article-title":"Newly Substituted Anilino-Fluoroquinolones with Proliferation Inhibition Potential against a Panel of Cancer Cell Lines","volume":"23","author":"Salih","year":"2022","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_32","unstructured":"DrugBank Online (2024, May 10). Etoposide. Available online: https:\/\/go.drugbank.com\/drugs\/DB00773."},{"key":"ref_33","unstructured":"DrugBank Online (2024, May 10). Teniposide. Available online: https:\/\/go.drugbank.com\/drugs\/DB00444."},{"key":"ref_34","unstructured":"DrugBank Online (2024, May 10). Amsacrine. Available online: https:\/\/go.drugbank.com\/drugs\/DB00276."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.apsb.2018.07.008","article-title":"Recent Developments in Topoisomerase-Targeted Cancer Chemotherapy","volume":"8","author":"Hevener","year":"2018","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Spallarossa, A., Lusardi, M., Caneva, C., Profumo, A., Rosano, C., and Ponassi, M. (2021). Bicyclic Basic Merbarone Analogues as Antiproliferative Agents. Molecules, 26.","DOI":"10.3390\/molecules26030557"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sharma, P.C., Goyal, R., Sharma, A., Sharma, D., Saini, N., Rajak, H., Sharma, S., and Thakur, V.K. (2020). Insights on Fluoroquinolones in Cancer Therapy: Chemistry and Recent Developments. Mater. Today Chem., 17.","DOI":"10.1016\/j.mtchem.2020.100296"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.ejmech.2013.08.040","article-title":"Novel N-4-Piperazinyl-Ciprofloxacin-Chalcone Hybrids: Synthesis, Physicochemical Properties, Anticancer and Topoisomerase I and II Inhibitory Activity","volume":"69","author":"Park","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_39","first-page":"345","article-title":"The Influence of Ciprofloxacin on Hamster Ovarian Cancer Cell Line CHO AA8","volume":"67","author":"Kloskowski","year":"2010","journal-title":"Acta Pol. Pharm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3892\/or.2020.7602","article-title":"Ciprofloxacin Promotes Polarization of CD86+CD206- Macrophages to Suppress Liver Cancer","volume":"44","author":"Fan","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.pharep.2017.07.007","article-title":"Ciprofloxacin-Mediated Induction of S-Phase Cell Cycle Arrest and Apoptosis in COLO829 Melanoma Cells","volume":"70","author":"Beberok","year":"2018","journal-title":"Pharmacol. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.3892\/ijo.2012.1653","article-title":"Ciprofloxacin Is a Potential Topoisomerase II Inhibitor for the Treatment of NSCLC","volume":"41","author":"Kloskowski","year":"2012","journal-title":"Int. J. Oncol."},{"key":"ref_43","first-page":"1727","article-title":"Ciprofloxacin Triggers the Apoptosis of Human Triple-Negative Breast Cancer MDA-MB-231 Cells via the P53\/Bax\/Bcl-2 Signaling Pathway","volume":"52","author":"Beberok","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_44","first-page":"119","article-title":"Evaluation of the Cytotoxic Effects of Ciprofloxacin on Human Glioblastoma A-172 Cell Line","volume":"8","author":"Zandi","year":"2017","journal-title":"Middle East J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Yadav, V., Varshney, P., Sultana, S., Yadav, J., and Saini, N. (2015). Moxifloxacin and Ciprofloxacin Induces S-Phase Arrest and Augments Apoptotic Effects of Cisplatin in Human Pancreatic Cancer Cells via ERK Activation. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1560-y"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Yadav, V., Sultana, S., Yadav, J., and Saini, N. (2012). Gatifloxacin Induces S and G2-Phase Cell Cycle Arrest in Pancreatic Cancer Cells via P21\/P27\/P53. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047796"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.bbrc.2016.02.072","article-title":"Repositioning of Antibiotic Levofloxacin as a Mitochondrial Biogenesis Inhibitor to Target Breast Cancer","volume":"471","author":"Yu","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Kloskowski, T., Fr\u0105ckowiak, S., Adamowicz, J., Szeliski, K., Rasmus, M., Drewa, T., and Pokrywczy\u0144ska, M. (2022). Quinolones as a Potential Drug in Genitourinary Cancer Treatment\u2014A Literature Review. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.890337"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Kloskowski, T., Szeliski, K., Fekner, Z., Rasmus, M., D\u0105browski, P., Wolska, A., Siedlecka, N., Adamowicz, J., Drewa, T., and Pokrywczy\u0144ska, M. (2021). Ciprofloxacin and Levofloxacin as Potential Drugs in Genitourinary Cancer Treatment\u2014The Effect of Dose\u2013Response on 2D and 3D Cell Cultures. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111970"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"548","DOI":"10.4161\/epi.24519","article-title":"Enoxacin Inhibits Growth of Prostate Cancer Cells and Effectively Restores MicroRNA Processing","volume":"8","author":"Sousa","year":"2013","journal-title":"Epigenetics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1080\/09723757.2005.11885917","article-title":"Evaluation of Antiproliferative Activity of Enoxacin on a Human Breast Cancer Cell Line","volume":"5","author":"Mukherjee","year":"2005","journal-title":"Int. J. Hum. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1002\/ddr.21499","article-title":"Evaluation of Selected Commercial Pharmacotherapeutic Drugs as Potential Pancreatic Lipase Inhibitors and Antiproliferative Compounds","volume":"80","author":"Mamdooh","year":"2019","journal-title":"Drug Dev. Res."},{"key":"ref_53","unstructured":"ClinicalTrials.gov (2024, May 14). Study  of Vosaroxin or Placebo in Combination with Cytarabine in Patients with First Relapsed or Refractory AML, Available online: https:\/\/clinicaltrials.gov\/study\/NCT01191801."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-L\u00f3pez, H., S\u00e1nchez-Miranda, G., Araujo-Huitrado, J.G., Granados-L\u00f3pez, A.J., L\u00f3pez, J.A., Leyva-Ramos, S., and Chac\u00f3n-Garc\u00eda, L. (2019). Synthesis of Hybrid Fluoroquinolone-Boron Complexes and Their Evaluation in Cervical Cancer Cell Lines. J. Chem., 2019.","DOI":"10.1155\/2019\/5608652"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1007\/s40265-016-0614-z","article-title":"Molecular and Pharmacologic Properties of the Anticancer Quinolone Derivative Vosaroxin: A New Therapeutic Agent for Acute Myeloid Leukemia","volume":"76","author":"Jamieson","year":"2016","journal-title":"Drugs"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1038\/leu.2011.157","article-title":"A Phase Ib Study of Vosaroxin, an Anticancer Quinolone Derivative, in Patients with Relapsed or Refractory Acute Leukemia","volume":"25","author":"Lancet","year":"2011","journal-title":"Leukemia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1016\/j.bmc.2016.07.070","article-title":"New Antiproliferative 7-(4-(N-Substituted Carbamoylmethyl)Piperazin-1-Yl) Derivatives of Ciprofloxacin Induce Cell Cycle Arrest at G2\/M Phase","volume":"24","author":"Mohammed","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Chrzanowska, A., Roszkowski, P., Bielenica, A., Olejarz, W., St\u0119pie\u0144, K., and Struga, M. (2020). Anticancer and Antimicrobial Effects of Novel Ciprofloxacin Fatty Acids Conjugates. Eur. J. Med. Chem., 185.","DOI":"10.1016\/j.ejmech.2019.111810"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1002\/jhet.3670","article-title":"Moxifloxacin\/Gatifloxacin-1,2,3-triazole-isatin Hybrids with Hydrogen-Bond Donor and Their In Vitro Anticancer Activity","volume":"56","author":"Chen","year":"2019","journal-title":"J. Heterocycl. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.1002\/jhet.3684","article-title":"Ciprofloxacin\/Gatifloxacin-1,2,3-triazole-isatin Hybrids and Their in Vitro Anticancer Activity","volume":"56","author":"Jiang","year":"2019","journal-title":"J. Heterocycl. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"16494","DOI":"10.1039\/C8RA02578A","article-title":"Synthesis and Biological Evaluation of Novel Quinolone Derivatives Dual Targeting Histone Deacetylase and Tubulin Polymerization as Antiproliferative Agents","volume":"8","author":"Wang","year":"2018","journal-title":"RSC Adv."},{"key":"ref_62","first-page":"1495","article-title":"Synthesis and Biological Evaluation of Novel N1-Decyl and C7- Sec Amine Substituted Fluoroquinolones as Antitubercular and Anticancer Agents","volume":"54","author":"Kumar","year":"2015","journal-title":"Indian J. Chem. Sect. B"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1248\/cpb.c13-00797","article-title":"New Hydroxamic Acid Derivatives of Fluoroquinolones: Synthesis and Evaluation of Antibacterial and Anticancer Properties","volume":"62","author":"Rajulu","year":"2014","journal-title":"Chem. Pharm. Bull."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"115","DOI":"10.33899\/ijvs.2012.168748","article-title":"Synthesis of New 1,2 Dithiol 3-Thione Fluoroquinolone Esters Possessing Anticancer Activity in-Vitro","volume":"26","author":"Saeed","year":"2012","journal-title":"IJVS"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.1016\/j.ejmech.2011.10.014","article-title":"Synthesis of Lipophilic Dimeric C-7\/C-7-Linked Ciprofloxacin and C-6\/C-6-Linked Levofloxacin Derivatives. Versatile in Vitro Biological Evaluations of Monomeric and Dimeric Fluoroquinolone Derivatives as Potential Antitumor, Antibacterial or Antimycobacterial Agents","volume":"46","author":"Guidetti","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1016\/j.bmcl.2011.01.061","article-title":"Synthesis, Characterization and Anti-Tumor Activity of Moxifloxacin\u2013Copper Complexes against Breast Cancer Cell Lines","volume":"21","author":"Patitungkho","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.biopha.2008.01.016","article-title":"N-Substituted Piperazinyl Quinolones as Potential Cytotoxic Agents: Structure\u2013Activity Relationships Study","volume":"63","author":"Foroumadi","year":"2009","journal-title":"Biomed. Pharmacother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1016\/j.tiv.2007.03.011","article-title":"In Vitro Cytotoxicity and Phototoxicity of N-Piperazinyl Quinolone Derivatives with a 2-Thienyl Group","volume":"21","author":"Pardakhty","year":"2007","journal-title":"Toxicol. Vitro"},{"key":"ref_69","first-page":"153","article-title":"Functionalized N-(2-Oxyiminoethyl) Piperazinyl Quinolones as New Cytotoxic Agents","volume":"10","author":"Rajabalian","year":"2007","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_70","first-page":"134","article-title":"Recent Strategies in Design of Antitumor and Antibacterial Fluoroquinolones","volume":"4","author":"Samir","year":"2021","journal-title":"J. Adv. Biomed. Pharm. Sci."},{"key":"ref_71","first-page":"269","article-title":"Antitumor Activity of Trovafloxacin in an Animal Model","volume":"19","author":"Thadepalli","year":"2005","journal-title":"Vivo"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Moldovan, O.-L., Rusu, A., Tanase, C., and Vari, C.-E. (2021). Glutamate\u2014A Multifaceted Molecule: Endogenous Neurotransmitter, Controversial Food Additive, Design Compound for Anti-Cancer Drugs. A Critical Appraisal. Food Chem. Toxicol., 153.","DOI":"10.1016\/j.fct.2021.112290"},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Moldovan, O.-L., Sandulea, A., Lungu, I.-A., G\u00e2z, A., and Rusu, A. (2023). Identification of Some Glutamic Acid Derivatives with Biological Potential by Computational Methods. Molecules, 28.","DOI":"10.3390\/molecules28104123"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1517\/17460441.2012.714363","article-title":"The Influence of Lipophilicity in Drug Discovery and Design","volume":"7","author":"Arnott","year":"2012","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/jps.21494","article-title":"Calculation of Molecular Lipophilicity: State-of-the-Art and Comparison of LogP Methods on More than 96,000 Compounds","volume":"98","author":"Mannhold","year":"2009","journal-title":"J. Pharm. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1021\/ci700257y","article-title":"Computation of Octanol\u2212Water Partition Coefficients by Guiding an Additive Model with Knowledge","volume":"47","author":"Cheng","year":"2007","journal-title":"J. Chem. Inf. Model."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1021\/ci990307l","article-title":"Prediction of Physicochemical Parameters by Atomic Contributions","volume":"39","author":"Wildman","year":"1999","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1248\/cpb.40.127","article-title":"Simple Method of Calculating Octanol\/Water Partition Coefficient","volume":"40","author":"Moriguchi","year":"1992","journal-title":"Chem. Pharm. Bull."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1248\/cpb.42.976","article-title":"Comparison of Reliability of Log P Values for Drugs Calculated by Several Methods","volume":"42","author":"Moriguchi","year":"1994","journal-title":"Chem. Pharm. Bull."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1023\/A:1015810312465","article-title":"Predicting Skin Permeability","volume":"9","author":"Ro","year":"1992","journal-title":"Pharm. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"3743","DOI":"10.1002\/(SICI)1521-3773(19991216)38:24<3743::AID-ANIE3743>3.0.CO;2-U","article-title":"The Design of Leadlike Combinatorial Libraries","volume":"38","author":"Teague","year":"1999","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Liu, W., Liang, Y., and Si, X. (2020). Hydroxamic Acid Hybrids as the Potential Anticancer Agents: An Overview. Eur. J. Med. Chem., 205.","DOI":"10.1016\/j.ejmech.2020.112679"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Fathi-Karkan, S., Arshad, R., Rahdar, A., Ramezani, A., Behzadmehr, R., Ghotekar, S., and Pandey, S. (2023). Recent Advancements in the Targeted Delivery of Etoposide Nanomedicine for Cancer Therapy: A Comprehensive Review. Eur. J. Med. Chem., 259.","DOI":"10.1016\/j.ejmech.2023.115676"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/1097-0142(19910101)67:1+<215::AID-CNCR2820671302>3.0.CO;2-D","article-title":"Etoposide. Current and Future Status","volume":"67","author":"Aisner","year":"1991","journal-title":"Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Zhang, W., Gou, P., Dupret, J.-M., Chomienne, C., and Rodrigues-Lima, F. (2021). Etoposide, an Anticancer Drug Involved in Therapy-Related Secondary Leukemia: Enzymes at Play. Transl. Oncol., 14.","DOI":"10.1016\/j.tranon.2021.101169"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1126\/science.1204117","article-title":"Structural Basis of Type II Topoisomerase Inhibition by the Anticancer Drug Etoposide","volume":"333","author":"Wu","year":"2011","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1021\/ci034001x","article-title":"Analysis and Display of the Size Dependence of Chemical Similarity Coefficients","volume":"43","author":"Holliday","year":"2003","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"591","DOI":"10.12688\/f1000research.8357.1","article-title":"Activity-Relevant Similarity Values for Fingerprints and Implications for Similarity Searching","volume":"5","author":"Jasial","year":"2016","journal-title":"F1000Research"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13321-016-0127-5","article-title":"Impact of Similarity Threshold on the Topology of Molecular Similarity Networks and Clustering Outcomes","volume":"8","author":"Bologa","year":"2016","journal-title":"J. Cheminform."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.yrtph.2018.11.002","article-title":"Molecular Fingerprint-Derived Similarity Measures for Toxicological Read-across: Recommendations for Optimal Use","volume":"101","author":"Mellor","year":"2019","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Miranda-Quintana, R.A., Bajusz, D., R\u00e1cz, A., and H\u00e9berger, K. (2021). Differential Consistency Analysis: Which Similarity Measures Can Be Applied in Drug Discovery?. Mol. Inform., 40.","DOI":"10.1002\/minf.202060017"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Bero, S.A., Muda, A.K., Choo, Y.H., Muda, N.A., and Pratama, S.F. (2017). Similarity Measure for Molecular Structure: A Brief Review. J. Phys. Conf. Ser., 892.","DOI":"10.1088\/1742-6596\/892\/1\/012015"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Chung, N.C., Miasojedow, B., Startek, M., and Gambin, A. (2019). Jaccard\/Tanimoto Similarity Test and Estimation Methods for Biological Presence-Absence Data. BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-3118-5"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"749","DOI":"10.21474\/IJAR01\/3872","article-title":"Study of Molar Refraction and Polarizability Constant of Aqueous Solutions of KNO3 and KBrO3 at Different Temperatures","volume":"5","author":"Nikumbh","year":"2017","journal-title":"Int. J. Adv. Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2174\/092986709787002817","article-title":"Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR","volume":"16","author":"Prasanna","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1021\/ci0341114","article-title":"Determination of McGowan Volumes for Ions and Correlation with van Der Waals Volumes","volume":"43","author":"Zhao","year":"2003","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"177","DOI":"10.5599\/admet.1022","article-title":"Drug-like Properties and Fraction Lipophilicity Index as a Combined Metric","volume":"9","author":"Demopoulos","year":"2021","journal-title":"ADMET DMPK"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Saiful Islam, M., and Mitra, S. (2023). Effect of Nano Graphene Oxide (NGO) Incorporation on the Lipophilicity of Hydrophobic Drugs. Hybrid Adv., 3.","DOI":"10.1016\/j.hybadv.2023.100074"},{"key":"ref_101","unstructured":"(2024, June 12). Marvinsketch (Version 23.11). Available online: https:\/\/chemaxon.com\/marvin."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/cn100008c","article-title":"Moving beyond Rules: The Development of a Central Nervous System Multiparameter Optimization (CNS MPO) Approach To Enable Alignment of Druglike Properties","volume":"1","author":"Wager","year":"2010","journal-title":"ACS Chem. Neurosci."},{"key":"ref_103","first-page":"9","article-title":"Screening of Phytochemicals from Couroupita Guianensis as Drug Candidates against Lethal Diseases Using Insilico Analysis","volume":"3","author":"Chauhan","year":"2022","journal-title":"Int. J. Appl. Chem. Biol. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Rameshbabu, S., Alehaideb, Z., Alghamdi, S.S., Suliman, R.S., Almourfi, F., Yacoob, S.A.M., Venkataraman, A., Messaoudi, S., and Matou-Nasri, S. (2024). Identification of Anastatica hierochuntica L. Methanolic Leaves Extract-Derived Metabolites Exhibiting Xanthine Oxidase Inhibitory Activities: In Vitro and in Silico Approaches. Metabolites, 14.","DOI":"10.20944\/preprints202405.1500.v1"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Elbouzidi, A., Taibi, M., Laaraj, S., Loukili, E.H., Haddou, M., Hachlafi, N.E., Mrabti, H.N., Baraich, A., Bellaouchi, R., and Asehraou, A. (2024). Chemical Profiling of Volatile Compounds of the Essential Oil of Grey-Leaved Rockrose (Cistus albidus L.) and Its Antioxidant, Anti-Inflammatory, Antibacterial, Antifungal, and Anticancer Activity in Vitro and in Silico. Front. Chem., 12.","DOI":"10.3389\/fchem.2024.1334028"},{"key":"ref_106","unstructured":"(2024, May 28). SMARTCyp (Version 3.0). Available online: https:\/\/smartcyp.sund.ku.dk\/mol_to_som."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"3174","DOI":"10.1093\/bioinformatics\/btz037","article-title":"SMARTCyp 3.0: Enhanced Cytochrome P450 Site-of-Metabolism Prediction Server","volume":"35","author":"Olsen","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_108","first-page":"101","article-title":"Fundamental Physical and Chemical Concepts behind \u201cDrug-Likeness\u201d and \u201cNatural Product-Likeness\u201d","volume":"4","author":"Athar","year":"2019","journal-title":"Phys. Sci. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.chembiol.2014.08.013","article-title":"Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates","volume":"21","author":"Doak","year":"2014","journal-title":"Chem. Biol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2245","DOI":"10.1002\/cmdc.201600288","article-title":"Oral Administration of Peptide-Based Drugs: Beyond Lipinski\u2019s Rule","volume":"11","author":"Santos","year":"2016","journal-title":"ChemMedChem"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2636","DOI":"10.1021\/acs.jmedchem.7b00717","article-title":"Beyond the Rule of 5: Lessons Learned from AbbVie\u2019s Drugs and Compound Collection: Miniperspective","volume":"61","author":"DeGoey","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"65","DOI":"10.2174\/2211352512666141021002621","article-title":"Synthesis, Anti-HIV, Antimicrobial Evaluation and Structure Activity Relationship Studies of Some Novel Benzimidazole Derivatives","volume":"13","author":"Yadav","year":"2015","journal-title":"AIA"},{"key":"ref_113","unstructured":"(2024, May 18). Molecular Properties Prediction\u2014Osiris Property Explorer. Available online: https:\/\/www.organic-chemistry.org\/prog\/peo\/."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1021\/jm0492002","article-title":"A Bioavailability Score","volume":"48","author":"Martin","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_115","unstructured":"Price, G., and Patel, D.A. (2024). Drug Bioavailability. StatPearls, StatPearls Publishing."},{"key":"ref_116","first-page":"7850","article-title":"Synthesis, Structural Elucidation, In Silico and In Vitro Studies of New Class of Methylenedioxyphenyl-Based Amide Derivatives as Potential Myeloperoxidase Inhibitors for Cardiovascular Protection","volume":"9","author":"Rajan","year":"2024","journal-title":"ACS Omega"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Polinsky, A. (2008). Lead-Likeness and Drug-Likeness. The Practice of Medicinal Chemistry, Elsevier.","DOI":"10.1016\/B978-0-12-374194-3.00012-3"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.cbpa.2004.04.003","article-title":"Pursuing the Leadlikeness Concept in Pharmaceutical Research","volume":"8","author":"Hann","year":"2004","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_119","unstructured":"(2024, May 11). SwissADME. Available online: http:\/\/www.swissadme.ch\/."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13321-023-00678-z","article-title":"Critical Assessment of Synthetic Accessibility Scores in Computer-Assisted Synthesis Planning","volume":"15","author":"Kitlas","year":"2023","journal-title":"J. Cheminform."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1758-2946-1-8","article-title":"Estimation of Synthetic Accessibility Score of Drug-like Molecules Based on Molecular Complexity and Fragment Contributions","volume":"1","author":"Ertl","year":"2009","journal-title":"J. Cheminform."},{"key":"ref_122","unstructured":"Molinspiration (2024, May 31). Calculation of Molecular Properties and Bioactivity Score (Version v2022.08). Available online: https:\/\/molinspiration.com\/cgi\/properties."},{"key":"ref_123","unstructured":"(2024, May 29). Way2Drug\u2014Main (Version 2.0). Available online: http:\/\/www.way2drug.com\/PASSOnline\/index.php."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1211\/jpp.61.10.0012","article-title":"Enhanced Anticancer Activity of Glutamate Prodrugs of All-Trans Retinoic Acid","volume":"61","author":"Cui","year":"2010","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0923-1811(98)00026-7","article-title":"Quinolone Photoallergy: Photosensitivity Dermatitis Induced by Systemic Administration of Photohaptenic Drugs","volume":"18","author":"Tokura","year":"1998","journal-title":"J. Dermatol. Sci."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"S6","DOI":"10.1016\/S0923-1811(99)00071-7","article-title":"Immune Responses to Photohaptens: Implications for the Mechanisms of Photosensitivity to Exogenous Agents","volume":"23","author":"Tokura","year":"2000","journal-title":"J. Dermatol. Sci."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Rusu, A., Munteanu, A.-C., Arb\u0103na\u0219i, E.-M., and Uivarosi, V. (2023). Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15030804"},{"key":"ref_128","unstructured":"(2024, June 08). OECD Test Guidelines for Chemicals\u2014OECD. Available online: https:\/\/www.oecd.org\/chemicalsafety\/testing\/oecdguidelinesforthetestingofchemicals.html."},{"key":"ref_129","unstructured":"Croner-i (2024, May 29). Harmonisation of Classification of Corrosives for Supply and Transport. Available online: https:\/\/app.croneri.co.uk\/feature-articles\/harmonisation-classification-corrosives-supply-and-transport?product=139."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/0887-2333(96)00014-8","article-title":"The Use of in Vitro Cytotoxicity Measurements in QSAR Methods for the Prediction of the Skin Corrosivity Potential of Acids","volume":"10","author":"Barratt","year":"1996","journal-title":"Toxicol. Vitro"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.tiv.2009.05.019","article-title":"A Proposed Eye Irritation Testing Strategy to Reduce and Replace in Vivo Studies Using Bottom-Up and Top-Down Approaches","volume":"24","author":"Scott","year":"2010","journal-title":"Toxicol. Vitro"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.yrtph.2017.01.009","article-title":"The Isolated Chicken Eye Test to Replace the Draize Test in Rabbits","volume":"85","author":"Prinsen","year":"2017","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1021\/ci6002637","article-title":"Docking Ligands into Flexible and Solvated Macromolecules. 1. Development and Validation of FITTED 1.0","volume":"47","author":"Corbeil","year":"2007","journal-title":"J. Chem. Inf. Model."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1021\/ci700398h","article-title":"Docking Ligands into Flexible and Solvated Macromolecules. 2. Development and Application of Fitted 1.5 to the Virtual Screening of Potential HCV Polymerase Inhibitors","volume":"48","author":"Corbeil","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1021\/ci8004176","article-title":"Docking Ligands into Flexible and Solvated Macromolecules. 3. Impact of Input Ligand Conformation, Protein Flexibility, and Water Molecules on the Accuracy of Docking Programs","volume":"49","author":"Corbeil","year":"2009","journal-title":"J. Chem. Inf. Model."},{"key":"ref_136","unstructured":"Molecular Forecaster (2024, June 08). Resources, (Version 6453). Available online: https:\/\/molecularforecaster.com\/resources\/."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Wan, S., Bhati, A.P., Zasada, S.J., and Coveney, P.V. (2020). Rapid, Accurate, Precise and Reproducible Ligand\u2013Protein Binding Free Energy Prediction. Interface Focus, 10.","DOI":"10.1098\/rsfs.2020.0007"},{"key":"ref_138","unstructured":"(2024, October 09). 21.4: Chemistry of Acid Halides. Available online: https:\/\/chem.libretexts.org\/Bookshelves\/Organic_Chemistry\/Organic_Chemistry_(Morsch_et_al.)\/21%3A_Carboxylic_Acid_Derivatives-_Nucleophilic_Acyl_Substitution_Reactions\/21.04%3A_Chemistry_of_Acid_Halides."},{"key":"ref_139","first-page":"551","article-title":"Synthesis and in-Vitro Antibacterial Activity of Some Novel N-nicotinoyl-1-ethyl-6-fluoro-1,4-dihydro-7-piperazin-1-yl-4- oxoquinoline-3-carboxylates","volume":"65","author":"Sharma","year":"2008","journal-title":"Acta Pol. Pharm. Drug Res."},{"key":"ref_140","unstructured":"Syst\u00e8mes, D. (2024, May 05). BIOVIA Draw for Academics (Version 21.1). Available online: https:\/\/discover.3ds.com\/biovia-draw-academic."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1021\/ci034243x","article-title":"ESOL: Estimating Aqueous Solubility Directly from Molecular Structure","volume":"44","author":"Delaney","year":"2004","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1021\/ci200387c","article-title":"Revisiting the General Solubility Equation: In Silico Prediction of Aqueous Solubility Incorporating the Effect of Topographical Polar Surface Area","volume":"52","author":"Ali","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"3867","DOI":"10.1021\/jm000292e","article-title":"Prediction of Drug Absorption Using Multivariate Statistics","volume":"43","author":"Egan","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Verber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1021\/cc9800071","article-title":"A Knowledge-Based Approach in Designing Combinatorial or Medicinal Chemistry Libraries for Drug Discovery. 1. A Qualitative and Quantitative Characterization of Known Drug Databases","volume":"1","author":"Ghose","year":"1999","journal-title":"J. Comb. Chem."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1021\/jm015507e","article-title":"Simple Selection Criteria for Drug-like Chemical Matter","volume":"44","author":"Muegge","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_147","unstructured":"(2024, May 30). AquaSol: Predict Aqueous Solublity of Small Molecules Using UG-RNN Ensembles (Version 2.0). Available online: http:\/\/cdb.ics.uci.edu\/cgibin\/tools\/AquaSolWeb.py."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Lagunin, A.A., Dubovskaja, V.I., Rudik, A.V., Pogodin, P.V., Druzhilovskiy, D.S., Gloriozova, T.A., Filimonov, D.A., Sastry, N.G., and Poroikov, V.V. (2018). CLC-Pred: A Freely Available Web-Service for in Silico Prediction of Human Cell Line Cytotoxicity for Drug-like Compounds. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191838"},{"key":"ref_149","unstructured":"(2024, May 23). Gusar\u2014Create QSAR\/QSPR Models on the Basis of the Appropriate Training Sets. Available online: http:\/\/www.way2drug.com\/gusar\/acutoxpredict.html."},{"key":"ref_150","unstructured":"Jeliazkova, N., Martinov, M., Tcheremenskaia, O.J.K., Networks, M., Rydberg, P., Avramova, S., Kochev, N., Jeliazkov, V., and Iliev, L. (2024, May 25). Toxtree\u2014Toxtree-Toxic Hazard Estimation by Decision Tree Approach. Version 3.1.0.1851. Available online: https:\/\/toxtree.sourceforge.net\/."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0015-6264(76)80522-6","article-title":"Estimation of Toxic Hazard\u2014A Decision Tree Approach","volume":"16","author":"Cramer","year":"1976","journal-title":"Food Cosmet. Toxicol."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.fct.2003.08.006","article-title":"Structure-Based Thresholds of Toxicological Concern (TTC): Guidance for Application to Substances Present at Low Levels in the Diet","volume":"42","author":"Kroes","year":"2004","journal-title":"Food Chem. Toxicol."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/0045-6535(92)90280-5","article-title":"Classifying Environmental Pollutants","volume":"25","author":"Verhaar","year":"1992","journal-title":"Chemosphere"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/S0045-6535(99)00317-3","article-title":"Classifying Environmental Pollutants: Part 3. External Validation of the Classification System","volume":"40","author":"Verhaar","year":"2000","journal-title":"Chemosphere"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1021\/cr100222q","article-title":"Mechanisms of Chemical Carcinogenicity and Mutagenicity: A Review with Implications for Predictive Toxicology","volume":"111","author":"Benigni","year":"2011","journal-title":"Chem. Rev."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1002\/em.20355","article-title":"Mechanistic QSAR of Aromatic Amines: New Models for Discriminating between Homocyclic Mutagens and Nonmutagens, and Validation of Models for Carcinogens","volume":"48","author":"Benigni","year":"2007","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2940","DOI":"10.1021\/cr300206t","article-title":"Nongenotoxic Carcinogenicity of Chemicals: Mechanisms of Action and Early Recognition through a New Set of Structural Alerts","volume":"113","author":"Benigni","year":"2013","journal-title":"Chem. Rev."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1002\/qsar.200430880","article-title":"Use of Physicochemical Property Limits to Develop Rules for Identifying Chemical Substances with No Skin Irritation or Corrosion Potential","volume":"23","author":"Gerner","year":"2004","journal-title":"QSAR Comb. Sci."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/qsar.200430905","article-title":"Use of Structural Alerts to Develop Rules for Identifying Chemical Substances with Skin Irritation or Skin Corrosion Potential","volume":"24","author":"Hulzebos","year":"2005","journal-title":"QSAR Comb. Sci."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1002\/qsar.200430906","article-title":"The Skin Irritation Corrosion Rules Estimation Tool (SICRET)","volume":"24","author":"Walker","year":"2005","journal-title":"QSAR Comb. Sci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1177\/026119290503300307","article-title":"Assessment of the Eye Irritating Properties of Chemicals by Applying Alternatives to the Draize Rabbit Eye Test: The Use of QSARs and In Vitro Tests for the Classification of Eye Irritation","volume":"33","author":"Gerner","year":"2005","journal-title":"Altern. Lab. Anim."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"783","DOI":"10.3109\/10408444.2011.598141","article-title":"A Review of the Electrophilic Reaction Chemistry Involved in Covalent Protein Binding Relevant to Toxicity","volume":"41","author":"Enoch","year":"2011","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"728","DOI":"10.3109\/10408444.2010.494175","article-title":"A Review of the Electrophilic Reaction Chemistry Involved in Covalent DNA Binding","volume":"40","author":"Enoch","year":"2010","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1021\/ml100016x","article-title":"SMARTCyp: A 2D Method for Prediction of Cytochrome P450-Mediated Drug Metabolism","volume":"1","author":"Rydberg","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1021\/acs.accounts.6b00185","article-title":"Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods","volume":"49","author":"Moitessier","year":"2016","journal-title":"Acc. Chem. Res."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_168","first-page":"390","article-title":"Thiazolyl-oxadiazole Derivatives Targeting Lanosterol 14\u03b1-demethylase As Potential Antifungal Agents: Design, Synthesis and Molecular Docking Studies","volume":"64","author":"Stoica","year":"2016","journal-title":"Farmacia"},{"key":"ref_169","unstructured":"Syst\u00e8mes, D. (2024, May 27). Free Download: BIOVIA Discovery Studio Visualizer (Version 21.1.0.20298). Available online: https:\/\/discover.3ds.com\/discovery-studio-visualizer-download."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A Visualization System for Exploratory Research and Analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1593\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:39:59Z","timestamp":1760114399000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/17\/12\/1593"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,26]]},"references-count":170,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ph17121593"],"URL":"https:\/\/doi.org\/10.3390\/ph17121593","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,26]]}}}