{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T19:23:31Z","timestamp":1783711411594,"version":"3.55.0"},"reference-count":100,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Scientific Research at Philadelphia University","award":["467\/34\/100 PU"],"award-info":[{"award-number":["467\/34\/100 PU"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Thieno[2,3-c]pyridines and their analogs are not well explored for their anticancer properties. Hence, our research aimed to establish the anticancer potential of thieno[2,3-c]pyridines through cell-based assays and in silico evaluations. Methods: Thieno[2,3-c]pyridine derivatives 6(a\u2013k) were synthesized and characterized using FT-IR, 1H-NMR, 13C-NMR, and HRMS. All the synthesized compounds were screened initially for their anticancer activity against MCF7 and T47D (breast cancer), HSC3 (head and neck cancer), and RKO (colorectal cancer) cell lines using MTT assay. Apoptosis and cell cycle analyses were conducted using Annexin V\/propidium iodide (PI) double staining for apoptosis assessment and PI staining for cell cycle analysis to investigate the mechanisms underlying the reduced cell viability. In silico molecular docking was accomplished for the synthesized compounds against the Hsp90 and determined pharmacokinetics properties. Results: From the screening assay, compounds 6a and 6i were identified as potential inhibitors and were further subjected to IC50 determination. The compound 6i showed potent inhibition against HSC3 (IC50 = 10.8 \u00b5M), T47D (IC50 = 11.7 \u00b5M), and RKO (IC50 = 12.4 \u00b5M) cell lines, all of which indicated a broad spectrum of anticancer activity. Notably, 6i was found to induce G2 phase arrest, thereby inhibiting cell cycle progression. Molecular docking results indicated crucial molecular interactions of the synthesized ligands against the target Hsp90. Conclusion: The compound 6i induced cell death via mechanisms that are different from apoptosis. Thus, the synthesized thieno[2,3-c]pyridine derivatives can be suitable lead compounds to be optimized to obtain potent anticancer agents through Hsp90 inhibition.<\/jats:p>","DOI":"10.3390\/ph18020153","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T03:26:31Z","timestamp":1737689191000},"page":"153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Synthesis, Anticancer Screening, and In Silico Evaluations of Thieno[2,3-c]pyridine Derivatives as Hsp90 Inhibitors"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4198-8679","authenticated-orcid":false,"given":"Balakumar","family":"Chandrasekaran","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1736-1799","authenticated-orcid":false,"given":"Mohammad F.","family":"Bayan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Hmedat","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Pharmaceutics, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3308-8697","authenticated-orcid":false,"given":"Bilal A.","family":"Al-Jaidi","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8671-1134","authenticated-orcid":false,"given":"Deniz M.","family":"Al-Tawalbeh","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Yarmouk University, Irbid 21163, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5277-5703","authenticated-orcid":false,"given":"Duaa","family":"Abuarqoub","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Medical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4203-7031","authenticated-orcid":false,"given":"Anas J.","family":"Rasras","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Al-Balqa Applied University, P.O. Box 206, Al-Salt 19117, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9853-3272","authenticated-orcid":false,"given":"Da\u2019san M. M.","family":"Jaradat","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, Al-Balqa Applied University, P.O. Box 206, Al-Salt 19117, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdel Naser","family":"Dakkah","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafa","family":"Hourani","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1247-5754","authenticated-orcid":false,"given":"Rajshekhar","family":"Karpoormath","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4000, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA","volume":"74","author":"Bray","year":"2024","journal-title":"Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103635","DOI":"10.1016\/j.esmoop.2024.103635","article-title":"Patients with Cancer Who Will Be Cured and Projections of Complete Prevalence in Italy from 2018 to 2030","volume":"9","author":"Guzzinati","year":"2024","journal-title":"ESMO Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"448","DOI":"10.21037\/jtd.2017.02.75","article-title":"Cancer Prevention from the Perspective of Global Cancer Burden Patterns","volume":"9","author":"Nagai","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_4","unstructured":"American Cancer Society (2024). Global Cancer Facts & Figures, American Cancer Society, Inc.. [5th ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2336","DOI":"10.1200\/JCO.24.00542","article-title":"Palliative Care for Patients with Cancer: ASCO Guideline Update","volume":"42","author":"Sanders","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/s41392-024-01856-7","article-title":"Exploring Treatment Options in Cancer: Tumor Treatment Strategies","volume":"9","author":"Liu","year":"2024","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0140-6736(21)00233-6","article-title":"Contemporary Radiotherapy: Present and Future","volume":"398","author":"Chandra","year":"2021","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/s43018-023-00619-7","article-title":"Harnessing Progress in Radiotherapy for Global Cancer Control","volume":"4","author":"Jaffray","year":"2023","journal-title":"Nat. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1515\/mr-2022-0033","article-title":"Therapeutic Antibodies for Precise Cancer Immunotherapy: Current and Future Perspectives","volume":"2","author":"Liu","year":"2022","journal-title":"Med. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fmmed.2023.1140977","article-title":"Cancer Immunotherapies: A Hope for the Uncurable?","volume":"3","author":"Hamdan","year":"2023","journal-title":"Front. Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41416-024-02590-1","article-title":"Menopausal Hormone Therapy and Breast Cancer Risk: A Population-Based Cohort Study of 1.3 Million Women in Norway","volume":"131","author":"Vangen","year":"2024","journal-title":"Br. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.mpmed.2019.11.007","article-title":"Hormonal Therapy for Cancer","volume":"48","author":"Abraham","year":"2020","journal-title":"Medicine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3197","DOI":"10.1245\/s10434-023-13352-3","article-title":"A Review of the Current State of Global Surgical Oncology and the Role of Surgeons Who Treat Cancer: Our Profession\u2019s Imperative to Act Upon a Worldwide Crisis in Evolution","volume":"30","author":"Saunders","year":"2023","journal-title":"Ann. Surg. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"9584","DOI":"10.3390\/curroncol30110693","article-title":"Advances in the Surgical Treatment of Breast Cancer","volume":"30","author":"Cheifetz","year":"2023","journal-title":"Curr. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1016\/j.gendis.2022.02.007","article-title":"Cancer Chemotherapy and beyond: Current Status, Drug Candidates, Associated Risks and Progress in Targeted Therapeutics","volume":"10","author":"Anand","year":"2023","journal-title":"Genes Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101056","DOI":"10.1016\/j.tranon.2021.101056","article-title":"Chemotherapeutic Drugs: Cell Death- and Resistance-Related Signaling Pathways. Are They Really as Smart as the Tumor Cells?","volume":"14","author":"Mollaei","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Rajora, A.K., Ravishankar, D., Zhang, H., and Rosenholm, J.M. (2020). Recent Advances and Impact of Chemotherapeutic and Antiangiogenic Nanoformulations for Combination Cancer Therapy. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12060592"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Eslami, M., Memarsadeghi, O., Davarpanah, A., Arti, A., Nayernia, K., and Behnam, B. (2024). Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review. Biomedicines, 12.","DOI":"10.3390\/biomedicines12010183"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"D\u2019Orazi, G., and Cirone, M. (2024). Cancer Chemotherapy: Combination with Inhibitors (Volume I). Cancers, 16.","DOI":"10.3390\/cancers16030607"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"James, N., Owusu, E., Rivera, G., and Bandyopadhyay, D. (2024). Small Molecule Therapeutics in the Pipeline Targeting for Triple-Negative Breast Cancer: Origin, Challenges, Opportunities, and Mechanisms of Action. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116285"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6","DOI":"10.3892\/or.2022.8443","article-title":"HSP90 Inhibitors and Cancer: Prospects for Use in Targeted Therapies (Review)","volume":"49","author":"Li","year":"2022","journal-title":"Oncol. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hoter, A., El-Sabban, M.E., and Naim, H.Y. (2018). The HSP90 Family: Structure, Regulation, Function, and Implications in Health and Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092560"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/bip.22835","article-title":"Review: The HSP90 Molecular Chaperone\u2014An Enigmatic ATPase","volume":"105","author":"Pearl","year":"2016","journal-title":"Biopolymers"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1158\/1541-7786.MCR-15-0234","article-title":"Maximizing the Therapeutic Potential of HSP90 Inhibitors","volume":"13","author":"Butler","year":"2015","journal-title":"Mol. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s12276-019-0360-x","article-title":"Unleashing the Full Potential of Hsp90 Inhibitors as Cancer Therapeutics through Simultaneous Inactivation of Hsp90, Grp94, and TRAP1","volume":"52","author":"Park","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Maiti, S., and Picard, D. (2022). Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance. Biomolecules, 12.","DOI":"10.3390\/biom12091166"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Birbo, B., Madu, E.E., Madu, C.O., Jain, A., and Lu, Y. (2021). Role of Hsp90 in Cancer. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910317"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Zarguan, I., Ghoul, S., Belayachi, L., and Benjouad, A. (2024). Plant-Based HSP90 Inhibitors in Breast Cancer Models: A Systematic Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25105468"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/13543776.2024.2327295","article-title":"Recent Developments of HSP90 Inhibitors: An Updated Patent Review (2020\u2013Present)","volume":"34","author":"Liu","year":"2024","journal-title":"Expert. Opin. Ther. Pat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1021\/acs.jmedchem.9b00940","article-title":"Heat Shock Protein 90 Inhibitors: An Update on Achievements, Challenges, and Future Directions","volume":"63","author":"Li","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.cstres.2024.05.005","article-title":"An Update on the Status of HSP90 Inhibitors in Cancer Clinical Trials","volume":"29","author":"Rastogi","year":"2024","journal-title":"Cell Stress. Chaperones"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1016\/j.bbamcr.2011.10.008","article-title":"Advances in the Clinical Development of Heat Shock Protein 90 (Hsp90) Inhibitors in Cancers","volume":"1823","author":"Jhaveri","year":"2012","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.ejmech.2016.07.022","article-title":"Synthesis, Anticancer Activity and Photostability of Novel 3-Ethyl-2-Mercapto-Thieno [2,3-d]Pyrimidin-4(3H)-Ones","volume":"123","author":"Mavrova","year":"2016","journal-title":"Eur. J. Med. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s40265-022-01764-6","article-title":"Pimitespib: First Approval","volume":"82","author":"Hoy","year":"2022","journal-title":"Drugs"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"507","DOI":"10.2217\/fon-2022-1172","article-title":"Pimitespib for the Treatment of Advanced Gastrointestinal Stromal Tumors and Other Tumors","volume":"20","author":"Doi","year":"2024","journal-title":"Futur. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44247","DOI":"10.1039\/D0RA09198G","article-title":"Prescribed Drugs Containing Nitrogen Heterocycles: An Overview","volume":"10","author":"Heravi","year":"2020","journal-title":"RSC Adv."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3687","DOI":"10.1080\/07391102.2017.1396255","article-title":"Ligand- and Structure-Based in Silico Studies to Identify Kinesin Spindle Protein (KSP) Inhibitors as Potential Anticancer Agents","volume":"36","author":"Balakumar","year":"2018","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6282","DOI":"10.1016\/j.bmcl.2010.08.088","article-title":"Novel Thienopyridine Derivatives as Specific Anti-Hepatocellular Carcinoma (HCC) Agents: Synthesis, Preliminary Structure\u2014Activity Relationships, and in Vitro Biological Evaluation","volume":"20","author":"Zeng","year":"2010","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"7217","DOI":"10.3390\/molecules17067217","article-title":"Synthesis and Biological Evaluation of Thiophene Derivatives as Acetylcholinesterase Inhibitors","volume":"17","author":"Ismail","year":"2012","journal-title":"Molecules"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ejmech.2018.04.028","article-title":"Discovery and Structure-Activity Relationships Study of Thieno[2,3-b]Pyridine Analogues as Hepatic Gluconeogenesis Inhibitors","volume":"152","author":"Ma","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"595934","DOI":"10.1155\/2010\/595934","article-title":"Current Concepts on Antiplatelet Therapy: Focus on the Novel Thienopyridine and Non-Thienopyridine Agents","volume":"2010","author":"Testa","year":"2010","journal-title":"Adv. Hematol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1046\/j.1365-2044.2003.02960.x","article-title":"The Thienopyridine Derivatives (Platelet Adenosine Diphosphate Receptor Antagonists), Pharmacology and Clinical Developments","volume":"58","author":"Kam","year":"2003","journal-title":"Anaesthesia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/978-3-642-29423-5_7","article-title":"Thienopyridines and Other ADP-Receptor Antagonists","volume":"Volume 210","author":"Gresele","year":"2012","journal-title":"Antiplatet Agents"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.1080\/00397911.2020.1778033","article-title":"Synthesis, cytotoxicity, in-vitro antibacterial screening and in-silico study of novel thieno[2,3-b]pyridines as potential pim-1 inhibitors","volume":"50","author":"Mekky","year":"2020","journal-title":"Synth. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"7089","DOI":"10.1016\/j.bmcl.2011.09.109","article-title":"Thiophene Inhibitors of PDE4: Crystal Structures Show a Second Binding Mode at the Catalytic Domain of PDE4D2","volume":"21","author":"Nankervis","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_46","unstructured":"Lee, B.H., Geary, T.G., Davis, J.P., and Bowman, J.W. (2003). Anthelmintic and Insecticidal Thiophene Derivatives. (WO2003101979A1), Patent."},{"key":"ref_47","first-page":"100185","article-title":"Recent advancements in the synthesis of fused thienopyridines and their therapeutic applications","volume":"12","author":"Shaw","year":"2024","journal-title":"Eur. J. Med. Chem. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1007\/s00044-017-2099-z","article-title":"Synthesis and Adenosine Receptors Binding Studies of New Fluorinated Analogues of Pyrido[2,3-d]Pyrimidines and Quinazolines","volume":"27","author":"Chandrasekaran","year":"2018","journal-title":"Med. Chem. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1158\/1535-7163.MCT-10-0055","article-title":"Preclinical Antitumor Activity of the Orally Available Heat Shock Protein 90 Inhibitor NVP-BEP800","volume":"9","author":"Massey","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Mateev, E., Kondeva-Burdina, M., Georgieva, M., Mateeva, A., Valkova, I., Tzankova, V., and Zlatkov, A. (2024). Synthesis, Biological Evaluation, Molecular Docking and ADME Studies of Novel Pyrrole-Based Schiff Bases as Dual Acting MAO\/AChE Inhibitors. Sci. Pharm., 92.","DOI":"10.3390\/scipharm92020018"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ukrainets, I.V., Burian, A.A., Baumer, V.N., Shishkina, S.V., Sidorenko, L.V., Tugaibei, I.A., Voloshchuk, N.I., and Bondarenko, P.S. (2018). Synthesis, Crystal Structure, and Biological Activity of Ethyl 4-Methyl-2,2-Dioxo-1h-2\u03bb6,1-Benzothiazine-3-Carboxylate Polymorphic Forms. Sci. Pharm., 86.","DOI":"10.3390\/scipharm86020021"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Khan, M.I.H., Mahdi, F., Penfornis, P., Akins, N.S., Hossain, M.I., Kim, S.J., Sulochana, S.P., Adam, A.T., Tran, T.D., and Tan, C. (2023). Synthesis and biological evaluation of tert-butyl ester and ethyl ester prodrugs of L-\u03b3-methyleneglutamic acid amides for cancer. Bioorg. Med. Chem., 78.","DOI":"10.1016\/j.bmc.2022.117137"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1016\/j.bmc.2009.04.031","article-title":"Investigation of Various N-Heterocyclic Substituted Piperazine Versions of 5\/7-{[2-(4-Aryl-Piperazin-1-Yl)-Ethyl]-Propyl-Amino}-5,6,7,8-Tetrahydro-Naphthalen-2-Ol: Effect on Affinity and Selectivity for Dopamine D3 Receptor","volume":"17","author":"Brown","year":"2009","journal-title":"Bioorg. Med. Chem."},{"key":"ref_54","first-page":"100041","article-title":"A Comprehensive Review on the Synthesis of Substituted Piperazine and Its Novel Bio-Medicinal Applications","volume":"2","author":"Rizwan","year":"2024","journal-title":"Chem. Inorg. Mater."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Filipova, A., Marek, J., Havelek, R., Pejchal, J., Jelicova, M., Cizkova, J., Majorosova, M., Muckova, L., Kucera, T., and Prchal, L. (2020). Substituted Piperazines as Novel Potential Radioprotective Agents. Molecules, 25.","DOI":"10.3390\/molecules25030532"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.ejmech.2012.12.055","article-title":"New 2-Benzylsulfanyl-Nicotinic Acid Based 1,3,4-Oxadiazoles: Their Synthesis and Biological Evaluation","volume":"62","author":"Patel","year":"2013","journal-title":"Eur. J. Med. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Ardestani, M., Khorsandi, Z., Keshavarzipour, F., Iravani, S., Sadeghi-Aliabadi, H., and Varma, R.S. (2022). Heterocyclic Compounds as Hsp90 Inhibitors: A Perspective on Anticancer Applications. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14102220"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1039\/C2CC37070K","article-title":"Facile Assembly of Two 6-Membered Fused N-Heterocyclic Rings: A Rapid Access to Novel Small Molecules via Cu-Mediated Reaction","volume":"49","author":"Adepu","year":"2013","journal-title":"Chem. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1016\/j.bmcl.2019.07.033","article-title":"Applications of Amide Isosteres in Medicinal Chemistry","volume":"29","author":"Sun","year":"2019","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"12290","DOI":"10.1021\/acs.jmedchem.0c00530","article-title":"Amide Bond Bioisosteres: Strategies, Synthesis, and Successes","volume":"63","author":"Kumari","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e202402267","DOI":"10.1002\/anie.202402267","article-title":"Unlocking Amides: A General Method for the Self-Immolative Release of Amide-Containing Molecules","volume":"63","author":"Wharton","year":"2024","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Karunanidhi, S., Chandrasekaran, B., Karpoormath, R., Patel, H.M., Kayamba, F.B., Reddy Merugu, S., Kumar, V., Dhawan, S., Kushwaha, B., and Cleopus Mahlalela, M. (2021). Novel Thiomorpholine Tethered Isatin Hydrazones as Potential Inhibitors of Resistant Mycobacterium Tuberculosis. Bioorg. Chem., 115.","DOI":"10.1016\/j.bioorg.2021.105133"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.ejmech.2015.04.060","article-title":"Discovery and Biological Evaluation of Tetrahydrothieno[2,3-c]Pyridine Derivatives as Selective Metabotropic Glutamate Receptor 1 Antagonists for the Potential Treatment of Neuropathic Pain","volume":"97","author":"Nam","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1021\/jm401551n","article-title":"Heat Shock Protein 70 Inhibitors. 1. 2,5\u2032-Thiodipyrimidine and 5-(Phenylthio)Pyrimidine Acrylamides as Irreversible Binders to an Allosteric Site on Heat Shock Protein 70","volume":"57","author":"Kang","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2849","DOI":"10.1002\/anie.201411206","article-title":"Tracing Binding Modes in Hit-to-Lead Optimization: Chameleon-like Poses of Aspartic Protease Inhibitors","volume":"54","author":"Kuhnert","year":"2015","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ejmech.2014.02.028","article-title":"Development of Antimycobacterial Tetrahydrothieno[2,3-c]Pyridine-3- Carboxamides and Hexahydrocycloocta[b]Thiophene-3-Carboxamides: Molecular Modification from Known Antimycobacterial Lead","volume":"76","author":"Nallangi","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3571","DOI":"10.1002\/cber.19650981120","article-title":"Heterocyclen Aus CH-Aciden Nitrilen, VII. 2-Amino-Thiophene Aus \u03b1-Oxo-Mercaptanen Und Methylenaktiven Nitrilen","volume":"98","author":"Gewald","year":"1965","journal-title":"Chem. Ber."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-1-61779-080-5_20","article-title":"Cell Sensitivity Assays: The MTT Assay","volume":"731","author":"Kaspers","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2298\/JSC240109018H","article-title":"In Vitro Anticancer Studies of a Small Library of Cyclic Lipopeptides against the Human Cervix Adenocarcinoma HeLa Cells","volume":"89","author":"Hmedat","year":"2024","journal-title":"J. Serbian Chem. Soc."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Salmaso, V., and Moro, S. (2018). Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00923"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4794","DOI":"10.1021\/jm900357y","article-title":"Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]Pyrimidine Inhibitors of the Hsp90 Molecular Chaperone","volume":"52","author":"Brough","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/sj.bjc.6605066","article-title":"Targeting HSP90 for Cancer Therapy","volume":"100","author":"Mahalingam","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1111\/j.1349-7006.2007.00561.x","article-title":"Extracellular Heat Shock Protein 90: A Role for a Molecular Chaperone in Cell Motility and Cancer Metastasis","volume":"98","author":"Tsutsumi","year":"2007","journal-title":"Cancer Sci."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Dagan-Wiener, A., Nissim, I., Ben Abu, N., Borgonovo, G., Bassoli, A., and Niv, M.Y. (2017). Bitter or Not? BitterPredict, a Tool for Predicting Taste from Chemical Structure. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-12359-7"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.ddtec.2004.11.007","article-title":"Lead- and Drug-like Compounds: The Rule-of-Five Revolution","volume":"1","author":"Lipinski","year":"2004","journal-title":"Drug Discov. Today Technol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1080\/17460441.2019.1660642","article-title":"Estimating Human ADME Properties, Pharmacokinetic Parameters and Likely Clinical Dose in Drug Discovery","volume":"14","author":"Lucas","year":"2019","journal-title":"Expert. Opin. Drug Discov."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1002\/jcc.27086","article-title":"Development and Test of Highly Accurate Endpoint Free Energy Methods. 2: Prediction of Logarithm of n-Octanol\u2013Water Partition Coefficient (LogP) for Druglike Molecules Using MM-PBSA Method","volume":"44","author":"Sun","year":"2023","journal-title":"J. Comput. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Mohamed, G.A., Abdallah, H.M., Sindi, I.A., Ibrahim, S.R.M., and Alzain, A.A. (2024). Unveiling the Potential of Phytochemicals to Inhibit Nuclear Receptor Binding SET Domain Protein 2 for Cancer: Pharmacophore Screening, Molecular Docking, ADME Properties, and Molecular Dynamics Simulation Investigations. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0308913"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0169-409X(02)00008-X","article-title":"Prediction of Drug Solubility from Structure","volume":"54","author":"Jorgensen","year":"2002","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.toxrep.2020.01.004","article-title":"Determination and Prediction of Permeability across Intestinal Epithelial Cell Monolayer of a Diverse Range of Industrial Chemicals\/Drugs for Estimation of Oral Absorption as a Putative Marker of Hepatotoxicity","volume":"7","author":"Kamiya","year":"2020","journal-title":"Toxicol. Rep."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1002\/jps.1031","article-title":"Evaluation of Human Intestinal Absorption Data and Subsequent Derivation of a Quantitative Structure\u2014Activity Relationship (QSAR) with the Abraham Descriptors","volume":"90","author":"Zhao","year":"2001","journal-title":"J. Pharm. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Lee, H.M., Yu, M.S., Kazmi, S.R., Oh, S.Y., Rhee, K.H., Bae, M.A., Lee, B.H., Shin, D.S., Oh, K.S., and Ceong, H. (2019). Computational Determination of HERG-Related Cardiotoxicity of Drug Candidates. BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-2814-5"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Bittermann, K., and Goss, K.U. (2017). Predicting Apparent Passive Permeability of Caco-2 and MDCK Cell-Monolayers: A Mechanistic Model. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0190319"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s11095-018-2551-x","article-title":"Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein","volume":"36","author":"Smith","year":"2019","journal-title":"Pharm. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"140438","DOI":"10.1016\/j.molstruc.2024.140438","article-title":"Evaluation of Anticancer Activity of Some New Hybrids of 1,3,4-Oxadiazole Tethered Cinnamamides","volume":"1322","author":"Rasras","year":"2025","journal-title":"J. Mol. Struct."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"3004","DOI":"10.1021\/acs.jmedchem.9b01689","article-title":"Novel, Self-Assembling Dimeric Inhibitors of Human \u03b2 Tryptase","volume":"63","author":"Giardina","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","article-title":"OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space","volume":"17","author":"Lu","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1021\/ci100026x","article-title":"Drug-like Bioactive Structures and Conformational Coverage with the Ligprep\/Confgen Suite: Comparison to Programs MOE and Catalyst","volume":"50","author":"Chen","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1186\/2193-1801-2-353","article-title":"An in Silico Evaluation of the ADMET Profile of the StreptomeDB Database","volume":"2","year":"2013","journal-title":"SpringerPlus"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Malik, N., Dhiman, P., and Khatkar, A. (2019). In Silico Design and Synthesis of Targeted Rutin Derivatives as Xanthine Oxidase Inhibitors. BMC Chem., 13.","DOI":"10.1186\/s13065-019-0585-8"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s12094-008-0150-8","article-title":"Cardiac Toxicity: Old and New Issues in Anti-Cancer Drugs","volume":"10","author":"Sereno","year":"2008","journal-title":"Clin. Transl. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.addr.2015.03.003","article-title":"Computational Investigations of HERG Channel Blockers: New Insights and Current Predictive Models","volume":"86","author":"Villoutreix","year":"2015","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Sakharov, D., Maltseva, D., Knyazev, E., Nikulin, S., Poloznikov, A., Shilin, S., Baranova, A., Tsypina, I., and Tonevitsky, A. (2019). Towards Embedding Caco-2 Model of Gut Interface in a Microfluidic Device to Enable Multi-Organ Models for Systems Biology. BMC Syst. Biol., 13.","DOI":"10.1186\/s12918-019-0686-y"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/jps.21010","article-title":"Variability in Caco-2 and MDCK Cell-Based Intestinal Permeability Assays","volume":"97","author":"Volpe","year":"2008","journal-title":"J. Pharm. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"2562","DOI":"10.1016\/j.xphs.2021.01.029","article-title":"Predicting oral absorption for compounds outside the rule of five property space","volume":"110","author":"Huth","year":"2021","journal-title":"J. Pharm. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"106699","DOI":"10.1016\/j.ejps.2024.106699","article-title":"Pitfalls in Evaluating Permeability Experiments with Caco-2\/MDCK Cell Monolayers","volume":"194","author":"Ebert","year":"2024","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Ciura, K., Ulenberg, S., Kapica, H., Kawczak, P., Belka, M., and B\u0105czek, T. (2020). Drug Affinity to Human Serum Albumin Prediction by Retention of Cetyltrimethylammonium Bromide Pseudostationary Phase in Micellar Electrokinetic Chromatography and Chemically Advanced Template Search Descriptors. J. Pharm. Biomed. Anal., 188.","DOI":"10.1016\/j.jpba.2020.113423"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"4661","DOI":"10.1016\/j.bmc.2008.02.033","article-title":"The Role of Lipophilicity in Determining Binding Affinity and Functional Activity for 5-HT2A Receptor Ligands","volume":"16","author":"Parker","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Fagerholm, U., Hellberg, S., and Spjuth, O. (2021). Advances in Predictions of Oral Bioavailability of Candidate Drugs in Man with New Machine Learning Methodology. Molecules, 26.","DOI":"10.3390\/molecules26092572"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"108851","DOI":"10.1016\/j.jmgm.2024.108851","article-title":"Research on Prediction of Human Oral Bioavailability of Drugs Based on Improved Deep Forest","volume":"133","author":"Ma","year":"2024","journal-title":"J. Mol. Graph. Model."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:35:09Z","timestamp":1759919709000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/2\/153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,24]]},"references-count":100,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ph18020153"],"URL":"https:\/\/doi.org\/10.3390\/ph18020153","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,24]]}}}