Novel Indole-Based Sulfonylhydrazones as Potential Anti-Breast Cancer Agents: Synthesis, In Vitro Evaluation, ADME, and QSAR Studies
Abstract
1. Introduction
2. Results
2.1. Design of Novel Indolyl-methylidene-Substituted Phenylsulfonylhydrazones
2.2. In Silico Screening of the Designed Compounds for Drug Likeness
2.2.1. Physicochemical Properties
2.2.2. ADME Properties
2.2.3. Pharmacokinetic (PK) Parameters
2.3. Synthesis of the Novel Indolyl-methylidene Substituted Phenylsulfonylhydrazones 3a–j and Bis(indolyl methylidene)diazine Derivative 4
2.4. X-Ray Crystallography of N′-[(E)-(5-Bromo-1H-indol-3-yl)methylidene]-4-methylbenzene-1-sulfonohydrazide, 3e
2.5. Anticancer Activity of the Novel Indolyl-methylidene Substituted Phenylsulfonylhydrazones
2.6. Quantitative Structure–Activity Relationships (QSAR) of the Novel Indolyl-methylidene Substituted Phenylsulfonylhydrazones
3. Discussion
4. Materials and Methods
4.1. Materials and Reagents
4.2. In Silico Screening for Drug Likeness, ADME Properties, and Pharmacokinetic Parameters
4.3. Synthesis
4.3.1. General Information
4.3.2. General Procedure for the Synthesis of the Compounds 3a–h
N′-[(E)-(1-Acetyl-1H-indol-3-yl)methylidene]-4-methoxybenzene-1-sulfonohydrazide, 3a
N′-[(E)-(1-Acetyl-1H-indol-3-yl)methylidene]-2,4,6-trimethylbenzene-1-sulfonohydrazide, 3b
N′-[(E)-(5-Bromo-1H-indol-3-yl)methylidene]-4-methoxybenzene-1-sulfonohydrazide, 3c
N′-[(E)-(5-Bromo-1H-indol-3-yl)methylidene]-2,4,6-trimethylbenzene-1-sulfonohydrazide, 3d
N′-[(E)-(5-Bromo-1H-indol-3-yl)methylidene]-4-methylbenzene-1-sulfonohydrazide, 3e
N′-[(E)-(5-Bromo-1H-indol-3-yl)methylidene]benzene-1-sulfonohydrazide, 3f
N′-[(E)-(5-Chloro-1H-indol-3-yl)methylidene]-4-methoxybenzene-1-sulfonohydrazide, 3g
N′-[(E)-(5-Chloro-1H-indol-3-yl)methylidene]-2,4,6-trimethylbenzene-1-sulfonohydrazide, 3h
4.3.3. General Procedure for the Synthesis of the Compounds 3i,3g
N′-[(E)-(5-Chloro-1H-indol-3-yl)methylidene]-2,4-dimethylbenzene-1-sulfonohydrazide, 3i
N′-[(E)-(5-Chloro-1H-indol-3-yl)methylidene]-3,4-dimethylbenzene-1-sulfonohydrazide, 3j
4.3.4. General Procedure for the Synthesis of the 5-Chloro-3-[(E)-[(2E)-[(5-chloro-1H-indol-3-yl)methylidene]hydrazinylidene]methyl]-1H-indole, Alternative Name is 3,3′-[(1E,2E)-Hydrazinediylidenedi-(E)-methanylylidene]bis(5-chloro-1H-indole) 4
4.3.5. Single-Crystal X-Ray Analysis of N′-[(E)-(5-Bromo-1H-indol-3-yl)methylidene]-4-methylbenzene-1-sulfonohydrazide, 3e
4.4. In Vitro Anticancer Activity
4.5. Quantitative Structure-Activity Relationship (QSAR) Protocol
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ADME | Absorption, distribution, metabolism, and excretion |
BA | Bioavailability |
BBB | Blood–brain barier |
BC | Breast cancer |
CYP | Cytochrome P450 enzymes |
ER+ | Estrogen receptor-positive breast cancer |
LE | Ligand efficiency |
MDR | Multidrug resistance |
MLR | Multiple linear regression |
QSAR | Quantitative structure–activity relationship |
QSPkR | Quantitative structure–pharmacokinetics relationship |
SI | Similarity index |
TNBC | Triple-negative breast cancer |
References
- Xiong, X.; Zheng, L.-W.; Ding, Y.; Chen, Y.-F.; Cai, Y.-W.; Wang, L.-P.; Huang, L.; Liu, C.-C.; Shao, Z.-M.; Yu, K.-D. Breast cancer: Pathogenesis and treatments. Signal Transduct. Target. Ther. 2025, 10, 49. [Google Scholar] [CrossRef]
- Adams, E.; Wildiers, H.; Neven, P.; Punie, K. Sacituzumab govitecan and trastuzumab deruxtecan: Two new antibody–drug conjugates in the breast cancer treatment landscape. ESMO Open 2021, 6, 100204. [Google Scholar] [CrossRef]
- Kim, J.; Harper, A.; McCormack, V.; Sung, H.; Houssami, N.; Morgan, E.; Mutebi, M.; Garvey, G.; Soerjomataram, I.; Fidler-Benaoudia, M.M. Global patterns and trends in breast cancer incidence and mortality across 185 countries. Nat. Med. 2025, 31, 1–9. [Google Scholar] [CrossRef]
- Coleman, M.P. Opinion: Why the variation in breast cancer survival in Europe? Breast Cancer Res. 1999, 1, 1–5. [Google Scholar] [CrossRef]
- Wang, J.; Wu, S.-G. Breast cancer: An overview of current therapeutic strategies, challenge, and perspectives. Breast Cancer Targets Ther. 2023, 15, 721–730. [Google Scholar] [CrossRef]
- Brandstetter, L.S.; Jírů-Hillmann, S.; Störk, S.; Heuschmann, P.U.; Wöckel, A.; Reese, J.-P. Differences in preferences for drug therapy between patients with metastatic versus early-stage breast cancer: A systematic literature review. Patient-Patient-Centered Outcomes Res. 2024, 17, 349–362. [Google Scholar] [CrossRef]
- Rai, V.; Gupta, Y.; Srivastava, S.P.; Shukla, A.; Bano, N.; Khan, S. Targeted Therapies in Cancer Treatment: Unveiling the Latest Breakthroughs and Promising Approaches. J. Res. Appl. Sci. Biotechnol. 2024, 2, 175–183. [Google Scholar] [CrossRef]
- Kim, J.; Shim, M.K.; Yang, S.; Moon, Y.; Song, S.; Choi, J.; Kim, J.; Kim, K. Combination of cancer-specific prodrug nanoparticle with Bcl-2 inhibitor to overcome acquired drug resistance. J. Control. Release 2021, 330, 920–932. [Google Scholar] [CrossRef]
- Mir, M.A.; Qayoom, H.; Mehraj, U.; Nisar, S.; Bhat, B.; Wani, N.A. Targeting different pathways using novel combination therapy in triple negative breast cancer. Curr. Cancer Drug Targets 2020, 20, 586–602. [Google Scholar] [CrossRef]
- Díaz-Rodríguez, E.; Gandullo-Sánchez, L.; Ocaña, A.; Pandiella, A. Novel ADCs and strategies to overcome resistance to anti-HER2 ADCs. Cancers 2021, 14, 154. [Google Scholar] [CrossRef]
- Gámez-Chiachio, M.; Sarrió, D.; Moreno-Bueno, G. Novel therapies and strategies to overcome resistance to anti-HER2-targeted drugs. Cancers 2022, 14, 4543. [Google Scholar] [CrossRef]
- Saha, T.; Lukong, K.E. Breast cancer stem-like cells in drug resistance: A review of mechanisms and novel therapeutic strategies to overcome drug resistance. Front. Oncol. 2022, 12, 856974. [Google Scholar] [CrossRef]
- Wu, X.; Yang, H.; Yu, X.; Qin, J.-J. Drug-resistant HER2-positive breast cancer: Molecular mechanisms and overcoming strategies. Front. Pharmacol. 2022, 13, 1012552. [Google Scholar] [CrossRef]
- Guidi, L.; Pellizzari, G.; Tarantino, P.; Valenza, C.; Curigliano, G. Resistance to antibody-drug conjugates targeting HER2 in breast cancer: Molecular landscape and future challenges. Cancers 2023, 15, 1130. [Google Scholar] [CrossRef]
- Ferro, A.; Campora, M.; Caldara, A.; De Lisi, D.; Lorenzi, M.; Monteverdi, S.; Mihai, R.; Bisio, A.; Dipasquale, M.; Caffo, O. Novel treatment strategies for hormone receptor (HR)-positive, HER2-negative metastatic breast cancer. J. Clin. Med. 2024, 13, 3611. [Google Scholar] [CrossRef]
- Wang, T.; Gautam, P.; Rousu, J.; Aittokallio, T. Systematic mapping of cancer cell target dependencies using high-throughput drug screening in triple-negative breast cancer. Comput. Struct. Biotechnol. J. 2020, 18, 3819–3832. [Google Scholar] [CrossRef]
- Wang, H.; Li, S.; Wang, Q.; Jin, Z.; Shao, W.; Gao, Y.; Li, L.; Lin, K.; Zhu, L.; Wang, H. Tumor immunological phenotype signature-based high-throughput screening for the discovery of combination immunotherapy compounds. Sci. Adv. 2021, 7, eabd7851. [Google Scholar] [CrossRef]
- Miles, H.N.; Delafield, D.G.; Li, L. Recent developments and applications of quantitative proteomics strategies for high-throughput biomolecular analyses in cancer research. RSC Chem. Biol. 2021, 2, 1050–1072. [Google Scholar] [CrossRef]
- Lee, S.-Y.; Hwang, H.J.; Ku, B.; Lee, D.W. Cell proliferation receptor-enhanced 3D high-throughput screening model for optimized drug efficacy evaluation in breast cancer cells. Anal. Chem. 2022, 94, 11838–11847. [Google Scholar] [CrossRef]
- Rao, X.; Qiao, Z.; Yang, Y.; Deng, Y.; Zhang, Z.; Yu, X.; Guo, X. Unveiling epigenetic vulnerabilities in triple-negative breast cancer through 3d organoid drug screening. Pharmaceuticals 2024, 17, 225. [Google Scholar] [CrossRef]
- Sui, H.; Fan, Z.; Li, Q. Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J. Int. Med. Res. 2012, 40, 426–435. [Google Scholar] [CrossRef]
- Sabbah, D.A.; Al-Azaideh, B.A.A.; Talib, W.H.; Hajjo, R.; Sweidan, K.; Al-Zuheiri, A.M.; Abu Sheikha, G.; Shraim, S. New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation. Acta Pharm. 2021, 71, 545–565. [Google Scholar] [CrossRef] [PubMed]
- Thakuria, R.; Nath, N.K.; Roy, S.; Nangia, A. Polymorphism and isostructurality in sulfonylhydrazones. CrystEngComm 2014, 16, 4681–4690. [Google Scholar] [CrossRef]
- Aslan, H.G.; Özcan, S.; Karacan, N. The antibacterial activity of some sulfonamides and sulfonyl hydrazones, and 2D-QSAR study of a series of sulfonyl hydrazones. Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2012, 98, 329–336. [Google Scholar] [CrossRef] [PubMed]
- Aydin Terzioğlu, M.; Öztürk, A.; Duran, T.; Özdemir Özmen, Ü.; Şumlu, E. Effect of New Sulfonyl Hydrazone Compounds Against Candida Biofilms. In Proceedings of the Seventh International Mediterranean Symposium on Medicinal and Aromatic Plants MESMAP–7, Djerba, Tunesia, 11–14 April 2025. [Google Scholar]
- Angelova, V.T.; Pencheva, T.; Vassilev, N.; Yovkova, E.-K.; Mihaylova, R.; Petrov, B.; Valcheva, V. Development of new antimycobacterial sulfonyl hydrazones and 4-methyl-1, 2, 3-thiadiazole-based hydrazone derivatives. Antibiotics 2022, 11, 562. [Google Scholar] [CrossRef]
- Aydin, M.; Ozturk, A.; Duran, T.; Ozmen, U.O.; Sumlu, E.; Ayan, E.B.; Korucu, E.N. In vitro antifungal and antibiofilm activities of novel sulfonyl hydrazone derivatives against Candida spp. J. Med. Mycol. 2023, 33, 101327. [Google Scholar] [CrossRef]
- Shaker, A.M.; Abdelall, E.K.; Abdellatif, K.R.; Abdel-Rahman, H.M. Synthesis and biological evaluation of 2-(4-methylsulfonyl phenyl) indole derivatives: Multi-target compounds with dual antimicrobial and anti-inflammatory activities. BMC Chem. 2020, 14, 1–15. [Google Scholar] [CrossRef]
- Demirci, Y.; Kalay, E.; Kara, Y.; Güler, H.İ.; Can, Z.; Şahin, E. Synthesis of arylsulfonyl hydrazone derivatives: Antioxidant activity, acetylcholinesterase inhibition properties, and molecular docking study. ChemistrySelect 2023, 8, e202301474. [Google Scholar] [CrossRef]
- Aktar, B.S.K.; Sıcak, Y.; Tatar, G.; Oruç-Emre, E.E. Synthesis, antioxidant and some enzyme inhibition activities of new sulfonyl hydrazones and their molecular docking simulations. Pharm. Chem. J. 2022, 56, 559–569. [Google Scholar] [CrossRef]
- Başaran, E. Synthesis, antioxidant, and anticholinesterase activities of novel N-arylsulfonyl hydrazones bearing sulfonate ester scaffold. J. Chin. Chem. Soc. 2023, 70, 1580–1590. [Google Scholar] [CrossRef]
- Kurşun Aktar, B.S. Design, Synthesis, Anticholinesterase and Antidiabetic Inhibitory Activities, and Molecular Docking of Novel Fluorinated Sulfonyl Hydrazones. ACS Omega 2024, 9, 42037–42048. [Google Scholar] [CrossRef]
- Bilen, E.; Özmen, Ü.Ö.; Çete, S.; Alyar, S.; Yaşar, A. Bioactive sulfonyl hydrazones with alkyl derivative: Characterization, ADME properties, molecular docking studies and investigation of inhibition on choline esterase enzymes for the diagnosis of Alzheimer’s disease. Chem. Biol. Interact. 2022, 360, 109956. [Google Scholar] [CrossRef]
- Fernandes, T.B.; Cunha, M.R.; Sakata, R.P.; Candido, T.M.; Baby, A.R.; Tavares, M.T.; Barbosa, E.G.; Almeida, W.P.; Parise-Filho, R. Synthesis, molecular modeling, and evaluation of novel sulfonylhydrazones as acetylcholinesterase inhibitors for alzheimer’s disease. Arch. Der Pharm. 2017, 350, 1700163. [Google Scholar] [CrossRef] [PubMed]
- Angelova, V.T.; Georgiev, B.; Pencheva, T.; Pajeva, I.; Rangelov, M.; Todorova, N.; Zheleva-Dimitrova, D.; Kalcheva-Yovkova, E.; Valkova, I.V.; Vassilev, N. Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole-and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer’s Disease. Pharmaceuticals 2023, 16, 1194. [Google Scholar] [CrossRef] [PubMed]
- Ibrahim, K.M.; Elsisi, D.M.; Ammar, Y.A.; Araki, F.F.; Micky, J.A. Sulfonylhydrazide Derivatives as Potential Anti-cancer Agents: Synthesis, In Vitro and In Silico Studies. Protein J. 2024, 43, 949–966. [Google Scholar] [CrossRef] [PubMed]
- Murugappan, S.; Dastari, S.; Jungare, K.; Barve, N.M.; Shankaraiah, N. Hydrazide-hydrazone/hydrazone as enabling linkers in anti-cancer drug discovery: A comprehensive review. J. Mol. Struct. 2024, 1307, 138012. [Google Scholar] [CrossRef]
- Sroor, F.M.; Mahrous, K.F.; El-Kader, H.A.A.; Othman, A.M.; Ibrahim, N.S. Impact of trifluoromethyl and sulfonyl groups on the biological activity of novel aryl-urea derivatives: Synthesis, in-vitro, in-silico and SAR studies. Sci. Rep. 2023, 13, 17560. [Google Scholar] [CrossRef]
- Maluleka, M.M.; Mphahlele, M.J. Synthesis, crystal structure, cytotoxicity (MCF-7 and HeLa) and free radical scavenging activity of the hydrazones derived from 2-methylsulfonyl-5-nitrobenzaldehyde. Results Chem. 2024, 12, 101896. [Google Scholar] [CrossRef]
- Şenkardeş, S.; Han, M.İ.; Kulabaş, N.; Abbak, M.; Çevik, Ö.; Küçükgüzel, İ.; Küçükgüzel, Ş.G. Synthesis, molecular docking and evaluation of novel sulfonyl hydrazones as anticancer agents and COX-2 inhibitors. Mol. Divers. 2020, 24, 673–689. [Google Scholar] [CrossRef]
- Zhang, X.; Sivaguru, P.; Pan, Y.; Wang, N.; Zhang, W.; Bi, X. The Carbene Chemistry of N-Sulfonyl Hydrazones: The Past, Present, and Future. Chem. Rev. 2025, 125, 1049–1190. [Google Scholar] [CrossRef]
- Karaman, N.; Oruç-Emre, E.E.; Sıcak, Y.; Çatıkkaş, B.; Karaküçük-İyidoğan, A.; Öztürk, M. Microwave-assisted synthesis of new sulfonyl hydrazones, screening of biological activities and investigation of structure–activity relationship. Med. Chem. Res. 2016, 25, 1590–1607. [Google Scholar] [CrossRef]
- Yadav, A.; Singh, V.K.; Kumar, R.; Yadav, V.; Kushwaha, A.K.; Rana, V.K.; Kumar, A.; Prasad, V. Regioselective sulfenylation of indoles using sulfonyl hydrazides: In silico design, DFT calculation, hirshfeld surface analysis, ADMET study, molecular docking and anticancer activity. J. Mol. Struct. 2025, 1329, 141346. [Google Scholar] [CrossRef]
- Gaur, A.; Peerzada, M.N.; Khan, N.S.; Ali, I.; Azam, A. Synthesis and anticancer evaluation of novel indole based arylsulfonylhydrazides against human breast cancer cells. ACS Omega 2022, 7, 42036–42043. [Google Scholar] [CrossRef] [PubMed]
- Mushtaq, I.; Ahmed, A. Synthesis of biologically active sulfonamide-based indole analogs: A review. Future J. Pharm. Sci. 2023, 9, 46. [Google Scholar] [CrossRef]
- Ammar, Y.A.; El-Sharief, A.; Mohamed, Y.A.; Mehany, A.B.; Ragab, A. Synthesis, spectral characterization and pharmacological evaluation of novel thiazole-oxoindole hybrid compounds as potential anticancer agents. Al-Azhar Bull. Sci. 2018, 29, 25–37. [Google Scholar] [CrossRef]
- Şenkardeş, S.; İhsan Han, M.; Gürboğa, M.; Özakpinar, Ö.B.; Güniz Küçükgüzel, Ş. Synthesis and anticancer activity of novel hydrazone linkage-based aryl sulfonate derivatives as apoptosis inducers. Med. Chem. Res. 2022, 31, 368–379. [Google Scholar] [CrossRef]
- Angelova, V.T.; Tatarova, T.; Mihaylova, R.; Vassilev, N.; Petrov, B.; Zhivkova, Z.; Doytchinova, I. Novel Arylsulfonylhydrazones as Breast Anticancer Agents Discovered by Quantitative Structure-Activity Relationships. Molecules 2023, 28, 2058. [Google Scholar] [CrossRef]
- Rabee, A.R.; Hagar, M.M.; Soliman, S.A.; Mohamed, A.Y.; Mohamed, M.M.; Anwer, M.H.; Ahmed, S.; Gerges, M.Q.; Alshargabi, T.; Zakaria, A. X-ray Structure, Conformational Analysis and Stability Studies of 1, 2-Bis-Indole Hydrazine; a Step for Click Reaction for the Synthesis of Innovative Triazole Derivative and its Anticancer Potentials. SSRN. 2024. Available online: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=5018026 (accessed on 9 July 2025).
- Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 2017, 7, 42717. [Google Scholar] [CrossRef]
- Daina, A.; Zoete, V. A boiled-egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 2016, 11, 1117–1121. [Google Scholar] [CrossRef]
- Martin, Y.C. A bioavailability score. J. Med. Chem. 2005, 48, 3164–3170. [Google Scholar] [CrossRef]
- Ghose, A.K.; Viswanadhan, V.N.; Wendoloski, J.J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem. 1999, 1, 55–68. [Google Scholar] [CrossRef]
- Veber, D.F.; Johnson, S.R.; Cheng, H.-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem. 2002, 45, 2615–2623. [Google Scholar] [CrossRef]
- Egan, W.J.; Merz, K.M.; Baldwin, J.J. Prediction of drug absorption using multivariate statistics. J. Med. Chem. 2000, 43, 3867–3877. [Google Scholar] [CrossRef]
- Muegge, I.; Heald, S.L.; Brittelli, D. Simple selection criteria for drug-like chemical matter. J. Med. Chem. 2001, 44, 1841–1846. [Google Scholar] [CrossRef] [PubMed]
- Zhivkova, Z. Quantitative structure-pharmacokinetics relationship for plasma protein binding of neutral drugs. Int. J. Pharm. Pharmac. Sci 2018, 10, 88–93. [Google Scholar] [CrossRef]
- Zhivkova, Z. Quantitative structure-pharmacokinetics relationship for the steady state volume of distribution of basic and neutral drugs. World J. Pharm Pharm Sci. 2018, 7, 94–105. [Google Scholar]
- Schmidt, S.; Gonzalez, D.; Derendorf, H. Significance of protein binding in pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 2010, 99, 1107–1122. [Google Scholar] [CrossRef]
- Wasan, K.M.; Brocks, D.R.; Lee, S.D.; Sachs-Barrable, K.; Thornton, S.J. Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: Implications for drug discovery. Nat. Rev. Drug Discov. 2008, 7, 84–99. [Google Scholar] [CrossRef]
- De Oliveira, K.N.; Nunes, R.J. Synthesis and characterization of benzenesulfonyl hydrazones and benzenesulfonamides. Synth. Commun. 2006, 36, 3401–3409. [Google Scholar] [CrossRef]
- Obach, R.S.; Lombardo, F.; Waters, N.J. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab. Dispos. 2008, 36, 1385–1405. [Google Scholar] [CrossRef]
- Tan, X.-J.; Wang, D.; Hei, X.-M.; Yang, F.-C.; Zhu, Y.-L.; Xing, D.-X.; Ma, J.-P. Synthesis, crystal structures, antiproliferative activities and reverse docking studies of eight novel Schiff bases derived from benzil. Cryst. Struct. Commun. 2020, 76, 44–63. [Google Scholar] [CrossRef] [PubMed]
- Horwitz, K.; Costlow, M.; McGuire, W.L. MCF-7: A human breast cancer cell line with estrogen, androgen, progesterone, and glucocorticoid receptors. Steroids 1975, 26, 785–795. [Google Scholar] [CrossRef] [PubMed]
- Chavez, K.J.; Garimella, S.V.; Lipkowitz, S. Triple negative breast cancer cell lines: One tool in the search for better treatment of triple negative breast cancer. Breast Dis. 2011, 32, 35–48. [Google Scholar] [CrossRef] [PubMed]
- Klebe, R. Neuroblastoma: Cell culture analysis of a differentiating stem cell system. J. Cell Boil. 1969, 43, 69a. [Google Scholar]
- Olmsted, J.; Carlson, K.; Klebe, R.; Ruddle, F.; Rosenbaum, J. Isolation of microtubule protein from cultured mouse neuroblastoma cells. Proc. Natl. Acad. Sci. USA 1970, 65, 129–136. [Google Scholar] [CrossRef]
- Peña-Morán, O.A.; Villarreal, M.L.; Álvarez-Berber, L.; Meneses-Acosta, A.; Rodríguez-López, V. Cytotoxicity, post-treatment recovery, and selectivity analysis of naturally occurring podophyllotoxins from Bursera fagaroides var. fagaroides on breast cancer cell lines. Molecules 2016, 21, 1013. [Google Scholar] [CrossRef]
- Eldehna, W.M.; Abo-Ashour, M.F.; Ibrahim, H.S.; Al-Ansary, G.H.; Ghabbour, H.A.; Elaasser, M.M.; Ahmed, H.Y.; Safwat, N.A. Novel [(3-indolylmethylene) hydrazono] indolin-2-ones as apoptotic anti-proliferative agents: Design, synthesis and in vitro biological evaluation. J. Enzym. Inhib. Med. Chem. 2018, 33, 686–700. [Google Scholar] [CrossRef]
- Eldehna, W.M.; Al-Wabli, R.I.; Almutairi, M.S.; Keeton, A.B.; Piazza, G.A.; Abdel-Aziz, H.A.; Attia, M.I. Synthesis and biological evaluation of certain hydrazonoindolin-2-one derivatives as new potent anti-proliferative agents. J. Enzym. Inhib. Med. Chem. 2018, 33, 867–878. [Google Scholar] [CrossRef]
- Kumar, D.; Kumar, N.M.; Ghosh, S.; Shah, K. Novel bis (indolyl) hydrazide–hydrazones as potent cytotoxic agents. Bioorganic Med. Chem. Lett. 2012, 22, 212–215. [Google Scholar] [CrossRef]
- Bruker. APEX, SAINT and SADABS; Bruker AXS Inc.: Madison, WI, USA, 2009. [Google Scholar]
- Sheldrick, G.M. SHELXT–Integrated space-group and crystal-structure determination. Found. Crystallogr. 2015, 71, 3–8. [Google Scholar] [CrossRef]
- Sheldrick, G.M. Crystal structure refinement with SHELXL. Cryst. Struct. Commun. 2015, 71, 3–8. [Google Scholar] [CrossRef]
- Mossman, B.T. In vitro approaches for determining mechanisms of toxicity and carcinogenicity by asbestos in the gastrointestinal and respiratory tracts. Environ. Health Perspect. 1983, 53, 155–161. [Google Scholar] [CrossRef]
ID | R | Ar |
---|---|---|
3a | 1-acetyl | 4-methoxyphenyl |
3b | 1-acetyl | 2,4,6-trimethylphenyl |
3c | 5-bromo | 4-methoxyphenyl |
3d | 5-bromo | 2,4,6-trimethylphenyl |
3e | 5-bromo | 4-methylphenyl |
3f | 5-bromo | phenyl |
3g | 5-chloro | 4-methoxyphenyl |
3h | 5-chloro | 2,4,6-trimethyphenyl |
3i | 5-chloro | 2,4-dimethylphenyl |
3j | 5-chloro | 3,4-dimethylphenyl |
4 | 5-chloro | 1-(5-chloro-1H-indol-3-yl)methanimine |
ID | Mw | pKa(A) | pKa(B) | fA | fB | logP | logD7.4 | PSA | FRB | HBD | HBA |
---|---|---|---|---|---|---|---|---|---|---|---|
3a | 371.4 | 8.92 | 0.03 | 3.37 | 3.36 | 98.1 | 4 | 1 | 7 | ||
3b | 383.5 | 8.87 | 0.03 | 4.23 | 4.22 | 88.9 | 3 | 1 | 6 | ||
3c | 408.3 | 9.29 | 0.01 | 4.19 | 4.19 | 91.9 | 4 | 2 | 6 | ||
3d | 420.3 | 9.24 | 0.01 | 5.05 | 5.05 | 82.7 | 3 | 2 | 5 | ||
3e | 392.3 | 9.20 | 0.02 | 4.13 | 4.13 | 82.7 | 3 | 2 | 5 | ||
3f | 378.2 | 8.96 | 0.03 | 3.67 | 3.67 | 82.7 | 3 | 2 | 5 | ||
3g | 363.8 | 9.32 | 0.01 | 4.12 | 4.12 | 91.9 | 4 | 2 | 6 | ||
3h | 375.9 | 9.26 | 0.01 | 4.98 | 4.98 | 82.7 | 3 | 2 | 5 | ||
3i | 361.9 | 9.24 | 0.01 | 4.52 | 4.52 | 82.7 | 3 | 2 | 5 | ||
3j | 361.9 | 9.24 | 0.01 | 4.52 | 4.52 | 82.7 | 3 | 2 | 5 | ||
4 | 355.2 | 6.28 | 0.07 | 5.43 | 5.40 | 56.3 | 3 | 3 | 4 |
ID | Water Solubility | GI Absorption | Oral BA | BA Score | BBB Permeability | CYP Inhibition | P-gp Substrate | Drug Likeness | Synthetic Access |
---|---|---|---|---|---|---|---|---|---|
3a | moderate | high | INSATU | 0.55 | no | 2/5 | no | yes | 2.78 |
3b | moderate | high | INSATU | 0.55 | no | 3/5 | no | yes | 3.07 |
3c | moderate | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.67 |
3d | poor | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.96 |
3e | moderate | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.67 |
3f | moderate | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.57 |
3g | moderate | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.65 |
3h | poor | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.95 |
3i | moderate | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.84 |
3j | moderate | high | INSATU | 0.55 | no | 4/5 | no | yes | 2.84 |
4 | poor | high | INSATU | 0.55 | yes | 4/5 | no | yes | 2.40 |
ID | fu | CL L/h/kg | VDss L/kg | t1/2 h |
---|---|---|---|---|
3a | 0.016 | 0.407 | 0.733 | 1.25 |
3b | 0.010 | 0.445 | 1.330 | 2.07 |
3c | 0.018 | 0.483 | 1.238 | 1.78 |
3d | 0.006 | 0.277 | 1.776 | 4.44 |
3e | 0.014 | 0.504 | 1.253 | 1.72 |
3f | 0.022 | 0.166 | 1.059 | 4.43 |
3g | 0.012 | 0.328 | 1.042 | 2.20 |
3h | 0.005 | 0.237 | 1.623 | 4.74 |
3i | 0.007 | 0.293 | 1.356 | 3.21 |
3j | 0.007 | 0.290 | 1.362 | 3.26 |
4 | 0.002 | 0.373 | 2.730 | 5.07 |
Compound | 3e |
---|---|
Empirical formula | C16H14BrN3O2S |
Formula weight (MW) | 392.27 |
Temperature/K | 286.00 |
Crystal system | Orthorhombic |
Space group | Pbca |
a/Å | 8.9209(13) |
b/Å | 10.1438(16) |
c/Å | 35.817(5) |
α/° | 90 |
β/° | 90 |
γ/° | 90 |
Volume/Å3 | 3241.2(8) |
Z | 8 |
ρcalcg/cm3 | 1.608 |
μ/mm−1 | 2.678 |
F(000) | 1584.0 |
Crystal size/mm3 | 0.2 × 0.15 × 0.14 |
Radiation | MoKα (λ = 0.71073) |
2Θ range for data collection/° | 4.548 to 51.362 |
Index ranges | −10 ≤ h ≤ 9, −11 ≤ k ≤ 12, −43 ≤ l ≤ 43 |
Reflections collected/reflections | 33,099/307 |
Data/restraints/parameters | 3075/0/264 |
Goodness-of-fit on F2 | 1.151 |
Rint = 0.0407, Rsigma = 0.0224 | |
Final R indexes [I ≥ 2σ (I)] | R1 = 0.0403, wR2 = 0.0876 |
Final R indexes [all data] | R1 = 0.0477, wR2 = 0.0906 |
Largest diff. peak/hole/e Å−3 | 0.33/−0.50 |
CCDC number | 2425493 |
ID | MCF-7a | MDA-MB-231b | Neuro-2ac | |||||
---|---|---|---|---|---|---|---|---|
IC50 μM | LE | SI | IC50 μM | LE | SI | IC50 μM | LE | |
3a | 4.3 ± 1.3 | 0.206 | 13.488 | 20.1 ± 3.4 | 0.181 | 2.886 | 58 ± 8.2 | 0.163 |
3b | 4.0 ± 0.9 | 0.200 | 20.975 | 16.3 ± 4.1 | 0.177 | 5.147 | 83.9 ± 9.4 | 0.151 |
3c | 5.2 ± 1.0 | 0.220 | 3.577 | 17.7 ± 2.3 | 0.198 | 1.051 | 18.6 ± 3.9 | 0.197 |
3d | 4.2 ± 0.7 | 0.215 | 5.000 | 19.9 ± 1.6 | 0.188 | 1.055 | 21.0 ± 2.1 | 0.187 |
3e | 29.6 ± 5.1 | 0.197 | 1.176 | 18.7 ± 2.7 | 0.206 | 1.861 | 34.8 ± 5.7 | 0.194 |
3f | 5.9 ± 1.4 | 0.238 | 1.847 | 4.7 ± 1.4 | 0.242 | 2.319 | 10.9 ± 1.8 | 0.226 |
3g | 12.7 ± 2.8 | 0.204 | 2.063 | 14.7 ± 1.8 | 0.201 | 1.782 | 26.2 ± 3.5 | 0.191 |
3h | 15.2 ± 2.1 | 0.193 | 1.579 | 18.1 ± 2.5 | 0.190 | 1.326 | 24.0 ± 1.9 | 0.185 |
3i | 12.4 ± 3.2 | 0.204 | 1.282 | 9.5 ± 1.5 | 0.209 | 1.674 | 15.9 ± 1.6 | 0.200 |
3j | 11.5 ± 2.3 | 0.206 | 3.087 | 13.3 ± 2.2 | 0.203 | 2.669 | 35.5 ± 5.3 | 0.185 |
4 | 21.4 ± 4.9 | 0.195 | 2.509 | 66.0 ± 7.4 | 0.174 | 0.814 | 53.7 ± 3.1 | 0.178 |
Cisplatin | 50.3 ± 6.5 | 63.4 ± 7.2 | - |
Substituents in Ar | Model | LE MCF-7 | SI MCF-7 | LE MDA-MB-231 | SI MDA-MB-231 |
---|---|---|---|---|---|
Coefficients | |||||
b0 | 0.222 | 10.362 | 0.202 | 2.037 | |
phenyl | b1 | 0.037 | 6.401 | 0.037 | 1.464 |
4-methylphenyl | b2 | 0.002 | 6.901 | −0.002 | −0.216 |
4-methoxyphenyl | b3 | −0.008 | −6.274 | −0.006 | −0.359 |
2,4,6-trimethylphenyl | b4 | −0.016 | −3.465 | −0.014 | 0.244 |
2,4-dimethylphenyl | b5 | −0.019 | −5.378 | −0.007 | −1.320 |
3,4-dimethylphenyl | b6 | −0.017 | −3.573 | −0.013 | −0.325 |
5-chlorophenyl | b7 | −0.028 | −4.151 | −0.042 | −2.180 |
Substituents in R | |||||
1-acetyl | b8 | −0.004 | 18.918 | −0.025 | 0.478 |
5-methoxy | b9 | 0.020 | −10.180 | 0.006 | −1.587 |
5-bromo | b10 | −0.009 | −8.353 | 0.003 | −0.748 |
5-chloro | b11 | 0.001 | −3.702 | 0.015 | 0.957 |
R | 0.904 | 0.919 | 0.938 | 0.666 | |
RMSE | 0.012 | 4.052 | 0.009 | 1.247 | |
Q | 0.666 | 0.678 | 0.655 | −0.272 |
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Angelova, V.T.; Mihaylova, R.; Zhivkova, Z.; Vassilev, N.; Shivachev, B.; Doytchinova, I. Novel Indole-Based Sulfonylhydrazones as Potential Anti-Breast Cancer Agents: Synthesis, In Vitro Evaluation, ADME, and QSAR Studies. Pharmaceuticals 2025, 18, 1231. https://doi.org/10.3390/ph18081231
Angelova VT, Mihaylova R, Zhivkova Z, Vassilev N, Shivachev B, Doytchinova I. Novel Indole-Based Sulfonylhydrazones as Potential Anti-Breast Cancer Agents: Synthesis, In Vitro Evaluation, ADME, and QSAR Studies. Pharmaceuticals. 2025; 18(8):1231. https://doi.org/10.3390/ph18081231
Chicago/Turabian StyleAngelova, Violina T., Rositsa Mihaylova, Zvetanka Zhivkova, Nikolay Vassilev, Boris Shivachev, and Irini Doytchinova. 2025. "Novel Indole-Based Sulfonylhydrazones as Potential Anti-Breast Cancer Agents: Synthesis, In Vitro Evaluation, ADME, and QSAR Studies" Pharmaceuticals 18, no. 8: 1231. https://doi.org/10.3390/ph18081231
APA StyleAngelova, V. T., Mihaylova, R., Zhivkova, Z., Vassilev, N., Shivachev, B., & Doytchinova, I. (2025). Novel Indole-Based Sulfonylhydrazones as Potential Anti-Breast Cancer Agents: Synthesis, In Vitro Evaluation, ADME, and QSAR Studies. Pharmaceuticals, 18(8), 1231. https://doi.org/10.3390/ph18081231