Skip to main content

Advertisement

SpringerLink
Log in

Carboxamide appended quinoline moieties as potential anti-proliferative agents, apoptotic inducers and Pim-1 kinase inhibitors

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

The targeted approach of protein kinases (PKs), as PKs are the main regulators of cell survival and proliferation, has been a promising strategy for cancer treatments. Here we analyse the potential of quinoline-carboxamide derivatives for four cell lines: MCF-7, CACO, HepG-2 and HCT-116 as anticancer agents. 3e, 4b, 11b and 13d derivatives showed good anti-proliferative activities in comparison to the reference standard Doxorubicin, against the four cell lines tested. They have been chosen for further studies. First of all, the IC50 value surveys were carried out to ensure the protection of our hits and demonstrate that the cytotoxic effect (IC50 > 113 μM) is highly selective on normal human cells (WI-38). Secondly, apoptosis was accomplished by down-regulation of Bcl-2 and up-regulation of BAX and Caspase-3 by these active compounds. Also, the Pim-1 inhibitory activity of the active hybrids was done, which indicates that compound 3e was the most active with the percentage of inhibition 82.27% and IC50 equals 0.11 when compared to SGI-1776 as a reference standard. In addition, by in silico assessment of ADME properties, all of the strongest compounds are orally bioavailable without blood–brain barrier penetration.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Sawyers C. Targeted cancer therapy. Nature. 2004;432:294–7.

    Article  CAS  Google Scholar 

  2. Li Q, Xu W. Novel anticancer targets and drug discovery in post genomic age. Curr Med Chem Anti-Cancer Agents. 2005;5:53–63. https://doi.org/10.2174/1568011053352631.

    Article  CAS  PubMed  Google Scholar 

  3. Mencher SK, Wang LG. Promiscuous drugs compared to selective drugs (promiscuity can be a virtue). BMC Clin Pharmacol. 2005;5:1–7. https://doi.org/10.1186/1472-6904-5-3.

    Article  CAS  Google Scholar 

  4. Jimeno A, Hidalgo M. Multitargeted therapy: can promiscuity be praised in an era of political correctness?. Crit Rev Oncol Hematol. 2006;59:150–8. https://doi.org/10.1016/j.critrevonc.2006.01.005.

    Article  PubMed  Google Scholar 

  5. Teimoori S, Panjamurthy K, Vinaya K, Prasanna DS, Raghavan SC, Rangappa KS. Synthesis and biological evaluation of novel homopiperazine derivatives as anticancer agents. J Cancer Ther. 2011;02:507–14. https://doi.org/10.4236/jct.2011.24069.

    Article  CAS  Google Scholar 

  6. Porter AG, Jänicke RU. Emerging roles of Caspase-3 in apoptosis. Cell Death Differ. 1999;6:99–104. https://doi.org/10.1038/sj.cdd.4400476.

    Article  CAS  PubMed  Google Scholar 

  7. Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, et al. Apoptosis and cancer: mutations within Caspase genes. J Med Genet. 2009; 46: 497–510. Doi:10.1136/jmg.2009.066944..

  8. Perlman H, Zhang X, Chen MW, Walsh K, Buttyan R. An elevated bax/bcl-2 ratio corresponds with the onset of prostate epithelial cell apoptosis. Cell Death Differ. 1999;6:48–54. https://doi.org/10.1038/sj.cdd.4400453.

    Article  CAS  PubMed  Google Scholar 

  9. Chang F, Steelman LS, Lee JT, Shelton JG, Navolanic PM, Blalock WL. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia. 2003;17:1263–93. https://doi.org/10.1038/sj.leu.2402945.

    Article  CAS  PubMed  Google Scholar 

  10. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharm ExpTher. 2005;315:971–9.

    Article  CAS  Google Scholar 

  11. Faivre S, Djelloul S, Raymond E. New paradigms in anticancer therapy: targeting multiple signaling pathways with kinase inhibitors. Semin Oncol. 2006;33:407–20. https://doi.org/10.1053/j.seminoncol.2006.04.005.

    Article  CAS  PubMed  Google Scholar 

  12. Sai Harshita P, Soma Yasaswi P, Jyothi V, Saritha Jyostna T. Pim-1 kinase: a novel target for cancer chemotherapy - a review. Int J Pharm Sci Res. 2020;11:2528–38. https://doi.org/10.13040/IJPSR.0975-8232.

    Article  Google Scholar 

  13. Magnuson NS, Wang Z, Ding G, Reeves R. Why target PIM1 for cancer diagnosis and treatment?. Futur Oncol. 2010;6:1461–78. https://doi.org/10.2217/fon.10.106.

    Article  CAS  Google Scholar 

  14. Nawijn MC, Alendar A, Berns A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer. 2011;11:23–34. https://doi.org/10.1038/nrc2986.

    Article  CAS  PubMed  Google Scholar 

  15. Kumar A, Mandiyan V, Suzuki Y, Zhang C, Rice J, Tsai J. et al. Crystal structures V of proto-oncogene kinase Pim1: a target of aberrant somatic hypermutations in diffuse large cell lymphoma. J Mol Biol. 2005;348:183–93. https://doi.org/10.1016/j.jmb.2005.02.039.

    Article  CAS  PubMed  Google Scholar 

  16. Kattimani PP, Kamble RR, Kariduraganavar MY, Dorababu A, Hunnur RK. Synthesis, characterization and in vitro anticancer evaluation of novel 1,2,4-triazolin-3-one derivatives. Eur J Med Chem 2013;62:232–40. https://doi.org/10.1016/j.ejmech.2013.01.004.

    Article  CAS  PubMed  Google Scholar 

  17. Husain A, Rashid M, Shaharyar M, Siddiqui AA, Mishra R. Benzimidazole clubbed with triazolo-thiadiazoles and triazolo-thiadiazines: new anticancer agents, Eur. J Med Chem 2013;62:785–98. https://doi.org/10.1016/j.ejmech.2012.07.011.

    Article  CAS  Google Scholar 

  18. Firestone GL, Sundar SN. Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med 2009;11:e32 https://doi.org/10.1017/S1462399409001239.

    Article  PubMed  Google Scholar 

  19. Lu JJ, Meng LH, Cai YJ, Chen Q, Tong LJ, Lin LP, et al. Dihydroartemisinin induces apoptosis in HL-60 leukemia cells dependent of iron and p38 mitogen-activated protein kinase activation but independent of reactive oxygen species. Cancer Biol Ther 2008;7:1017–23. https://doi.org/10.4161/cbt.7.7.6035.

    Article  CAS  PubMed  Google Scholar 

  20. Gedawy EM, Kassab AE, El-Malah AA. Synthesis and anticancer activity of novel tetrahydroquinoline and tetrahydropyrimidoquinoline derivatives. Med Chem Res 2015;24:3387–97. https://doi.org/10.1007/s00044-7.

    Article  CAS  Google Scholar 

  21. Li K, Li Y, Zhou D, Fan Y, Guo H, Ma T. et al. Synthesis and biological evaluation of quinoline derivatives as potential anti-prostate cancer agents and Pim-1 kinase inhibitors. Bioorg Med Chem. 2016;24:1889–97. https://doi.org/10.1016/j.bmc.2016.03.016.

    Article  CAS  PubMed  Google Scholar 

  22. Silverman RB and Holladay MW. The organic chemistry of drug design and drug action. 3rd ed. Elsevier; 2015. p 1–517. https://doi.org/10.1016/C2009-0-64537-2.

  23. Allen S, Delisle RK, Greschuk JM, Hicken EJ, Lyssikatos JP, Marmsater FP, et al. Triazolopyridine compounds as Pim kinase inhibitors. Patent: WO2010022081A1.

  24. Ammar YA, Salem MA, Fayed EA, Helal MH, El-Gaby MSA, Thabet HK. Naproxen derivatives: synthesis, reactions, and biological applications. Synth Commun. 2017; 47: 1341–67. https://doi.org/10.1080/00397911.2017.1328066.

  25. Ammar YA, Fayed EA, Bayoumi AH, Saleh MA. Synthesis and biological evaluation of new amides pro-drugs containing naproxen moiety as anti-inflammatory and antimicrobial agents. Der Pharma Chem. 2016;8:495–508.

    Google Scholar 

  26. El Shehry MF, Ghorab MM, Abbas SY, Fayed EA, Shedid SA, Ammar YA.Quinoline derivatives bearing pyrazole moiety: synthesis and biological evaluation as possible antibacterial and antifungal agents.Eur J Med Chem. 2018;143:1463–73. https://doi.org/10.1016/j.ejmech.2017.10.046.

    Article  CAS  PubMed  Google Scholar 

  27. Eissa SI, Farrag AM, Abbas SY, El Shehry MF, Ragab A, Fayed EA, et al. Novel structural hybrids of quinolone and thiazole moieties: synthesis and evaluation of antibacterial and antifungal activities with molecular modeling studies. Bioorg Chem. 2021; https://doi.org/10.1016/j.bioorg.2021.104803.

  28. Fayed EA, Eldin RRE, Mehany A, Bayoumi AH, Ammar YA. Isatin-Schiff’s base and chalcone hybrids as chemically apoptotic inducers and EGFR inhibitors; design, synthesis, anti-proliferative activities and in silico evaluation. J Mol Struct. 2021;1234:130159.

    Article  CAS  Google Scholar 

  29. Ammar YA, Farag AA, Ali AM, Fayed EA, Elsisi DM, Ragab A. Antimicrobial evaluation of thiadiazino and thiazolo quinoxaline hybrids as potential DNA gyrase inhibitors; design, synthesis, characterization and morphological studies. Bioorg Chem. 2020;99:103841.

    Article  CAS  Google Scholar 

  30. Yahia E, Mohammad H, Abdelghany TM, Fayed EA, Seleem MN, Mayhoub AS. Phenylthiazole antibiotics: a metabolism-guided approach to overcome short duration of action. Eur J Med Chem. 2017;126:604–13.

    Article  CAS  Google Scholar 

  31. El-Kalyoubi SA, Fayed EA, Abdel-Razek AS. Erratum to: One pot synthesis, antimicrobial and antioxidant activities of fused uracils: pyrimidodiazepines, lumazines, triazolouracil and xanthines. Cent J.2017;11:69 https://doi.org/10.1186/s13065-017-0294-0.

    Article  CAS  Google Scholar 

  32. Fayed EA, Ahmed HY. Synthesis, characterization and pharmacological evaluation of some new 1,4-diazepine derivatives as anticancer agents. Der Pharma Chem. 2016;8:77–90.

    CAS  Google Scholar 

  33. AbdelFattah BA, Khalifa MMA, El-Sehrawi H, Fayed E, Bayoumi A. Synthesis and anxiolytic activity of some novel 5-oxo-1, 4-oxazepine derivatives. Lett Drug Des Discov. 2011;8:330–8. 10.2174/157018011794839448.

    Article  CAS  Google Scholar 

  34. Elkalyoubi S, Fayed E. Synthesis and evaluation of antitumour activities of novel fused tri- and tetracyclic uracil derivatives. J Chem Res. 2016;40:771–7. https://doi.org/10.3184/174751916X14798125870610.

    Article  CAS  Google Scholar 

  35. Fayed EA, Eissa SI, Bayoumi AH, Gohar NA, Mehany ABM, Ammar YA. Design, synthesis, cytotoxicity and molecular modeling studies of some novel fluorinated pyrazole-based heterocycles as anticancer and apoptosis-inducing agents. Mol Divers 2019;23:165–81. https://doi.org/10.1007/s11030-018-9865-9.

    Article  CAS  PubMed  Google Scholar 

  36. Fayed EA, Ammar YA, Ragab A, Gohar NA, Mehany ABM, Farrag AM. In vitro cytotoxic activity of thiazole-indenoquinoxaline hybrids as apoptotic agents, design, synthesis, physicochemical and pharmacokinetic studies. Bioorg Chem 2020;100:103951 https://doi.org/10.1016/j.bioorg.2020.103951.

    Article  CAS  PubMed  Google Scholar 

  37. Ammar YA, Fayed EA, Bayoumi AH, Ezz RR, Alsaid MS, Soliman AM, et al. New chalcones bearing isatin scaffold: synthesis, molecular modeling and biological evaluation as anticancer agents. Res Chem Intermed 2017;43:6765–86. https://doi.org/10.1007/s11164-017-3019-z.

    Article  CAS  Google Scholar 

  38. Fayed EA, Sabour R, Harras MF, Mehany ABM. Design, synthesis, biological evaluation and molecular modeling of new coumarin derivatives as potent anticancer agents. Med Chem Res 2019;28:1284–97. https://doi.org/10.1007/s00044-019-02373-x.

    Article  CAS  Google Scholar 

  39. Selim MR, Zahran MA, Belal A, Abusaif MS, Shedid SA, Mehany ABM, et al. Hybridized quinoline derivatives as anticancer agents: design, synthesis, biological evaluation and molecular docking. Anticancer Agents Med Chem 2018;19:439–52. https://doi.org/10.2174/1871520618666181112121058.

    Article  Google Scholar 

  40. Al-Marhabi AR, Abbas HAS, Ammar YA. Synthesis, characterization and biological evaluation of some quinoxaline derivatives: a promising and potent new class of antitumor and antimicrobial agents. Molecules. 2015;20:19805–22. https://doi.org/10.3390/molecules201119655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ismail MMF, Amin KM, Noaman E, Soliman DH, Ammar YA. New quinoxaline 1, 4-di-N-oxides: anticancer and hypoxia-selective therapeutic agents. Eur J Med Chem 2010;45:2733–8. https://doi.org/10.1016/j.ejmech.2010.02.052.

    Article  CAS  PubMed  Google Scholar 

  42. Abonia R, Insuasty D, Castillo J, Insuasty B, Quiroga J, Nogueras M.Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity.Eur J Medicinal Chem. 2012;57:29–40. https://doi.org/10.1016/j.ejmech.2012.08.039.

    Article  CAS  Google Scholar 

  43. Nirmal JP, Patel MP, Patel RG. Microwave-assisted synthesis of some new biquinoline compounds catalyzed by DMAP and their biological activities. Indian J Chem B Org Med Chem. 2009;48:712–7. https://doi.org/10.1002/chin.200938138.

    Article  Google Scholar 

  44. Igney FH, Krammer PH. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer. 2002;2:277–88. https://doi.org/10.1038/nrc776.

    Article  CAS  PubMed  Google Scholar 

  45. Zheng JY, Yang GS, Wang WZ, Li J, Li KZ, Guan WX. et al. Overexpression of Bax induces apoptosis and enhances drug sensitivity of hepatocellular cancer-9204 cells. World J Gastroenterol. 2005;11:3498–503. https://doi.org/10.3748/wjg.v11.i23.3498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Salman M, Nandi S. Pim kinase as the potential target for anticancer drug design. EC Microbiol. 2017;8.6:299–304.

    Google Scholar 

  47. Al-Blewi F, Rezki N, Adjet A, Qutb Uddin H, Al-Sodies S, Messali M, et al. A profile of the in vitro anti-tumor activity and in silico ADME predictions of novel benzothiazole amide-functionalized imidazolium ionic liquids. Int J Mol Sci. 2019;20:2865. https://doi.org/10.3390/ijms20122865.

  48. Fayed EA, Nosseir ES, Atef A, El-Kalyoubi SA. In vitro antimicrobial evaluation and in silico studies of coumarin derivatives tagged with pyrano-pyridine and pyrano-pyrimidine moieties as DNA gyrase inhibitors. Mol Divers. 2021; https://doi.org/10.1007/s11030-021-10224-4.

  49. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25.1. Adv Drug Deliv Rev 2001;46:3–26. https://doi.org/10.1016/S0169-409X(00)00129-0.

    Article  CAS  PubMed  Google Scholar 

  50. Ghose AK, Viswanadhan VN, Wendoloski JJ. Prediction of hydrophobic (lipophilic) properties of small organic molecules using fragmental methods: an analysis of ALOGP and CLOGP methods. J Phys Chem A. 1998;102:3762–72. https://doi.org/10.1021/jp980230o.

    Article  CAS  Google Scholar 

  51. Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002;45:2615–23. https://doi.org/10.1021/jm020017n.

    Article  CAS  PubMed  Google Scholar 

  52. Egan WJ, Lauri G. Prediction of intestinal permeability. Adv Drug Deliv Rev. 2002;54:273–89. https://doi.org/10.1016/s0169-409x(02)00004-2.

    Article  CAS  PubMed  Google Scholar 

  53. Muegge I, Heald SL, Brittelli D. Simple selection criteria for drug-like chemical matter. J Med Chem 2001;44:1841–6. https://doi.org/10.1021/jm015507e.

    Article  CAS  PubMed  Google Scholar 

  54. Martínez-Gonzalez S, Rodríguez-Arístegui S, Gomez de la Oliva CA, Hernandez AI, Cantalapiedra EG, Varela C, García AB, Rabal O, Oyarzabal J, Bischoff JR, Klett J, Albarran MI, Cebria A, Ajenjo N, García-Serelde B, Gomez-Casero E, Cuadrado-Urbano M, Cebrian D, Blanco-Aparicio C, Pastor J. Discovery of novel triazolo[4,3-b]pyridazin-3-yl-quinoline derivatives as PIM inhibitors. Eur J Med Chem 168:87e109. https://doi.org/10.1016/j.ejmech.2019.02.022.

  55. 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;7:1–13. https://doi.org/10.1038/srep42717.

    Article  Google Scholar 

  56. Fayed EA, Bayoumi AH, Saleh AS, Ezz Al-Arab EM, Ammar YA. In vivo and in vitro anti-inflammatory, antipyretic and ulcerogenic activities of pyridone and chromenopyridone derivatives, physicochemical and pharmacokinetic studies. Bioorg Chem. 2021;109:104742. https://doi.org/10.1016/j.bioorg.2021.104742.

    Article  PubMed  Google Scholar 

  57. Fayed EA, Ammar YA, Saleh MA, Bayoumi AH, Belald A, Mehany ABM, et al. Design, synthesis, antiproliferative evaluation, and molecular docking study of new quinoxaline derivatives as apoptotic inducers and EGFR inhibitors. J Mol Struct,. 2021;1236:130317. https://doi.org/10.1016/j.molstruc.2021.130317.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, Faculty of Science, Al-Azhar University, Cairo, 11884, Egypt

    Yousry A. Ammar, Moustafa S. Abusaif, Mohamed R. Selim & Medhat A. Zahran

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Helwan, Egypt

    Gamil A. M. Elhagali & Tamer Naser

  3. Department of Zoology, Faculty of Science (Boys), Al-Azhar University, Cairo, 11884, Egypt

    Ahmed B. M. Mehany

  4. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, 11754, Egypt

    Eman A. Fayed

Authors
  1. Yousry A. Ammar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gamil A. M. Elhagali
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Moustafa S. Abusaif
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohamed R. Selim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Medhat A. Zahran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tamer Naser
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ahmed B. M. Mehany
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eman A. Fayed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Yousry A. Ammar or Eman A. Fayed.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ammar, Y.A., Elhagali, G.A.M., Abusaif, M.S. et al. Carboxamide appended quinoline moieties as potential anti-proliferative agents, apoptotic inducers and Pim-1 kinase inhibitors. Med Chem Res 30, 1649–1668 (2021). https://doi.org/10.1007/s00044-021-02765-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02765-y

Keywords

Search

Navigation