Medicinal Chemistry Research

, Volume 26, Issue 10, pp 2520–2537 | Cite as

Synthesis and evaluation of pyrazolo[5,1-b]quinazoline-2-carboxylate, and its thiazole derivatives as potential antiproliferative agents and Pim-1 kinase inhibitors

  • Rafat M. Mohareb
  • Nadia Y. Megally Abdo
  • Wagnat W. Wardakhan
Original Research


The multi-component reactions of compounds 2ac with any of the aromatic aldehydes 3ac and cyclohexane-1,4-dione gave the 2-hydroxy-5,6,8,9-tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives 5ai, respectively. In addition compounds 5ai reacted with elemental sulfur and phenylisothiocyanate to give the 8-hydroxy-3-phenyl-4,5,7,11-tetrahydropyrazolo[5,1-b]thiazolo[5,4-f]quinazoline-2(3H)-thione derivatives 7ai. Compounds 5ai were reacted with cyanoacetylhydrazine to give the 2-cyano-N′-(2-hydroxy-5,6-dihydropyrazolo[5,1-b]quinazolin-7(3H,8H,9H)-ylidene)acetohydrazide derivatives 9ai. The reaction compounds 9ai with elemental sulfur and phenylisothiocyanate and with thioglycollic acid gave the thiazole derivatives 11ai and 13ai, respectively. In the present work a series of novel quinazoline and their fused derivatives were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase, prostate cancer cell lines and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG, and SMMC-7721). The most promising compounds 5b, 5h, 5i, 7h, 9h, 9i, 11b, 11c, 11e, 13h, and 13i were further investigated against tyrosin kinase (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Compounds 5h, 5i, 11e, and 13i were selected to examine their Pim-1 kinase inhibition activity where compounds 5i and 11e showed high activities. All target compounds were initially tested for their anti-proliferative activity against human prostatic cancer PC-3 cell line.


Cyclohexan-1,4-dione Quinoline Thiazole Antiproliferative activity 



R.M. Mohareb would like to thank the Alexander von Humboldt Foundation in Bonn, Germany for affording him regular fellowships in Germany for finance and completing his research work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. Ai Y, Liang YJ, Liu JC, He HW, Chen Y, Tang C, Yang GZ, Fu LW (2012) Synthesis and in vitro antiproliferative evaluation of pyrimido[5,4-c]quinoline-4-(3H)-one derivatives. Eur J Med Chem 47:206–213CrossRefPubMedGoogle Scholar
  2. Berger D, Dutia M, Powell D, Wu B, Wissner A, Boschelli DH, Floyd MB, Zhang N, Torres N, Levin J, Du X, Wojciehowicz D, Discafani C, Kohler C, Kim SC, Feldberg LR, Collins K, Mallon R (2003) Synthesis and evaluation of 4-Anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade. Bioorg Med Chem Lett 13:3031–3034CrossRefPubMedGoogle Scholar
  3. Berger DM, Dutia M, Powell D, Floyd MB, Torres N, Mallon R, Wojciechowicz D, Kim S, Feldberg L, Collins K, Chaudhary I (2008) 4-Anilino-7-alkenylquinoline-3-carbonitriles as potent MEK1 kinase inhibitors. Bioorg Med Chem 16:9202–9211CrossRefPubMedGoogle Scholar
  4. Dave SS, Rahatgaonkar AM (2016) Syntheses and anti-microbial evaluation of new quinoline scaffold derived pyrimidine derivatives. Arab J Chem 9:S451–S456CrossRefGoogle Scholar
  5. Elnagdi EM, Hassen NH, Abdel-Maksoud FA, Abdel-Motaleb RM, Maawad RA, Mahmoud FF (1989) Studies on condensed pyrazoles: synthesis of new methyl- and aminopyrazolo[1,5-a]pyrimidines and of pyrazolo[5,1-c][1,2,4]triazines. Collect Czach Chem Commun 54:1082–1091CrossRefGoogle Scholar
  6. Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Downs LCB, Kisliuk RL (2012) Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents. Bioorg Med Chem 20:4217–4225CrossRefPubMedPubMedCentralGoogle Scholar
  7. Gökşen US, Kelekçi NG, Göktaş Ö, Köysal Y, Kılıç E, Işık Ş, Aktay G, Özalp M (2007) 1-Acylthiosemicarbazides, 1,2,4-triazole-5(4H)-thiones, 1,3,4-thiadiazoles and hydrazones containing 5-methyl-2-benzoxazolinones: synthesis, analgesic-anti-inflammatory and antimicrobial activities. Bioorg Med Chem 15:5738–5751CrossRefGoogle Scholar
  8. He H, Wang X, Shi L, Yin W, Yang Z, He H, Liang Y (2016) Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide–hydrazone and carboxamide moiety. Bioorg Med Chem Lett 26:3263–3270CrossRefPubMedGoogle Scholar
  9. Jewers K, Manchanda AH, Rose HM (1973) Naturally-occurring antitumour agents. Prog Med Chem 9:1–63CrossRefGoogle Scholar
  10. Jorda R, Sierra NS, Voller J, Havlíček L, Kráčalíková K, Nowicki MW, Nasereddine A, Kryštof V, Strnad M, Walkinshaw MD (2011) Anti-leishmanial activity of disubstituted purines and related pyrazolo[4,3-d]pyrimidines. Bioorg Med Chem Lett 21:4233–4237CrossRefPubMedGoogle Scholar
  11. Joshi SD, Kumar D, Dixit SR, Tigadi N, More UA, Lherbet C, Aminabhavi TM, Yang KS (2016) Synthesis, characterization and antitubercular activities of novel pyrrolyl hydrazones and their Cu-complexes. Eur J Med Chem 121:21–39CrossRefPubMedGoogle Scholar
  12. Karrouchi K, Chemlal L, Taoufik J, Cherrah Y, Radi S, El Abbes Faouzi M, Ansar M (2016) Synthesis, antioxidant and analgesic activities of Schiff bases of 4-amino-1,2,4-triazole derivatives containing a pyrazole moiety. Annales Pharmaceutiques Françaises 74:431–438CrossRefPubMedGoogle Scholar
  13. Kumar A, Paliwal D, Saini D, Thakur A, Aggarwal S, Kaushik DA (2014) comprehensive review on synthetic approach for antimalarial agents. Eur J Med Chem 85:147–178CrossRefPubMedGoogle Scholar
  14. Kumar RS, Arif IA, Ahamed A, Idhayadhull A (2016) Anti-inflammatory and antimicrobial activities of novel pyrazole analogues. Saudi J Biol Sci. 23:614–620CrossRefGoogle Scholar
  15. Li S, Zhao Y, Wang K, Gao Y, Han J, Cui B, Gong P (2013) Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors. Bioorg Med Chem 21:2843–2855CrossRefPubMedGoogle Scholar
  16. Liao W, Xu C, Ji X, Hu G, Ren L, Liu Y, Li R, Gong P, Sun T (2014) Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors. Eur J Med Chem 87:508–518CrossRefPubMedGoogle Scholar
  17. Liu J, Nie M, Wang Y, Hu J, Zhang F, Gao Y, Liu Y, Gong P (2016) Design, synthesis and structure–activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors. Eur J Med Chem 123:431–446CrossRefPubMedGoogle Scholar
  18. Mohareb RM, Abdelazeem AM (2010) The reaction of cyanoacetylhydrazine with ω-bromo(4-methyl)acetophenone: synthesis of heterocyclic derivatives with antitumor activity. Molecules 15:3602–3617CrossRefPubMedGoogle Scholar
  19. Mohareb RM, Abdo NY (2015) Synthesis and cytotoxic evaluation of pyran, dihydropyridine and thiophene derivatives of 3-acetylcoumarin. Chem Pharm Bull 63:678–687CrossRefPubMedGoogle Scholar
  20. Mohareb RM, El-Omran F, Azam RA (2014) Heterocyclic ring extension of estrone: Synthesis and cytotoxicity of fused pyran, pyrimidine and thiazole derivatives. Steroids 84:46–45CrossRefPubMedGoogle Scholar
  21. Mohareb RM, Fleita DH, Sakka OK (2011) Novel synthesis of hydrazide-hydrazone derivatives and their utilization in the synthesis of coumarin, pyridine, thiazole and thiophene derivatives with antitumor activity. Molecules 16:16–27CrossRefGoogle Scholar
  22. Muscia GC, Bollini M, Carnevale JP, Bruno AM, Asis SE (2006) Microwave-assisted Friedländer synthesis of quinolines derivatives as potential antiparasitic agents. Tetrahedron Lett 47:8811–8815CrossRefGoogle Scholar
  23. Pieczonka AM, Strzelczyk A, Sadowska B, Mlostoń G, Stączek P (2013) Synthesis and evaluation of antimicrobial activity of hydrazones derived from 3-oxido-1H-imidazole-4-carbohydrazides. Eur J Med Chem 64:389–395CrossRefPubMedGoogle Scholar
  24. Solomon VR, Lee H (2009) Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur J Pharmacol 625:220–233CrossRefPubMedGoogle Scholar
  25. Srivastava SK, Chauhan PMS, Bhaduri AP, Fatima N, Chatterjee RJ (2000) Quinolones:  novel probes in antifilarial chemotheraphy. Med Chem 43:2275–2279CrossRefGoogle Scholar
  26. Suresh L, Kumar PSV, Poornachandra Y, Kumar CG, Chandramouli GVP (2016) An efficient one-pot synthesis of thiochromeno[3,4-d]pyrimidines derivatives: inducing ROS dependent antibacterial and anti-biofilm activities. Bioorg Chem 68:159–165CrossRefPubMedGoogle Scholar
  27. TabatabaeianK AF, Shojaei F, Shirini SZ, Hejazi M, Rassa (2014) A green multicomponent synthesis of bioactive pyrimido[4,5-b]quinoline derivatives as antibacterial agents in water catalyzed by RuCl3•×H2O. Chin Chem Lett 25:308–312CrossRefGoogle Scholar
  28. Tang C, Jardim DL, Falchook GS, Hess K, Fu S, Wheler JJ, Zinner RG, Naing A, Tsimberidou AM, De Melo Galgiato D, Westin SN, Meric-Bernstam F, Kurzrock R, Hong DS (2014) MET nucleotide variations and amplification in advanced ovarian cancer: characteristics and outcomes with c-Met inhibitors. Oncoscience [PubMed] 11;1(1):5–13.Google Scholar
  29. Tang Q, Wang L, Tu Y, Zhu W, Luo R, Tu Q, Wang P, Wu C, Gong P, Zheng P (2016) Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors. Bioorg Med Chem Lett 26:1680–1684CrossRefPubMedGoogle Scholar
  30. Theivendren Panneer Selvam TP, Kumarb PV, Saravanan G, Prakash CR (2014) Microwave-assisted synthesis, characterization and biological activity of novel pyrazole derivatives. J Saudi Chem Soc 18:1015–1021CrossRefGoogle Scholar
  31. Walcourt A, Loyevsky M, Lovejoy DB, Gordeuk VR, Richardson DR (2004) Novel aroylhydrazone and thiosemicarbazone iron chelators with anti-malarial activity against chloroquine-resistant and sensitive parasites. Int J Biochem Cell Biol 36:401–407CrossRefPubMedGoogle Scholar
  32. Wang S, Zhao LJ, Zheng YC, Shen DD, Miao EF, Qiao XP, Zhao LJ, Liu Y, Huang R, Yu B, Liu HM (2017) Design, synthesis and biological evaluation of [1,2,4]triazolo[1,5-a]pyrimidines as potent lysine specific demethylase 1 (LSD1/KDM1A). Eur J Med Chem 125:940–951CrossRefPubMedGoogle Scholar
  33. Wissner A, Johnson BD, Reich MF, Floyd MB, Kitchen DB, Tsou HR (1999) Substituted 3-cyano quinolines. US Patent 1999-6002008 filled Apr 3, 1997, issued 14 Dec, 1999Google Scholar
  34. Yadagiri B, Holagunda UD, Bantu R, Nagarapu L, Guguloth V, Polepally S, Jain N (2014) Rational design, synthesis and anti-proliferative evaluation of novel benzosuberone tethered with hydrazide–hydrazones. Bioorg Med Chem Lett 24:5041–5044CrossRefPubMedGoogle Scholar
  35. Zhang N, Wu B, Eudy N, Wang Y, Ye F, Powell D, Wissner A, Feldberg LR, Kim SC, Mallon R, Kovacs ED, Toral-Barza L, Kohler CA (2001) MEK (MAPKK) inhibitors. Part 2: structure–activity relationships of 4-anilino-3-cyano-6,7-dialkoxyquinolines. Bioorg Med Chem Lett 11:1407–1410CrossRefPubMedGoogle Scholar
  36. Zhang N, Wu B, Powell D, Wissner A, Floyd MB, Kovacs ED, Toral- Barza L, Kohler C (2000) Synthesis and structure–activity relationships of 3-cyano-4-(phenoxyanilino)quinolines as MEK (MAPKK) inhibitors. Bioorg Med Chem Lett 10:2825–2828CrossRefPubMedGoogle Scholar
  37. Zhou S, Liao H, Liu M, Feng G, Fu B, Li R, Cheng M (2014) Discovery and biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors. Bioorg Med Chem 22:6438–6452CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Rafat M. Mohareb
    • 1
  • Nadia Y. Megally Abdo
    • 2
  • Wagnat W. Wardakhan
    • 3
  1. 1.Department of Chemistry, Faculty of ScienceCairo UniversityGizaEgypt
  2. 2.Chemistry Department, Faculty of EducationAlexandria UniversityAlexandriaEgypt
  3. 3.National Organization for Drug control & ResearchCairoEgypt

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