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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

Abstract

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.

Keywords

Cyclohexan-1,4-dione Quinoline Thiazole Antiproliferative activity 

Notes

Acknowledgements

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.

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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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