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Letters in Drug Design & Discovery

Author(s): Rafat Milad Mohareb, Nadia Youssef Megally Abdo* and Waleed Nabeel Al-darkazali

DOI: 10.2174/1570180816666190618115128

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Uses of Cyclohexan-1,3-dione for the Synthesis of Thiazole, Pyrazole, Thiophene, Isoxazole and Pyran Derivatives with Antitumor Activities

Page: [597 - 609] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background: A wide range of thiazole, pyrazole and pyran derivatives gained special attention due to pharmacological activities especially therapeutic activities. Many pharmacological drugs containing the thiazole and pyrazole nuclei are known in the market.

Methods: The 2-arylidencyclohexan-1,3-dione 3a-c were the key starting compounds for many heterocyclic reactions to produce substituted heterocyclic derivatives.

Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 were measured in which the compounds showed high inhibition. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by assessing the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition.

Conclusion: Thirty compounds were synthesized. Ten of them (3a, 3c, 5a, 5c, 7a, 10f, 11a, 13c, 16a and 16c) were the most active compounds for selected cancer cell lines. Compounds 3c, 5c, 7a, 10f, 13c and 16c showed high inhibition toward the tyrosine kinases while compounds 3c, 5c and 10f were the most potent to inhibit Pim-1.

Keywords: Cyclohexan-1, 3-dione, pyrazole, thiophene, pyran, anti-proliferative activity, tyrosine kinases.

Graphical Abstract

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