Design, synthesis, anticancer evaluation and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A kinase inhibitors

Abstract

Introduction: Aurora-A kinase is associated with the Aurora kinase family which has been considered a striking anticancer target for the treatment of human cancers.

Objective: To design, synthesize, anticancer evaluation, and docking studies of novel 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives as Aurora-A Kinase inhibitors.

Method: A total of 21 Pyrazole derivatives P (1-21) were synthesized by using the Vilsmeier Haack reagent which was characterized by FT-IR, ¹H NMR, ¹³C NMR, and Mass spectroscopy. The synthesized derivatives were evaluated for their potential in vitro anticancer activity by MTT assay and Aurora-A kinase inhibition assay.

Results: The cytotoxicity assay (MTT assay) showed that compound P-6 exhibited potent cytotoxicity (IC₅₀ = 0.37-0.44 μM) against two cancer (HCT 116 and MCF-7) cell lines, which were comparable to the standard compound, VX-680. Compound P-6 also showed inhibition of Aurora-A kinase with an IC₅₀ value of 0.11 ± 0.03 µM. A Docking study was done to compound P-6 and P-20 into the active site of Aurora A kinase, in order to get the probable binding model for further study.

Conclusion: A series of 21 novel pyrazole derivatives P(1-21) were designed, synthesized, in vitro anticancer evaluation, and docking studies for Aurora A kinase inhibition. The results established that P-6 is a prospective aspirant for the development of anticancer agents targeting Aurora-A kinase.

Keywords: Aurora-A kinase; Cell cycle arrest; Docking studies; MTT assay; Pyrazole; Thiazolidin-4-one.

Fig. 1

a Scaffolds found in Aurora-A kinase reported inhibitors (A) pyrrolo-pyrazole scaffold; (B) pyrrolo- pyrimidine scaffold; (C) quinoline scaffold; (D) diaminopyrimidin-2-anilino-e scaffold. b Examples of potent Aurora-A kinase inhibitors

Fig. 2

The design strategy for the generation of pyrazole scaffolds with thiazolidin-4-one derivatives

Scheme 1

General synthesis of 2-(1-isonicotinoyl-3-phenyl-1H-pyrazol-4-yl)-3-phenylthiazolidin-4-one derivatives P (1–21). Reagents and conditions: (i) ethanol, glacial acetic acid, Conv.- reflux 30–40 min, MW-2–3 min (ii) DMF/POCl₃, Conv.-reflux, 4–5 h, MW-3–4 min (iii) Conv.-reflux, 1-2 h, MW-3–4 min (iv) thioglycollic acid/DMF, Anhyd. ZnCl₂, Conv.-1 h, MW-3–4 min

Fig. 3

SAR of cytotoxicity of compounds P(1–21)

Fig. 4

a Overlay of compound P-6 (orange) with Aurora-A co-crystallized ligand (Pdb-2bmc). b Docked surface of ligand P-6 with Aurora-A complex. c Surface model structure of compound P-6 with Aurora A complex. d 2D ligand interaction diagram of compound P-6 with Aurora-A using Discovery Studio program with essential amino acid residues at the binding site are tagged in circles. The purple circles show the amino acids which participate in hydrogen bonding, and electrostatic or polar interactions and the green circles show the amino acids which participate in the Vander Waals interactions

Fig. 5

Systematic conversion of MTT to formazan [34]

Fig. 6

Schematic representation of MTT assay protocol