Background: Recentlty, pyrazoloquinazoline derivatives acquired a special attention due to their
wide range of pharmacological activities, especially therapeutic. Through the market, it was found that many
pharmacological drugs containing the quinazoline nucleus were known.
Objective: The aim of this work is to synthesize target molecules possessing not only anti-tumor activities but
also kinase inhibitors. The target molecules were obtained through the synthesis of a series of 5,6,8,9-
tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives 4a-i using the multi-component reactions of cyclohexane-
1,4-dione (1), the 5-amino-4-(2-arylhydrazono)-4H-pyrazol-3-ol derivatives 2a-c, the aromatic aldehydes
3a-c, respectively. The synthesized compounds were evaluated against c-Met kinase, PC-3 cell line, and
different kinds of cancer cell lines together with normal cell line, tyrosine kinases, and Pim-1 kinase.
Methods: Multi-component reactions were adopted using compound 1 to get different 5,6,8,9-
tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one derivatives which underwent further heterocyclization reactions.
The c-Met kinase activity of all compounds was evaluated using Homogeneous Time-Resolved Fluorescence
(HTRF) assay, taking foretinib as the positive control. The anti-proliferative activity of all target compounds
against the human prostatic cancer PC-3 cell line was measured using MTT assay using SGI-1776 as the reference
drug. All the synthesized compounds were assessed for inhibitory activities against A549 (non-small cell
lung cancer), H460 (human lung cancer), HT-29 (human colon cancer), and MKN-45 (human gastric cancer)
cancer cell lines together with foretinib as the positive control by an MTT assay.
Results: Antiproliferative evaluations and c-Met kinase, Pim-1 kinase inhibitions were performed for the synthesized
compounds, where the varieties of substituents through the aryl ring and the thiophene moiety afforded
compounds with high activities.
Conclusion: The compounds with high antiproliferative activity were tested towards c-Met and the results
showed that compounds 4e, 4f, 4g, 4i, 6i, 6k, 6l, 8f, 8i, 10d, 10e, 10f, 10h, 12e, 12f, 12g, 12h, 12i, 14f, 14g, 14h,
and 14i were the most potent compounds. A further selection of compounds for the Pim-1 kinase inhibition activity
showed that compounds 4f, 6i, 6l, 8h, 8i, 8g, 10d, 12i, and 14f were the most active compounds to inhibit Pim-1.