Synthesis and Anti-Proliferative Evaluations of New Heterocyclic Derivatives using 5,6,8,9-tetrahydropyrazolo[5,1-b]quinazolin-7(3H)-one Derivatives Derived from Cyclohexa-1,4-dione.

BACKGROUND: Recentlty pyrazoloquinazoline derivatives acquired a special attention due to their wide range of pharmacological activities especially the therapeutic activities. Through the market it was found that many pharmacological drugs containing the quinazoline nucleus were known. OBJECTIVE: We are aiming in this work to synthesize target molecules not only possess 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 multicomponent reactions of cyclohexan-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: Muticomponent 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 TimeResolved 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 were measured using MTT assay using SGI-1776 as the reference drug. All the synthesized compounds were assessed the 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) cancer cell lines together with foretinib as the positive control by a MTT assay. RESULTS: Antiproliferative evaluations and c-Met kinase, Pim-1 kinse inhibitions were perform for the synthesized compounds where the varieties of substituent through the aryl ring and the thiophene moiety afforded compounds with high activities. CONCLUSION: The compounds with high antiprolifeative activity were tested toward 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. Further selection of compounds for the Fused Quinazoline Derivatives as Anticancer Agents 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.