Design and synthesis of novel pyridazinoquinazoline derivatives as potent VEGFR-2 inhibitors: In vitro and in vivo study.

ABSTRACT

Worldwide, Hepatocellular Carcinoma (HCC) endures to be a prominent cause of cancer death. Treatment of HCC follows multiple therapies which are not entirely applicable for treatment of all patients. HCC usually arises contextual to chronic liver diseases and is often discovered at later stages which makes treatment options more complex. The present study aimed at design, synthesis & evaluation of new pyridazinoquinazoline derivatives as potential nontoxic anti-hepatocellular carcinoma (HCC) agents, through inhibition of Vascular endothelial growth factor -2 (VEGFR-2). Novel Pyridazino[3, 4, 5-de]quinazoline derivatives (2-6) were designed & synthesized. Their structures were confirmed via spectral and microanalytical data. They were tested for their in vitro VEGFR-2 inhibition & anticancer activity against human liver cancer cell line (HEPG-2). Molecular docking was investigated into VEGFR-2 site. In vivo studies of VEGRF-2 inhibition and the anti-apoptotic effect of the new compounds were determined in liver of irradiated rats. Toxicity of synthesized compounds was also assessed. The results showed that compounds 3-6 have significant antitumor activity and proved to be non-toxic. The ethoxy aniline derivative 6, exhibited the highest activity both in vitro and in vivo compared to the reference drug used, sorafenib. Compound 6 could be considered a promising nontoxic anti HCC agent and this could be partially attributed to its VEGFR-2 inhibition. Future preclinical investigation would be carried out to confirm the specific and exact mechanism of action of these derivatives especially compound 6 as an effective pharmaceutical agent after full toxicological and pharmacological assessment.