Design and synthesis of quinoxaline-piperazine-pyrazolo conjugates as VEGFR-2 targeting agents and ADMET studies
B. Srinivas, B. Srinivas, Gouthami Dasari, Arshiya Banu Syeda, Rambabu Palabindela, Bandari Srinivas, Bandari Srinivas
Abstract
Herein, we describe the design and synthesis of new quinoxaline-piperazine-pyrazole conjugates ( 8a-n ). The synthesized conjugates were biologically evaluated for their in vitro cytotoxicity against two cancer cell lines, such as HepG2 (hepatocellular carcinoma) and MCF-7 (breast cancer). The results for cytotoxicity activity show that the conjugate had an 8d value (MCF-7 = 6.4 and HepG2 = 4.6 μM). Conjugate 8e (MCF-7 = 9.1 and HepG2 = 8.9 μM) and 8f (MCF-7 = 13.6 and HepG2 = 10.7 μM) display more potent anticancer activity as compared to the standard drug Sorafenib. The in-silico docking studies were performed to determine the possible interaction with the VEGFR-2 active site, and the results reveal that the 8d , 8e , and 8f exhibited more VEGFR-2 binding interactions. The potent conjugates were further screened for their in vitro VEGFR-2 inhibitory activity using Sorafenib as the reference drug. Compounds 8f and 8d had significantly higher activity as compared to the standard drug Sorafenib. We subjected the more potent conjugates 8d , 8e , and 8f to in silico pharmacokinetic assessment using SWISS, ADME, and pkCSM. The three conjugates ( 8d and 8e ) followed the Lipinski, Ghose, Veber, Egan, and Muegge rules without any deviation. But conjugate 8f followed four Lipinski , Veber, Egan, and Muegge rules with the exception of Ghose rule.