Design and synthesis of quinoxaline-piperazine-pyrazolo conjugates as VEGFR-2 targeting agents and ADMET studies

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. We synthesized novel quinoxaline derivatives by analysing the structure-activity correlations (SAR) of several VEGFR-2 inhibitors. We discovered that VEGFR-2 inhibitors shared fundamental pharmacophoric characteristics. (i). To inhabit the hinge area, the head group must be heteroaromatic. (ii). A hydrophobic spacer to fill the gap between the enzyme's ATP binding domain and its DFG domain (iii). A hydrogen-bonding (pharmacophore) moiety is required to form hydrogen bond interactions with Asp1044 and Glu883 in the DFG motif. (iv). A hydrophobic (tail) moiety that resides in the allosteric hydrophobic back pocket. Our design's primary idea was realised through the bio isosteric modification of VEGFR-2 inhibitors (sorafenib and sunitinib). Four locations were used to administer such drugs. Rational design of the new proposed VEGFR-2 inhibitors. • We describe the one-pot synthesis of quinoxaline-piperazine-pyrazolo conjugates. • These conjugates were biological investigated for their cytotoxicity activity. • The structures of synthesized compounds were determined by using spectroscopic techniques. • The molecular docking studies of these compounds (8d, 8e, and 8f) show that more potent compounds strongly bind with the VEGFR-2 receptor. • 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.