One pot synthesis of pyrazolo-piperazine-quinazoline hybrids: evaluation of anticancer activity, molecular docking and ADMET studies

The synthesis of pyrazolo-piperazine-quinazoline hybrids ( 7a-n ) was described, and their anticancer activity was assessed towards two cancer cell lines, such as HepG2 (hepatocellular carcinoma) and MCF-7 (breast cancer). The results show that three hybrids, 7e , 7f , and 7g , displayed good activity compared with sorafenib. Hybrid 7g exhibited the closest activity, with IC 50 values of 8.56 ± 0.13 μM and 9.52 ± 0.10 μM. Hybrids 7e and 7f showed lower activity, with IC 50 values of 9.54 ± 0.09 μM, 10.14 ± 0.06 μM, 10.23 ± 0.20 μM, and 12.10 ± 0.20 μM, respectively, compared with standard drug IC 50 values of 8.96 ± 0.45 μM and 9.84 ± 0.36 μM correspondingly. The hybrids 7e , 7f , and 7g were assessed for their ability to inhibit EGFR tyrosine kinase. Compound 7f exhibited relatively lesser activity with the standard drug, whereas compounds 7e and 7g had much greater activity than sorafenib. Furthermore, molecular docking studies were performed to elucidate the binding interactions of the most active hybrids, 7e , 7f , and 7g, with VEGFR-2 and to compare their binding profiles with that of the reference drug. Additionally, in silico pharmacokinetic studies were carried out on the three potent hybrids 7e , 7f , and 7g interestingly matched all five filters, with the exception of Ghose's rule of hybrid 7g . The synthesis of pyrazolo-piperazine-quinazoline hybrids ( 7a-n ) was described, and their anticancer activity was assessed towards two cancer cell lines, such as HepG2 (hepatocellular carcinoma) and MCF-7 (breast cancer). The results show that three hybrids, 7e , 7f , and 7g, displayed good activity compared with sorafenib. Hybrid 7g exhibited the closest activity, with IC 50 values of 8.56 ± 0.13 μM and 9.52 ± 0.10 μM. Hybrids 7e and 7f showed lower activity, with IC 50 values of 9.54 ± 0.09 μM, 10.14 ± 0.06 μM, 10.23 ± 0.20 μM, and 12.10 ± 0.20 μM, respectively, compared with sorafenib IC 50 values of 8.96 ± 0.45 μM and 9.84 ± 0.36 μM correspondingly. The hybrids 7e , 7f , and 7g were assessed for their ability to inhibit EGFR tyrosine kinase. Compound 7f exhibited relatively lesser activity (IC 50 = 16.70 nM) with the standard drug, whereas compounds 7e and 7g had much greater activity (IC 50 = 13.50 nM and 12.23 nM) than sorafenib (IC 50 = 14.70 nM). Furthermore, molecular docking studies were performed to elucidate the binding interactions of the most active hybrids, 7e , 7f , and 7g , with VEGFR-2 and to compare their binding profiles with that of the reference drug sorafenib. Additionally, in silico pharmacokinetic studies were carried out on the three potent hybrids 7e , 7f , and 7g using SWISS/ADME and pkCSM. The three hybrids ( 7e , 7f , and 7g ) interestingly matched all five of the above-mentioned conditions exactly, with the exception of Ghose's rule of hybrid 7g . We also carried out in silico pharmacokinetic studies on the standard drug sorafenib. The test values indicate that the hybrids showed nearer values. The standard drug followed the three rules, such as Lipinski's rule, Veber rule, Muegge rule, Ghose and Egan rules.