Rational design, anticancer evaluation and molecular docking studies of aryl amide linked oxazole-pyrazine-pyridine derivatives

A new series of aryl amide derivatives of oxazole-pyazine-pyridine ( 11a-j ) derivatives were synthesized and assessed their anticancer activity against a panel of four human cancer cell lines such as PC3 (human prostate cancer), A549 (human lung cancer), MCF-7 (human breast cancer) and DU-145 (human ovarian cancer) by using of MTT method with Etoposide as standard drug. Among the tested compounds, analogues 11a, 11b, 11c and 11d emerged as the most potent compounds wirh IC 50 values ranges from 0.01 ± 0.0067 μM to 6.33 ± 3.12 μM, whereas, standard showed IC 50 values ranges from 1.97 ± 0.45 μM to 3.08 ± 0.135 μM. The compound 11a with 3,4,5-trimethoxy electron donating group on phenyl ring showed more promising activity against PC-3, A549, MCF-7 & DU-145 cell lines with IC 50 values of 0.04 ± 0.0075 μM; 0.01 ± 0.0067 μM; 0.09 ± 0.0033 μM & 0.11 ± 0.056 μM. Where as another compound 11b with 3,5-dimethoxy electron donating group showed potent activity against PC-3, A549, MCF-7 & DU-145 cell lines with IC 50 values of 0.88 ± 0.099 μM; A549 = 0.32 ± 0.056 μM; MCF-7 = 0.34 ± 0.093 μM & DU-145 = 0.12 ± 0.043 μM. The standard drug, Etoposide showed anticancer activity against PC-3, A549, MCF-7 & DU-145 cell lines with IC 50 values of 2.39 ± 1.56 μM; 3.08 ± 0.135 μM; 2.11 ± 0.024 μM; & 1.97 ± 0.45 μM respectively. Molecular docking results revealed VEGFR2 as the most responsive target for the synthesized compounds, exhibiting strong binding energies between −10.1 and − 9.5 kcal/mol. All compounds complied with Lipinski's Rule of Five, indicating favorable drug-like properties with no violations. ADME predictions further revealed that the compounds are likely to inhibit multiple cytochrome P450 (CYP) isoforms primarily CYP2D6, CYP2C9, and CYP3A4. These interactions suggest possible effects on metabolic stability and raise concerns about the risk of drug-drug interactions.