Ketorolac-based ester derivatives as promising hits for malignant glioma: Synthesis, brain cancer activity, molecular docking, dynamic simulation and DFT investigation

Current research work aims to synthesize ester derivatives (2-12) bearing a scaffold of commonly used non- steroidal anti-inflammatory drug (ketorolac), and their anti-cancer activity. These analogues were structurally deduced using advance 1 H-, 13 C NMR and HRESIMS spectrometry. All the synthesized analogues were further evaluated against anti-cancer potential using malignant glioma (U-87) and human embryonic kidney (HEK-292) cell lines. In the series, four compounds 6 (IC50, 11.12 f 0.08 mu M), 10 (22.85 f 0.18 mu M), 8 (25.43 f 0.13 mu M), and 5 (29.36 f 0.09 mu M) exhibited notable inhibition, while the remaining ester derivatives exhibited moderate activity. Potent analogues were further exposed for molecular docking in order to investigate their protein-ligand interactions. The MD study determined the potency of compounds towards CK2 target for glioma with the help of s scores and best interactions with active site of CK2. Among this series, three compounds (5, 6 , and 10) were most potent against target. The chemical stability and reactivity of four compounds (5, 6, 8 , and 10) along with ketorolac, altered significantly when studied using TD-DFT with the PBE0-d4 functional and the D95v** basis set. Among the series, compound 6 stand out for their strong stability and electrophilicity, which could influence their anti-tumor activity. Based on the current findings, these compounds warrant further investigation, including experimental validation of their pharmacokinetic properties and assessment of their pharmacodynamics effects for future drug development.