Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents

• Isatin-pyridine hybrids 5a–o, 8 and 11a–d were designed and synthesized.
• Anti-proliferative activity was assessed against HepG2, HT-29 and MCF-7 cell lines.
• QSAR analysis was performed by means of the Discovery Studio 2.5 software.
• Compound 8 was the most active hybrid against HepG2 (IC50 = 2.5 μM).
• Compound 11c (IC50 = 6.3) was equipotent as doxorubicin (IC50 = 6.1) in MCF-7.

A hybrid pharmacophore approach was adopted to design and synthesize new series of isatin–pyridine hybrids. All the newly prepared hybrids (5a–o, 8 and 11a–d) were in vitro evaluated for their anti-proliferative activity against three human cancer cell lines, namely HepG2 hepatocellular carcinoma, A549 lung cancer and MCF-7 breast cancer. Compound 8 emerged as the most active member against HepG2 cell line (IC50 = 2.5 ± 0.39 μM), with 2.7-fold increased activity than the reference drug, doxorubicin (IC50 = 6.9 ± 2.05 μM). Whilst, compound 11c was found to be the most potent counterpart against A549 and MCF-7 cell lines with IC50 values of 10.8 ± 1.15 and 6.3 ± 0.79, respectively. The weightiness of the utilization of non-cleavable linker, as the chalcone linker, and simplification of the first group, was explored via the SAR study. Furthermore, a QSAR model was built to explore the structural requirements controlling the cytotoxic activities. Notably, the predicted activities by the QSAR model were very close to those experimentally observed, hinting that this model could be safely applied for prediction of more efficacious hits comprising the same skeletal framework. Finally, a theoretical kinetic study was established to predict the ADME of the active hybrids.

Three different sets of isatin-pyridine hybrids were designed and synthesized to evaluate their anti-proliferative activity against HepG2, A549 and MCF-7 cancer cell lines. Two structural modifications for the first series were utilized to improve the activity.Figure optionsDownload as PowerPoint slide