Novel quinoline-3-carboxamides (Part 2): Design, optimization and synthesis of quinoline based scaffold as EGFR inhibitors with potent anticancer activity.

EGFR has a key role in cell growth. Its mutation and overexpression share in epithelial malignancies and tumor growth. Quinazoline and quinoline derivatives are common anticancer intracellular inhibitors of EGFR kinase, and their optimization is an important issue for development of potent targeted anticancer agents. Based on these facts, different strategies were used for optimizing our reported quinoline-3-carboxamide compound III (EGFR IC50 = 5.283 µM and MCF-7 IC50 = 3.46 µM) through different molecular modeling techniques. The optimized compounds were synthesized and subjected to EGFR binding assay and accordingly some more potent inhibitors were obtained. The most potent quinoline-3-carboxamides were the furan derivative 5o; thiophene derivative 6b; and benzyloxy derivative 10 showing EGFR IC50 values 2.61, 0.49 and 1.73 µM, respectively. Furthermore, the anticancer activity of compounds eliciting potent EGFR inhibition (5o, 5p, 6b, 8a, 8b, and 10) was evaluated against MCF-7 cell line where they exhibited IC50 values 3.355, 3.647, 5.069, 3.617, 0.839 and 10.85 µM, respectively. Compound 6b was selected as lead structure for further optimization hoping to produce more potent EGFR inhibitors.

Molecular design and synthesis of certain new quinoline derivatives having potential anticancer activity.

EGFR, which plays a vital role as a regulator of cell growth, is one of the intensely studied TK targets of anticancer inhibitors. The most two common anticancer inhibitors are anilinoquiazolines and anilinoquinolines that inhibit EGFR kinase intracellularly. The present investigation dealt with design (pharmacophore, docking and binding energy) and synthesis of a new series of 4-anilinoquinoline-3-carboxamide derivatives as potential anticancer agents targeting EGFR. All the newly synthesized compounds were screened for their anticancer activity against MCF-7 and compounds 4f, 7a and 7b showed significant activity with IC50 values 13.96 µM, 2.16 µM and 3.46 µM, respectively. Most of the synthesized compounds were subjected to enzyme assay (EGFR TK) for measuring their inhibitory activity with the determination of IC50 values and the preliminary results revealed that compound 7b, which had potent inhibitory activity in tumor growth and had potent activity on the EGFR TK enzyme with 67% inhibition compared to ATP would be a potential anticancer agent.