Design, synthesis, docking studies and biological screening of 2-pyrimidinyl-2, 3-dihydro-1 H -naphtho [1, 2- e ][1, 3] oxazines as potent tubulin polymerization inhibitors.

A series of novel substituted 2-pyrimidinyl-2,3-dihydro-1-naphtho[1,2-][1, 3]oxazine analogs have been designed and synthesized based on structure-activity relationships from 2-naphthol, substituted pyrimidinyl amines and formalin through ring closure by one-pot three component reaction. These derivatives were evaluated for their cytotoxicity, cell cycle assay and their inhibitory effect on tubulin polymerization. From the MTT assay, it is clear that most of the synthesized compounds displayed potent cytotoxic activities on HeLa (cervical cancer) and B16F10 (melanoma) cancerous cell lines. The compounds and were found to be more effective against HeLa cell lines and exhibited significant cytotoxicity (with IC values 1.26 ± 0.12 µM and 1.16 ± 0.27 µM respectively), accumulation of HeLa cells in G2/M phase and exhibiting induced apoptosis. The immunohistochemistry and fluorescence assays showed that these compounds and inhibited the microtubule assembly in human cervical cancer cells (HeLa) at 2 µM concentration. Furthermore, molecular docking studies of these molecules revealed their better-fit potential as anticancer molecules and have a high affinity for colchicine binding site, indicating more inhibitory potential at the cellular level. Our studies suggest that the newly synthesized compounds may become promising leads for the development of new anti-cancer agents.Communicated by Ramaswamy H. Sarma.