Molecular Docking, Synthesis, characterization and preliminary cytotoxic evaluation of new 1, 3,4-Thiadiazole derivatives as EGFR inhibitors

Abstract

A new 1,3,4-Thiadiazole derivatives derived from the Methyl-3-hydroxy benzoate were synthesized by a conventional method. The molecular-docking study of the synthesized compounds(s) against EGFR kinase revealed that such compounds occupied the critical site of EGFR kinase pocket with good positioning.compounds (M1,M2,M3 and M4) showed an inhibitory effect against EGFR kinase. Novel compounds were synthesized and confirmed by spectroscopic analysis, including AT-IR, 1HNMRS and13C-NMRS. The crystal structure of EGFR with a Gefitinib as a co-crystalized ligand was gained from the protein data-bank (PDB code 4WKQ). The docking was carried by Autodock vina and the visualization by chimera, the charge of the protein molecules was modelled by AMBERff14SB force field, while the small molecules by AM1-BCC. Compounds M2,M4 IC50 (11 mM) and (7.9 mM) respectively, exhibited cytotoxic activity against A549 lung cancer cells better than standard (gefitinib IC50 = 20.8 Mm). which were matched by the molecular docking studies that showed that the target compounds may be considered as potential inhibitors of EGFR kinase. From the docking study, it was concluded that piperidine, morpholine and methyl-piperazine moiety were very successful to bind tightly to EGFR kinase pocket receptors by making numerous interaction modes.