Design Synthesis Characterisation and Biological Evaluation of Novel Uracilcoumarin Hybrids as Cytotoxic Agents

Abstract

The current research dealt with rationally designed library of novel uracil-coumarin based bifunctional molecular hybrids roped by 1,2,3-triazole moiety. The target hybrids were synthesized and tested against a panel of six human cancer cell lines namely Colo-205, MCF-7, A-549, PA-1, PC-3 and Hela cells by Sulforhodamine B assay. The results indicated that the hybrid molecules can specifically inhibit the MCF-7 cancer cell proliferation amongst which A-2 was found to be most potent hybrid (GI50 = 1.55 and#956;M) with fluorine atom as R with two carbon chain length between triazole and coumarin moieties. Cell cycle analysis revealed that A-2 significantly arrest the G2/M phase to inhibit proliferation of MCF-7 cells. Molecular docking studies were performed on two popular cancer targets (EGFR and Tubulin). In Silico results revealed that A-2 binds in the tyrosine kinase domain of EGFR(target-I) and further molecular dynamics studies proves that category A ligand; A-5 forms a stable complex in EGFR tyrosine kinase domain with RMSD of 0.3 nm and the plateau phase started just after 10 nano second. Another molecular docking study depicted the binding of A-2 in vinblastine binding site of tubulin (target-II). Validation of computational studies was done via in-vitro target assays using protein kits of both EGFR and tubulin. For further exploration of cytotoxic potential, antibacterial properties of all the synthetics was also evaluated which comes out with two hit lead molecules A-2 (MIC= 11.7 and#956;g/ml) and A-3 (MIC= 7.23 and#956;g/ml) that can significantly inhibit the bacterial strain Staphylococcus aureus comparable to that of standard drug levofloxacin (MIC= 3.12 and#956;g/ml). Binding interactions within the active site of dihydrofolate reductase (DHFR) were also streamlined by using molecular docking studies. Overall studies revealed that hybrid A-2 arrest the mitotic phase of breast cancer cells by inhibiting EGFR and tubulin polymerization. newline