Design, synthesis, cytotoxic and enzyme inhibitory activities of 1,3,4-oxadiazole and 1,3,4-thiadiazine hybrids against non-small cell lung cancer

Abstract

Certain new 1,3,4-oxadiazole and 1,3,4-thiadiazine hybrids attached through thioacetamide linker (3a-p) were synthesized and tested in vitro for their cytotoxic activities towards a non-small cell lung cancer (NSCLC) cell line A549. The results indicated that eight compounds (3b, 3d, 3e, 3f, 3 g, 3 h, 3 k and 3n) exhibited more potent activity than the standard drug doxorubicin with IC50 range of 0.44 ± 0.02 – 2.84 ± 0.14 µM. Compound 3 g which displayed the highest cytotoxicity caught our interest for further investigation. It arrested the cell cycle at G2/M phase and showed proapoptotic action as reflected by Annexin-V-FITC assay. The activities of 3 g against certain enzymes which are reported to be overexpressed in NSCLC were studied. Promising inhibitory activities were demonstrated against vascular endothelial growth factor receptor2 (VEGFR2) (IC50 = 0.268 ± 0.006 µM), B-RAF (IC50 = 0.176 ± 0.009 µM), matrix metalloproteinases (MMPs) MMP1 (IC50 = 0.277 ± 0.006 µM) and MMP9 (0.084 ± 0.002 µM) with respect to corresponding reference drugs. Moreover, 3 g inhibited Telomerase activity by 36.55%. Docking study showed that 3 g bound to these target enzyme active sites similar to the co-crystallized ligands. Also, 3 g was more selective to A549 than WI-38 (a normal human fetal lung fibroblast cell line), with selectivity index (SI) = 59.79. In conclusion, 3 g is a promising multitarget anticancer compound which targets key pathways in NSCLC and requires further investigation.

Keywords

• Thiadiazine-oxadiazole hybrids
• NSCLC
• VEGFR2
• B-RAF
• MMPS
• Telomerase