Investigation of anticancer effects of novel piperidine-oxadiazole and piperidine-triazole derivatives as VEGFR inhibitors and evaluation of their molecular docking-dynamic studies

Abstract

Within the scope of this study, the design and synthesis of new triazole and oxadiazole compounds containing piperidine ring were carried out. The anticancer effects of the obtained compounds have been tested on lung and colon cancers. Especially in colon cancer, compounds 4Id, 4Ie, 4If and 4Ih exhibited significant activity profiles. Compounds 4Id, 4Ie, 4If and 4Ih showed activity against HT-29 cell line with IC50=19.238±0.652 μM, 14.861±0.409 μM, 20.876±0.374 μM and 16.132±0.787 μM, respectively. Compound 4Ie has an IC50 value greater than 100 μM against healthy cells (NIH3T3). While this compound (4Ie) effectively eliminates colon cancer cells, it exhibits a lower tendency to harm healthy cells. Since the importance of VEGFR-2 inhibition in colon cancer, the active compounds were evaluated by means of in vitro enzyme inhibition test. Compounds 4Id, 4Ie, 4If and 4Ih showed activity against VEGFR-2 enzyme with IC50=0.105±0.002 μM; 0.055±0.003 μM; 1.096±0.005 μM; 0.159±0.002 μM; 0.039±0.001 μM respectively. As a result of molecular docking and dynamics studies, it is seen that the stability of all compounds is excellent. However, especially compound 4Ie exhibited a strong inhibitory potential with its continuous interactions with Cys919, Glu885 and Asp1046. Dynamic investigations reveal the enzyme's stability within the active site, with particular emphasis on the cyano group's capability to engage with Cys919, rendering this compound the most potent derivative.