Design, synthesis and biological evaluation of new eugenol derivatives containing 1,3,4-oxadiazole as novel inhibitors of thymidylate synthase

Abstract

Natural products and their semi-synthetic analogues have provided many chemotherapeutic drugs. In the current study, eugenol, a natural anticancer agent, has been modified synthetically to produce new 1,3,4-oxadiazole analogues as inhibitors of thymidylate synthase (6–19). All the final analogues were characterized using different spectroscopic techniques and were tested for cytotoxicity against breast cancer MCF-7, ovarian cancer SKOV3 and prostate cancer PC3 cells using the MTT assay. Among all the tested analogues, compounds 9 and 17 were the most promising candidates with IC₅₀ values of 0.99 μM and 1.25 μM against MCF-7 cells and 1.17 μM and 0.26 μM against PC3 cells, respectively, and were better than doxorubicin in killing these cancerous cells. These two compounds were found to be potent thymidylate synthase inhibitors with an IC₅₀ of 0.61 μM (9) and 0.56 μM (17), compared with the chemotherapeutic agent pemetrexed (IC₅₀ 2.81 μM). Furthermore, compounds 9 and 17 significantly arrested the cell cycle at the S phase, analogous to 5-florouracil (5FU), and induced apoptosis in prostate cancer PC3 and breast cancer MCF-7 cells. ADMET studies confirmed that these analogues show excellent oral druglikeness properties with all pharmacokinetics parameters in an acceptable range, good TPSA values, and high % absorptions of 96.6% (9) and 95% (17). Furthermore, these compounds were found to be non-carcinogenic and showed no acute or chronic toxicity. From docking studies, compounds 9 and 17 showed binding interactions similar to 5FU with the thymidylate synthase protein. It can be concluded that compounds 9 and 17 could be promising chemotherapeutic agents as inhibitors of thymidylate synthase.