Synthesis, Molecular Docking and Anticancer Activity of Diflunisal Derivatives as Cyclooxygenase Enzyme Inhibitors

Abstract

Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new diflunisal thiosemicarbazides and 1,2,4-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3), colon carcinoma (HCT-116), human breast cancer (T47D), breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically, the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds 6, 10, 15 and 16 did not show cytotoxic effects for the HEK293 cell line. Among them, compounds 15 and 16 demonstrated anticancer activity for the breast cancer cell line T47D, whereas compounds 6 and 10 which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line, consistent with the literature. However, no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound 16 displayed activity against the HCT-116 cell line. Therefore, it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition, molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds 15, and 16. Both 15 and 16 showed high selectivity and affinity toward COX-2 isozyme over COX-1, which is in agreement with the experimental results.

Chemistry and Biological Activities of 1,2,4-Triazolethiones—Antiviral and Anti-Infective Drugs

“…The reaction of hydrazide 45 with various aryl isothiocyanates afforded substituted hydrazinecarbothioamides 46a – f . Cyclization of compounds 46a – f to the corresponding triazole-3-thiones 47a – f occurred in basic media ( Scheme 11 ) [ 57 ]. The screening of compounds 47a – f against cancer cells revealed that compound 47f was found to be active against the colon carcinoma HCT-116 cancer cell line with a 6.2 μM IC 50 value.…”

“…The screening of compounds 47a – f against cancer cells revealed that compound 47f was found to be active against the colon carcinoma HCT-116 cancer cell line with a 6.2 μM IC 50 value. In addition, compounds 47e and 47f were found active against the human breast cancer T47D cancer cell line with IC 50 values of 43.4 and 27.3 μM, respectively [ 57 ].…”

Synthesis and Anthelmintic Activity of New Thiosemicarbazide Derivatives—A Preliminary Study

“…Thiosemicarbazides are very similar to thiosemicarbazones. A thiosemicarbazide skeleton is part of the structure of many compounds with interesting biological activities, including anticancer [ 10 , 11 , 12 , 13 ], antibacterial [ 12 , 13 , 14 , 15 , 16 , 17 , 18 ], antifungal [ 19 ], and analgesic [ 20 ].…”

Synthesis, molecular modeling, in vivo study, and anticancer activity of 1,2,4‐triazole containing hydrazide–hydrazones derived from (S)‐naproxen

“…Anticancer activity and molecular modeling of NSAIDs derivatives have been studied and reported by Küçükgüzel and coworkers (Figure ).…”