Synthesis of New 1, 3, 4-Oxadiazole-Incorporated 1, 2, 3-Triazole Moieties as Potential Anticancer Agents Targeting Thymidylate Synthase and Their Docking Studies

Abstract

Thymidylate synthase (TS) has emerged as a hot spot in cancer treatment, as it is directly involved in DNA synthesis. In the present article, nine hybrids containing 1,2,3-triazole and 1,3,4-oxadiazole moieties (6–14) were synthesized and evaluated for anticancer and in vitro thymidylate synthase activities. According to in silico pharmacokinetic studies, the synthesized hybrids exhibited good drug likeness properties and bioavailability. The cytotoxicity results indicated that compounds 12 and 13 exhibited remarkable inhibition on the tested Michigan Cancer Foundation (MCF-7) and Human colorectal Carcinoma (HCT-116) cell lines. Compound 12 showed four-fold inhibition to a standard drug, 5-fluoruracil, and comparable inhibition to tamoxifen, whereas compound 13 exerted five-fold activity of tamoxifen and 24-fold activity of 5-fluorouracil for MCF-7 cells. Compounds 12 and 13 inhibited thymidylate synthase enzyme, with an half maximal inhibitory concentration, IC50 of 2.52 µM and 4.38 µM, while a standard drug, pemetrexed, showed IC50 = 6.75 µM. The molecular docking data of compounds 12 and 13 were found to be in support of biological activities data. In conclusion, hybrids (12 and 13) may inhibit thymidylate synthase enzyme, which could play a significant role as a chemotherapeutic agent.

Naproxen Based 1,3,4-Oxadiazole Derivatives as EGFR Inhibitors: Design, Synthesis, Anticancer, and Computational Studies

“…The synthetic path of naproxen hybrids 8 – 16 and 19 – 26 are presented in Scheme 1 and Scheme 2 . The key intermediates 4 and 5 were prepared according to the reported methods with little modification [ 30 ]. Firstly, Naproxen 1 was converted into methyl ester 2 by reacting with methanol in presence of concentrated sulphuric acid as catalyst.…”

“…In continuation of our previously reported work to find new leads with potential anticancer activity [29][30][31], we thought to explore naproxen incorporated 1,3,4-oxadiazole derivatives for anticancer potential. To the best of our knowledge, the anticancer effect of naproxen derivatives as EGFR has not been reported yet.…”

Synthesis and Biological Evaluation of 1,2,3-Triazole Tethered Thymol-1,3,4-Oxadiazole Derivatives as Anticancer and Antimicrobial Agents

“…These inhibitors induce apoptosis and cause cell cycle arrests by halting deoxythymidine monophosphate, which is responsible for formation of dTTP (a DNA synthesis precursor) [ 22 ]. From the literature, it is reported that 1,3,4-oxadiazole and 1,2,3-triazole derivatives exhibit antiproliferative activity by inhibiting thymidylate synthase [ 23 , 24 , 25 , 26 , 27 , 28 ] ( Figure 1 ). Our research group has been involved in the development of anticancer leads targeting thymidylate synthase.…”

Synthesis and Anticancer Evaluation of New 1,3,4-Oxadiazole Derivatives

“…The versatility and the usefulness of the 1,3,4-oxadiazole scaffold is demonstrated by its use as a core structure in the inhibitors of methionine aminopeptidase (MetAP2) [ 12 ], telomerase [ 13 , 14 ], focal adhesion kinase (FAK) [ 15 ], thymidylate synthase (TS) [ 16 ], glycogen synthase kinase-3 (GSK-3) [ 17 ], and thymidine phosphorylase (TP) [ 18 , 19 ]. The antitumor potency of 1,3,4-oxadiazoles derivatives is also related to their ability to inhibit grow factors such as epidermal growth factor receptor (EGFR) [ 20 , 21 ] or vascular endothelial growth factor (VEGF) [ 22 ], to inhibit tubulin polymerization [ 23 ], histone deacetylases (HDAC) [ 24 , 25 ], or to interact with DNA structures [ 26 ].…”