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

Alam, Mohammad Mahboob; Elbehairi, Serag Eldin I.; Shati, Ali A.; Hussien, Rania A.; Alfaifi, Mohammad Y.; Malebari, Azizah M.; Asad, Mohammad; Elhenawy, Ahmed A.; Asiri, Abdullah M.; Mahzari, Ali; Alshehri, Reem F.; Nazreen, Syed

doi:10.1039/d2nj05711e

Cited by 6 publications

(6 citation statements)

References 46 publications

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“…Compounds 6-14 were prepared according to our previous published work with little modification. [42] To a dry clean RBF, compound 5…”

Section: Discussionmentioning

confidence: 99%

“…Compounds 6–14 were prepared according to our previous published work with little modification. [ 42 ] To a dry clean RBF, compound 5 (1 mmol) and a mixture of tertiary butanol and water (1:1, 20 mL) were transferred. Then, sodium ascorbate (1 mmol), copper sulfate (1 mmol), and different aromatic azides were charged and stirred at 25–50°C for 4–10 h. Following the complete conversion of compound 5 , monitored by TLC, water (50 mL) was added and the products were extracted with MDC.…”

Section: Methodsmentioning

confidence: 99%

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New paracetamol hybrids as anticancer and COX‐2 inhibitors: Synthesis, biological evaluation and docking studies

Alam,

Alsenani,

Abdelhamid

et al. 2023

Archiv der Pharmazie

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Drug repurposing is an emerging field in drug development that has provided many successful drugs. In the current study, paracetamol, a known antipyretic and analgesic agent, was chemically modified to generate paracetamol derivatives as anticancer and anticyclooxygenase‐2 (COX‐2) agents. Compound 11 bearing a fluoro group was the best cytotoxic candidate with half‐maximal inhibitory concentration (IC50) values ranging from 1.51 to 6.31 μM and anti‐COX‐2 activity with IC50 = 0.29 μM, compared to the standard drugs, doxorubicin and celecoxib. The cell cycle and apoptosis studies revealed that compound 11 possesses the ability to induce cell cycle arrest in the S phase and apoptosis in colon Huh‐7 cells. These results were strongly supported by docking studies, which showed strong interactions with the amino acids of the COX‐2 protein, and in silico pharmacokinetic predictions were found to be favorable for these newly synthesized paracetamol derivatives. It can be concluded that compound 11 could block cell growth and proliferation by inhibiting the COX‐2 enzyme in cancer therapy.

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“…Compounds 6-14 were prepared according to our previous published work with little modification. [42] To a dry clean RBF, compound 5…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

New paracetamol hybrids as anticancer and COX‐2 inhibitors: Synthesis, biological evaluation and docking studies

Alam,

Alsenani,

Abdelhamid

et al. 2023

Archiv der Pharmazie

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“…For instance, compound I showed a telomerase inhibitory activity with IC 50 2.30 μM, compound II as HDAC1 inhibitor with IC 50 = 0.017 μM, compound III was found to be 8-fold (IC 50 2.1 μM) more effective as FAK inhibitor than Cisplatin (IC 50 8.6 μM), while compound IV was 15-fold more potent TS inhibitor with IC 50 0.62 μM than pemetrexed . Moreover, conjugation of oxadiazole scaffold with bioactive natural products also represents a promising approach. − Oxadiazole fused thymol ( V ), furanolabdane, and isosteviol derivatives have shown significant inhibitory activities with IC 50 1.95 μM, GI 50 0.08–0.34 μM, and IC 50 0.95–3.36 μM, respectively, toward tested cancer cells (Figure ). These abovementioned reports of eugenol and 1,3,4-oxadiazole with broad biological targets for antiproliferative effect encouraged us to conjugate natural product eugenol with 1,3,4 oxadiazole scaffold.…”

Section: Introductionmentioning

confidence: 99%

“… 25 Moreover, conjugation of oxadiazole scaffold with bioactive natural products also represents a promising approach. 26 − 28 Oxadiazole fused thymol ( V ), 29 furanolabdane, 30 and isosteviol derivatives 31 have shown significant inhibitory activities with IC 50 1.95 μM, GI 50 0.08–0.34 μM, and IC 50 0.95–3.36 μM, respectively, toward tested cancer cells ( Figure 1 ). These abovementioned reports of eugenol and 1,3,4-oxadiazole with broad biological targets for antiproliferative effect encouraged us to conjugate natural product eugenol with 1,3,4 oxadiazole scaffold.…”

Section: Introductionmentioning

confidence: 99%

New Natural Eugenol Derivatives as Antiproliferative Agents: Synthesis, Biological Evaluation, and Computational Studies

et al. 2023

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Semisynthetic modifications of natural products have bestowed us with many anticancer drugs. In the present work, a natural product, eugenol, has been modified synthetically to generate new anticancer agents. The final compounds were structurally confirmed by NMR, IR, and mass techniques. From the cytotoxicity results, compound 17 bearing morpholine was found to be the most active cytotoxic agent with IC 50 1.71 (MCF-7), 1.84 (SKOV3), and 1.1 μM (PC-3) and a thymidylate synthase (TS) inhibitor with an IC 50 of 0.81 μM. Further cellular studies showed that compound 17 could induce apoptosis and arrest the cell cycle at the S phase in PC-3 carcinoma. The docking study strongly favors compound 17 to be a TS inhibitor as it displayed a similar interaction to 5-fluorouracil. The in silico pharmacokinetics and DFT computational studies support the results obtained from docking and biological evaluation and displayed favorable pharmacokinetic profile for a drug to be orally available. Compound 17 was found to be a promising TS inhibitor which could suppress DNA synthesis and consequently DNA damage in prostate cancer cells.

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“…Therefore, it was deduced that 1,3,4-oxadiazole could also serve as an indispensable pharmacophore for new DMI fungicides (Figure 1). In addition, 1,3,4-oxadiazole derivatives are a classic type of fivemembered heterocyclic compounds containing C, N, and O atoms, and have attracted more and more attention due to the importance of oxadiazole derivatives in medicinal chemistry and extensive biological activities, such as antiviral, [16] nematocidal, [17] antifungal, [4,18,19] antitumor, [20][21][22][23] antiinflammatory, [24] α-glucosidase inhibition, [25] and antitubercular activities. [26] Moreover, electron-donating groups (e. g., À O-and-SÀ ) linked with a heteroatomic ring would be conducive to the enhancement of the binding affinity between receptor and ligand, and thus the biological activities of the hybrids could be improved.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Antifungal Activity, and Molecular Simulation Study of L–Carvone‐Derived 1,3,4‐Oxadiazole‐Thioether Compounds

Wen

Fan

Lin

et al. 2023

Chemistry & Biodiversity

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To discover potent antifungal molecules with new and distinctive structures, 20 novel L-carvone-derived 1,3,4-oxadiazolethioether compounds 5 a-5 t were synthesized through multistep reaction of L-carvone, and their structures were confirmed by FT-IR, 1 H-NMR, 13 C-NMR, and HR-MS. The antifungal activities of compounds 5 a-5 t were preliminarily tested by in vitro method, and the results indicated that all of the title compounds displayed certain antifungal activities against the eight tested plant fungi, especially for P. piricola. Among them, compound 5 i (R = p-F) with the most significant antifungal activity deserved further study for discovering and developing novel natural product-based antifungal agents. Moreover, two molecular simulation technologies were employed for the investigation of their structure-activity relationships (SARs). Firstly, a reasonable and effective 3D-QSAR model was established by the comparative molecular field (CoMFA) method, and the relationship of the substituents linked with the benzene rings and the inhibitory activities of the title compounds against P. piricola was elucidated. Then, the binding mode of compound 5 i (R = p-F) and its potential biological target (CYP51) was simulated by molecular docking, and it was found that compound 5 i could readily bind with CYP51 in the active site, and the ligand-receptor interactions involved three hydrogen bonds and several hydrophobic effects.

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

Abstract: We report the preparation and cytotoxicity of two new eugenol derivatives that contain 1,3,4-oxadiazole, as novel inhibitors of thymidylate synthase; these derivatives are shown to be promising chemotherapeutic agents.

Cited by 6 publications

References 46 publications

New paracetamol hybrids as anticancer and COX‐2 inhibitors: Synthesis, biological evaluation and docking studies

New paracetamol hybrids as anticancer and COX‐2 inhibitors: Synthesis, biological evaluation and docking studies

New Natural Eugenol Derivatives as Antiproliferative Agents: Synthesis, Biological Evaluation, and Computational Studies

Synthesis, Antifungal Activity, and Molecular Simulation Study of L–Carvone‐Derived 1,3,4‐Oxadiazole‐Thioether Compounds

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