Synthesis and Biological Evaluation of Novel Thiazole Analogs with Both Anti‐Proliferative and Mechanistic Analyses and Molecular Docking Studies

Bimoussa, Abdoullah; Oubella, Ali; Mansouri, Az-Eddine El; Fawzi, Mourad; Laamari, Yassine; Itto, My Youssef Ait; Morjani, Hamid; Auhmani, Aziz

doi:10.1002/slct.202104270

Cited by 10 publications

(3 citation statements)

References 51 publications

(46 reference statements)

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“…These results indicate that these compounds possess a considerable and selective cytotoxic activity toward breast cancer cell lines, with a low cytotoxic effect on the epithelial breast cells. Our results are in accordance with previously reported studies, which showed that 1,3-thiazole compounds are potent antiproliferative agents [ 48 , 49 , 50 , 51 , 52 , 53 ]. Among different investigated compounds, compounds 3c and 4 demonstrated the most potent anticancer activity toward the examined MCF-7 breast cancer cell line, with an IC 50 = 13.66 µM and 5.73 µM, respectively, compared to STU, with anIC 50 of 6.77 µM ( Figure 4 ).…”

Section: Resultssupporting

confidence: 94%

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

et al. 2022

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Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.

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Section: Resultssupporting

confidence: 94%

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

et al. 2022

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“…The YASARA dynamics version 18.4.24.W.64 simulations were carried out with MD. [ 52 ] They were run in an explicit water environment for 137 ns, using the AMBER‐14 force field with constant pressure and simulated temperature of 298 K. For the first time, a MD simulation has been performed at constant temperatures and pressures for 137 ns following a balance, and MD trajectory snapshots were kept every 100 ppm for subsequent examination for a duration of 2 ns. MD simulations include RMSF, root‐medium‐square deviation (RMSD), radon (Rg), solvent surface accessible (SASA), and RMSD ligand motion when overlaid on the receiver.…”

Section: Methodsmentioning

confidence: 99%

Novel isoxazoline‐linked 1,3,4‐thiadiazole hybrids as anticancer agents: Design, synthesis, biological evaluation, molecular docking, and molecular dynamics simulation

Oubella

Byadi

Bimoussa

et al. 2022

Archiv der Pharmazie

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In the current study, natural (R)‐carvone was utilized as a starting material for the efficient synthesis of two series of isoxazoline derivatives bearing the 1,3,4‐thiadiazole moiety. The new compounds were obtained in good yields and were characterized by 1H and 13C NMR and HRMS analysis. The newly synthesized monoterpenic isoxazoline 1,3,4‐thiadiazole and their thiosemicarbazone intermediate derivatives were evaluated for their anticancer activity in four cancer cell lines (HT‐1080, A‐549, MCF‐7, and MDA‐MB‐231). Most of the synthesized compounds exhibited moderate to high anticancer effects. Compound 13c showed the highest anticancer activity with IC50 values ranging from 19.33 ± 1.81 to 34.81 ± 3.03 µM. Further investigation revealed that compounds 12e and 13c could inhibit the cell growth of HT‐1080 and MCF‐7 cells by inducing apoptosis through caspase‐3/7 activation. The apoptotic effect was accompanied by an S phase and G2/M cell cycle arrest for 13c and 12e, respectively. Compounds 12e and 13c were assessed in silico using molecular docking and molecular dynamics. We found that compound 13c is moderately active against the caspase‐3 protein, which triggers apoptosis via intrinsic and extrinsic routes, making compound 13c a promising candidate to activate the proapoptotic protein (caspase‐3).

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“…Also, they are considered as starting material for the development of new drugs especially anti-cancer agents. For this reason, many compounds with anticancer activity have been designed by hybridization, bearing at least two or more pharmacophores in one chemical structure [1][2][3][4][5][6] Hybrid molecules incorporating five membered nitrogen and oxygen containing heterocycles were found to be particularly effective in terms of enhancing biological activities, when compared to that of individual pharmacophores. [7][8][9] These heterocycles include triazoles and isoxazoles which are absolutely a major class of nitrogen and oxygen containing five-membered heterocycles in drug design.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Cytotoxic Effect Evaluation and Molecular Docking of (R)‐Camphor‐Based Thiazolidinone‐Isoxazole and Thiazolidinone‐1,2,3‐triazole Hybrids“

et al. 2023

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A variety of hybrid compounds, combining a camphor thiazolidinone skeleton with either 1,2,3‐triazole or isoxazole nucleus, have been synthesized from natural (R)‐camphor. Our efficient procedure consists in a transformation of the (R)‐camphor into the corresponding thiazolidin‐4‐one. The latter is then N‐alkylated with propargyl bromide before submitting the resulting product to 1,3‐dipolar cycloaddition reactions, with a series of nitrile oxides and arylazides respectively. The chemical structures of all the newly synthesized hybrids were established using (1H and 13C) NMR and HRMS analysis. Preliminary in‐vitro cytotoxic assays on three human cancer cell lines MCF‐7 (breast), A‐549 (prostate) and HT‐1080 (fibrosarcoma) were performed on all the compounds. The thiazolidinone‐1,2,3‐isoxazole hybrid 8 c was revealed to be the most active with IC50 values ranging from 11.62±4.52 μM to 16.92±1.22 μM against selected cancer cells. Molecular docking studies carried out on the three compounds 8 c, 9 a and 9 c, confirmed, as expected, that these compounds possess a great inhibition potential against BCl‐2 protein, Caspase‐3 and COX‐2 enzymes. The results showed that the selected compounds had a significant binding property which could lead to the development of novel BCl‐2, Caspase‐3 and −2 inhibitors with improved selectivity. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti‐inflammatory agent.

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Synthesis and Biological Evaluation of Novel Thiazole Analogs with Both Anti‐Proliferative and Mechanistic Analyses and Molecular Docking Studies

Cited by 10 publications

References 51 publications

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study

Novel isoxazoline‐linked 1,3,4‐thiadiazole hybrids as anticancer agents: Design, synthesis, biological evaluation, molecular docking, and molecular dynamics simulation

Design, Synthesis, Cytotoxic Effect Evaluation and Molecular Docking of (R)‐Camphor‐Based Thiazolidinone‐Isoxazole and Thiazolidinone‐1,2,3‐triazole Hybrids“

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