New series of isoxazole derivatives targeting EGFR-TK: Synthesis, molecular modeling and antitumor evaluation

Warda, Eman T.; Shehata, Ihsan A.; El‐Ashmawy, Mahmoud B.; El‐Gohary, Nadia S.

doi:10.1016/j.bmc.2020.115674

Cited by 25 publications

(12 citation statements)

References 71 publications

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“…The series of novel isoxazole derivatives, morpholinyl propionamides, and piperazinyl propionamides were evaluated to determine their in vitro antitumor activity against HepG2, MCF-7, and HCT-116. Cell death was shown to occur mainly through apoptosis (supported by increased levels of caspases 3/9 and an increased Bax/Bcl-2 ratio) [16]. Moreover, 4,5,6,7-tetrahydro-isoxazole-[4,5-c]-pyridine derivatives showed significant antiproliferative and pro-apoptotic effects inducing both the early and late apoptosis of leukemic cell line K562 [17].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Study of Immunological Isoxazole Derivatives as a Potential Support for Melanoma Chemotherapy

Jęśkowiak

Wiatrak

Szeląg

et al. 2021

IJMS

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(1) Background: Melanoma is an aggressive neoplasm derived from melanocyte precursors with a high metastatic potential. Responses to chemotherapy and immunotherapy for melanoma remain weak, underlining the urgent need to develop new therapeutic strategies for the treatment of melanoma. (2) Methods: The viability of NHDF and A375 cell cultures after the administration of the tested isoxazole derivatives was assessed after 24-h and 48-h incubation periods with the test compounds in the MTT test. ROS and NO scavenging analyses, a glycoprotein-P activity analysis, a migration assay, a test of apoptosis, and a multiple-criteria decision analysis were also performed. (3) Results: All compounds that were tested resulted in a slower migration of melanoma neoplastic cells. The mechanism of the antitumor activity of the tested compounds was confirmed—i.e., the pro-apoptotic activity of the compounds in A375 cell cultures. Compound O7K qualified for further research. (4) Conclusions: All the tested compounds inhibited the formation of melanoma metastases and demonstrated the ability to reduce the risk of developing drug resistance in the tumor. The MCDA results showed that O7K showed the strongest antitumor activity.

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Section: Discussionmentioning

confidence: 99%

Preclinical Study of Immunological Isoxazole Derivatives as a Potential Support for Melanoma Chemotherapy

Jęśkowiak

Wiatrak

Szeląg

et al. 2021

IJMS

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Section: Introductionmentioning

confidence: 99%

“…[34] Moreover, Eman and coworkers investigated the synthesis of a new isoxazoline 4, which has been reported to have potential antitumor activity by targeting EGFR kinase function. [35] Similarly, a set of isoxazoline derivatives (compound 5 as an example) have been developed and investigated for their biological properties by Chaitanya et al They demonstrated that such compounds were able to induce apoptosis through DNA strand breaks and PARP1 cleavage. [36] According to these findings and to continue our efforts to discover other derivatives of monoterpenes and nucleoside analogs, which could also have interesting biological properties, [37][38][39][40] we report here the synthesis of new heterocyclic system hybrids incorporating isoxazoline and 1,3,4-thiadiazole, using 1,3-dipolar cycloaddition reaction.…”

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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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“…Isoxazole heterocycle [1] is tagged as a privileged motif owing to its representation in a variety of pharmacologically active compounds displaying bioactivities such as allosteric RORγt inverse agonist, [2] antimalarial, [3] antileishmanial, [4] σ2 receptor ligand, [5] EGFR‐TK inhibitor for cancer, [6] FLT3 inhibitors for acute myeloid leukemia [7] and antiviral agents [8] . Additionally, isoxazole derivatives form part of several agrochemicals, [9] advanced organic materials, [10] and serve as intermediates in organic synthesis for preparing chemically useful compounds [11] .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Substituted 3‐Isoxazolethioethers as Antileishmanial and Antibacterial Agents

et al. 2022

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The synthesis of substituted 3-isoxazolethioethers and their bioevaluation as anti-leishmanial and anti-bacterial agents are described. The DBU-catalyzed thioetherification of substituted 3-nitroisoxazoles via nucleophilic aromatic substitution (S N Ar) reaction using aromatic, aliphatic and heteroaromatic thiols gave the title compounds in good yields. These 3-thioisoxazole derivatives were synthetically modified to prepare new com- ,4]thiazepin-4(5H)-ones. Four compounds displayed promising activity against amastigote stage of L. donovani whereas two compounds displayed good antibacterial effect.

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New series of isoxazole derivatives targeting EGFR-TK: Synthesis, molecular modeling and antitumor evaluation

Cited by 25 publications

References 71 publications

Preclinical Study of Immunological Isoxazole Derivatives as a Potential Support for Melanoma Chemotherapy

Preclinical Study of Immunological Isoxazole Derivatives as a Potential Support for Melanoma Chemotherapy

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

Synthesis and Biological Evaluation of Substituted 3‐Isoxazolethioethers as Antileishmanial and Antibacterial Agents

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