Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway

Al-Wahaibi, Lamya H.; Mahmoud, Mohamed; Mostafa, Yaser A.; Raslan, Ali E.; Youssif, Bahaa G.M.

doi:10.1080/14756366.2022.2151593

Cited by 23 publications

(19 citation statements)

References 38 publications

(36 reference statements)

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“…The key intermediates, 3-cyano-4,6-bis(phenyl)-pyridones 7a–c , were efficiently synthesized using a one-pot four-component reaction without any solvent. Equimolar amounts of the appropriately substituted benzaldehydes 2b, 2c , or 2f ; the substituted acetophenones 5a, 5b, or 5c ; ethyl cyanoacetate; and ammonium acetate were directly stirred at 110 °C for 10–15 min, resulting in the formation of the target compounds in high yields ( Scheme 2 ) [ 55 ]. The sequential two-step reaction, which involved condensing benzaldehydes with acetophenones and then treating the resulting chalcones with ethyl cyanoacetate and excess ammonium acetate, resulted in a lower yield and a more time-consuming process.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways

Al-Wahaibi,

Abou-Zied,

Hisham

et al. 2023

Molecules

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A series of novel 3-cyanopyridone/pyrazoline hybrids (21–30) exhibiting dual inhibition against EGFR and BRAFV600E has been developed. The synthesized target compounds were tested in vitro against four cancer cell lines. Compounds 28 and 30 demonstrated remarkable antiproliferative activity, boasting GI50 values of 27 nM and 25 nM, respectively. These hybrids exhibited dual inhibitory effects on both EGFR and BRAFV600E pathways. Compounds 28 and 30, akin to Erlotinib, displayed promising anticancer potential. Compound 30 emerged as the most potent inhibitor against cancer cell proliferation and BRAFV600E. Notably, both compounds 28 and 30 induced apoptosis by elevating levels of caspase-3 and -8 and Bax, while downregulating the antiapoptotic Bcl2 protein. Molecular docking studies confirmed the potential of compounds 28 and 30 to act as dual EGFR/BRAFV600E inhibitors. Furthermore, in silico ADMET prediction indicated that most synthesized 3-cyanopyridone/pyrazoline hybrids exhibit low toxicity and minimal adverse effects.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways

Al-Wahaibi,

Abou-Zied,

Hisham

et al. 2023

Molecules

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“…The results were extremely encouraging in comparison to the cellular proteins used in this study. Molecular docking investigations of the EGFR (PDB ID: 1M17) and CDK2 (PDB ID: 1PYE) crystal structures and binding modes were performed using the Discovery Studio software (Al‐Wahaibi et al., 2023; Ibrahim et al., 2020; Shaykoon et al., 2020). Table S1 shows the energy of binding interactions as well as the root‐mean square deviations.…”

Section: Methodsmentioning

confidence: 99%

New pyrrolidine‐carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

Frejat,

Zhao,

Furaijit

et al. 2023

Chem Biol Drug Des

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Cancer is one of the leading causes of mortality worldwide, making it a public health concern. A novel series of pyrrolidine‐carboxamide derivatives 7a‐q were developed and examined in a cell viability assay utilizing a human mammary gland epithelial cell line (MCF‐10A), where all the compounds exhibited no cytotoxic effects and more than 85% cell viability at a concentration of 50 μM. Antiproliferative activity was evaluated in vitro against four panels of cancer cell lines A‐549, MCF‐7, Panc‐1, and HT‐29. Compounds 7e, 7g, 7k, 7n, and 7o were the most active as antiproliferative agents capable of triggering apoptosis. Compound 7g was the most potent of all the derivatives, with a mean IC50 of 0.90 μM compared to IC50 of 1.10 μM for doxorubicin. Compound 7g inhibited A‐549 (epithelial cancer cell line), MCF‐7 (breast cancer cell line), and HT‐29 (colon cancer cell line) more efficiently than doxorubicin. EGFR inhibitory assay results of 7e, 7g, 7k, 7n, and 7o demonstrated that the tested compounds inhibited EGFR with IC50 values ranging from 87 to 107 nM in comparison with the reference drug erlotinib (IC50 = 80 nM). 7e, 7g, 7k, 7n, and 7o inhibited CDK2 efficiently in comparison to the reference dinaciclib (IC50 = 20 nM), with IC50 values ranging from 15 to 31 nM. The results of inhibitory activity assay against different CDK isoforms revealed that the tested compounds had preferential inhibitory activity against the CDK2 isoform.

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“…Motivated by the promising anti-cancer activity of some benzimidazole-based derivatives and as part of our ongoing effort to develop a dual or multi-targeted anti-cancer agent [ 28 , 29 , 30 , 31 , 32 , 33 ], we present here the design, synthesis, and antiproliferative activity of a novel series of benzimidazole-based derivatives ( 4a – j , 5 , and 6 , Figure 2 ). NCI chose all newly synthesized compounds for an in vitro one-dose inhibitory experiment against a panel of 60 cancer cell lines.…”

Section: Introductionmentioning

confidence: 99%

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies

Youssif,

Morcoss,

Bräse

et al. 2024

Molecules

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A new class of benzimidazole-based derivatives (4a–j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a–j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.

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Novel piperine-carboximidamide hybrids: design, synthesis, and antiproliferative activity via a multi-targeted inhibitory pathway

Cited by 23 publications

References 38 publications

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways

Design, Synthesis, and Biological Evaluation of Novel 3-Cyanopyridone/Pyrazoline Hybrids as Potential Apoptotic Antiproliferative Agents Targeting EGFR/BRAFV600E Inhibitory Pathways

New pyrrolidine‐carboxamide derivatives as dual antiproliferative EGFR/CDK2 inhibitors

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies

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