Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors
A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2023.2220579 |
| _version_ | 1827123324329656320 |
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| author | Eman A. Sobh Mohammed A. Dahab Eslam B. Elkaeed Aisha A. Alsfouk Ibrahim M. Ibrahim Ahmed M. Metwaly Ibrahim H. Eissa |
| author_facet | Eman A. Sobh Mohammed A. Dahab Eslam B. Elkaeed Aisha A. Alsfouk Ibrahim M. Ibrahim Ahmed M. Metwaly Ibrahim H. Eissa |
| author_sort | Eman A. Sobh |
| collection | DOAJ |
| description | A group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549’s growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFRWT and EGFRT790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety. |
| first_indexed | 2024-03-09T02:02:35Z |
| format | Article |
| id | doaj.art-318328a3c2e245ceb70a910f300bc6ba |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2025-03-20T14:23:07Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-318328a3c2e245ceb70a910f300bc6ba2024-09-09T17:23:18ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742023-12-0138110.1080/14756366.2023.2220579Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitorsEman A. Sobh0Mohammed A. Dahab1Eslam B. Elkaeed2Aisha A. Alsfouk3Ibrahim M. Ibrahim4Ahmed M. Metwaly5Ibrahim H. Eissa6Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Menoufia University, Menoufia, EgyptPharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptDepartment of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Riyadh, Saudi ArabiaDepartment of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi ArabiaBiophysics Department, Faculty of Science, Cairo University, Cairo, EgyptPharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptPharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, EgyptA group of EGFR inhibitors derived from thieno[2,3-d]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b, the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFRWT and EGFRT790M, respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549’s growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFRWT and EGFRT790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.https://www.tandfonline.com/doi/10.1080/14756366.2023.2220579Anti-proliferativeapoptosisEGFR inhibitorsMD simulationsthieno[2,3-d]pyrimidines |
| spellingShingle | Eman A. Sobh Mohammed A. Dahab Eslam B. Elkaeed Aisha A. Alsfouk Ibrahim M. Ibrahim Ahmed M. Metwaly Ibrahim H. Eissa Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry Anti-proliferative apoptosis EGFR inhibitors MD simulations thieno[2,3-d]pyrimidines |
| title | Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors |
| title_full | Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors |
| title_fullStr | Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors |
| title_full_unstemmed | Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors |
| title_short | Design, synthesis, docking, MD simulations, and anti-proliferative evaluation of thieno[2,3-d]pyrimidine derivatives as new EGFR inhibitors |
| title_sort | design synthesis docking md simulations and anti proliferative evaluation of thieno 2 3 d pyrimidine derivatives as new egfr inhibitors |
| topic | Anti-proliferative apoptosis EGFR inhibitors MD simulations thieno[2,3-d]pyrimidines |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2023.2220579 |
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