Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors
<b>Background/Objectives:</b> New indole/1,2,4-triazole hybrids were synthesized and tested for antiproliferative activity against the NCI 60 cell line as tubulin polymerization inhibitors. <b>Methods:</b> All final compounds, <b>6a</b>–<b>j</b> and &l...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/2/275 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849719821303808000 |
|---|---|
| author | Esraa Mahmoud Dalia Abdelhamid Anber F. Mohammed Zainab M. Almarhoon Stefan Bräse Bahaa G. M. Youssif Alaa M. Hayallah Mohamad Abdel-Aziz |
| author_facet | Esraa Mahmoud Dalia Abdelhamid Anber F. Mohammed Zainab M. Almarhoon Stefan Bräse Bahaa G. M. Youssif Alaa M. Hayallah Mohamad Abdel-Aziz |
| author_sort | Esraa Mahmoud |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> New indole/1,2,4-triazole hybrids were synthesized and tested for antiproliferative activity against the NCI 60 cell line as tubulin polymerization inhibitors. <b>Methods:</b> All final compounds, <b>6a</b>–<b>j</b> and <b>7a</b>–<b>j</b> were evaluated at a single concentration of 10 µM against a panel of sixty cancer cell lines. <b>Results:</b> Compounds <b>7a</b>–<b>j</b>, featuring the NO-releasing oxime moiety, exhibited superior anticancer activity to their precursor ketones <b>6a</b>–<b>j</b> across all tested cancer cell lines. Compounds <b>6h</b>, <b>7h</b>, <b>7i</b>, and <b>7j</b> were chosen for five-dose evaluations against a comprehensive array of 60 human tumor cell lines. The data showed that all tested compounds had significant anticancer activity throughout the nine tumor subpanels studied, with selectivity ratios ranging from 0.52 to 2.29 at the GI<sub>50</sub> level. Compounds <b>7h</b> and <b>7j</b> showed substantial anticancer effectiveness against most cell lines across nine subpanels, with GI<sub>50</sub> values ranging from 1.85 to 5.76 µM and 2.45 to 5.23 µM. Compounds <b>6h</b>, <b>7h</b>, <b>7i</b>, and <b>7j</b> were assessed for their inhibitory effects on tubulin polymerization. <b>Conclusions:</b> The results showed that compound <b>7i</b>, an oxime-based derivative, was the most effective at blocking tubulin, with an IC<sub>50</sub> value of 3.03 ± 0.11 µM. This was compared to the standard drug CA-4, which had an IC<sub>50</sub> value of 8.33 ± 0.29 µM. Additionally, cell cycle analysis and apoptosis assays were performed for compound <b>7i</b>. Molecular computational investigations have been performed to examine the binding mode of the most effective compounds to the target enzyme. |
| format | Article |
| id | doaj-art-4b6797ffb12d40c5a8a64afe86be3cb5 |
| institution | DOAJ |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-4b6797ffb12d40c5a8a64afe86be3cb52025-08-20T03:12:04ZengMDPI AGPharmaceuticals1424-82472025-02-0118227510.3390/ph18020275Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization InhibitorsEsraa Mahmoud0Dalia Abdelhamid1Anber F. Mohammed2Zainab M. Almarhoon3Stefan Bräse4Bahaa G. M. Youssif5Alaa M. Hayallah6Mohamad Abdel-Aziz7Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia 2460271, EgyptDepartment of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 2431436, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, EgyptDepartment of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi ArabiaInstitute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, 76131 Karlsruhe, GermanyDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, EgyptDepartment of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 2431436, Egypt<b>Background/Objectives:</b> New indole/1,2,4-triazole hybrids were synthesized and tested for antiproliferative activity against the NCI 60 cell line as tubulin polymerization inhibitors. <b>Methods:</b> All final compounds, <b>6a</b>–<b>j</b> and <b>7a</b>–<b>j</b> were evaluated at a single concentration of 10 µM against a panel of sixty cancer cell lines. <b>Results:</b> Compounds <b>7a</b>–<b>j</b>, featuring the NO-releasing oxime moiety, exhibited superior anticancer activity to their precursor ketones <b>6a</b>–<b>j</b> across all tested cancer cell lines. Compounds <b>6h</b>, <b>7h</b>, <b>7i</b>, and <b>7j</b> were chosen for five-dose evaluations against a comprehensive array of 60 human tumor cell lines. The data showed that all tested compounds had significant anticancer activity throughout the nine tumor subpanels studied, with selectivity ratios ranging from 0.52 to 2.29 at the GI<sub>50</sub> level. Compounds <b>7h</b> and <b>7j</b> showed substantial anticancer effectiveness against most cell lines across nine subpanels, with GI<sub>50</sub> values ranging from 1.85 to 5.76 µM and 2.45 to 5.23 µM. Compounds <b>6h</b>, <b>7h</b>, <b>7i</b>, and <b>7j</b> were assessed for their inhibitory effects on tubulin polymerization. <b>Conclusions:</b> The results showed that compound <b>7i</b>, an oxime-based derivative, was the most effective at blocking tubulin, with an IC<sub>50</sub> value of 3.03 ± 0.11 µM. This was compared to the standard drug CA-4, which had an IC<sub>50</sub> value of 8.33 ± 0.29 µM. Additionally, cell cycle analysis and apoptosis assays were performed for compound <b>7i</b>. Molecular computational investigations have been performed to examine the binding mode of the most effective compounds to the target enzyme.https://www.mdpi.com/1424-8247/18/2/275NCIcancerCA-4tubulincolchicineanticancer |
| spellingShingle | Esraa Mahmoud Dalia Abdelhamid Anber F. Mohammed Zainab M. Almarhoon Stefan Bräse Bahaa G. M. Youssif Alaa M. Hayallah Mohamad Abdel-Aziz Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors Pharmaceuticals NCI cancer CA-4 tubulin colchicine anticancer |
| title | Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors |
| title_full | Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors |
| title_fullStr | Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors |
| title_full_unstemmed | Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors |
| title_short | Design, Synthesis, and Antiproliferative Activity of Novel Indole/1,2,4-Triazole Hybrids as Tubulin Polymerization Inhibitors |
| title_sort | design synthesis and antiproliferative activity of novel indole 1 2 4 triazole hybrids as tubulin polymerization inhibitors |
| topic | NCI cancer CA-4 tubulin colchicine anticancer |
| url | https://www.mdpi.com/1424-8247/18/2/275 |
| work_keys_str_mv | AT esraamahmoud designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors AT daliaabdelhamid designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors AT anberfmohammed designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors AT zainabmalmarhoon designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors AT stefanbrase designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors AT bahaagmyoussif designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors AT alaamhayallah designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors AT mohamadabdelaziz designsynthesisandantiproliferativeactivityofnovelindole124triazolehybridsastubulinpolymerizationinhibitors |