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...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/2/275 |
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| Summary: | <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. |
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| ISSN: | 1424-8247 |