Indole–1,2,4-triazole hybrids as selective ERK inhibitors: Synthesis, anticancer evaluation, and molecular modeling
Bibliographic record
Abstract
A new series of structurally diverse indole–1,2,4-triazole derivatives was designed and synthesized through a thiolated triazole intermediate derived from indole-3-propionic acid. The final compounds, including S-acetamide, bis-indolyl, triazolothiadiazole, and triazolothiadiazine analogues (3–8), were confirmed by NMR, IR, MS, and elemental analysis. Their cytotoxicity was tested against breast (MCF-7), colon (HCT-116), and liver (HepG2) cancer cell lines, alongside normal BJ-1 fibroblasts, using the LDH assay. Several compounds, especially 3, 6b, 7a, 7c, and 8a,b showed potent and selective antiproliferative effects on MCF-7 and HCT-116 cells with IC50 values between 2.3 and 3.0 μM, outperforming doxorubicin nearly twofold under the same conditions. Mechanistic studies revealed a significant decrease in phosphorylated ERK (pERK) protein levels in MCF-7 cells, with compound 3b showing the strongest inhibition (3.499 ± 0.21 pg/mL), consistent with its IC50 (2.3 μg/mL). Molecular docking supported the strong binding affinity of 3b within the ERK active site (−9.0 kcal/mol), involving hydrogen bonding and hydrophobic interactions. In silico ADMET predictions confirmed favorable drug-likeness, oral bioavailability, and pharmacokinetic safety for this compound. Overall, compound 3b emerges as a promising lead for ERK-targeted anticancer drug development, supported by combined synthetic, biological, and computational evidence.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".