New Bioactive Fused Triazolothiadiazoles as Bcl-2-Targeted Anticancer Agents
A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (<b>5a</b>–<b>l</b>) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a rea...
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| Main Authors: | , , , , , , , |
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| Format: | article |
| Language: | EN |
| Published: |
MDPI AG
2021
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| Subjects: | |
| Online Access: | https://doaj.org/article/af2a65ec3d3641878ea076cea3f09a8a |
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| Summary: | A series of 3-(6-substituted phenyl-[1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazol-3-yl)-1H-indoles (<b>5a</b>–<b>l</b>) were designed, synthesized and evaluated for anti-apoptotic Bcl-2-inhibitory activity. Synthesis of the target compounds was readily accomplished through a reaction of acyl hydrazide (<b>1</b>) with carbon disulfide in the presence of alcoholic potassium hydroxide to afford the corresponding intermediate potassium thiocarbamate salt (<b>2</b>), which underwent cyclization reaction in the presence of excess hydrazine hydrate to the corresponding triazole thiol (<b>3</b>). Further cyclisation reaction with substituted benzoyl chloride derivatives in the presence of phosphorous oxychloride afforded the final 6-phenyl-indol-3-yl [1,2,4]-triazolo[3,4-b]-[1,3,4]-thiadiazole compounds (<b>5a</b>–<b>l</b>). The novel series showed selective sub-micromolar IC<sub>50</sub> growth-inhibitory activity against Bcl-2-expressing human cancer cell lines. The most potent 6-(2,4-dimethoxyphenyl) substituted analogue (<b>5k</b>) showed selective IC<sub>50</sub> values of 0.31–0.7 µM against Bcl-2-expressing cell lines without inhibiting the Bcl-2-negative cell line (Jurkat). ELISA binding affinity assay (interruption of Bcl-2-Bim interaction) showed potent binding affinity for (<b>5k</b>) with an IC<sub>50</sub> value of 0.32 µM. Moreover, it fulfils drug likeness criteria as a promising drug candidate. |
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