Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM)
| Autor: | Manojit Pal, Raghu Chandrashekhar Hariharapura, Gautham G. Shenoy, Ampalam Venkata Snehalatha, Parimal Misra, Rebecca Kristina Edwin, Varadaraj Bhat Giliyaru, Gangireddy Sujeevan Reddy, Kazi Amirul Hossain |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Indoles Stereochemistry In silico Pyrazole Ring (chemistry) 01 natural sciences Biochemistry Catalysis chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery Moiety Animals Enzyme Inhibitors Molecular Biology Indole test Molecular Structure 010405 organic chemistry Triazines Organic Chemistry Mycobacterium tuberculosis In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry RAW 264.7 Cells chemistry Chorismate mutase Copper Palladium Chorismate Mutase |
| Zdroj: | Bioorganic chemistry. 91 |
| ISSN: | 1090-2120 |
| Popis: | The chorismate mutase (CM) is considered as an attractive target for the identification of potential antitubercular agents due to its absence in animals but not in bacteria. A series of 3-indolylmethyl substituted pyrazolotriazinone derivatives were designed and docked into CM in silico as potential inhibitors. These compounds were efficiently synthesized using the Pd/Cu-catalyzed coupling-cyclization in a single pot involving the construction of indole ring. The methodology was later extended to the preparation of corresponding benzo analogs of pyrazolotriazinones i.e. 3-indolylmethyl substituted benzotriazinone derivatives. Several of these novel compounds showed significant inhibition of CM when tested in vitro at 30 µM. The SAR (Structure-Activity-Relationship) studies suggested that benzotriazinone moiety was more favorable over the pyrazolotriazinone ring. The two best active compounds showed IC50 ∼ 0.4–0.9 µM (better than the reference/known compounds used) and no toxicity till 30 µM in vitro. |
| Databáze: | OpenAIRE |
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