Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM)

Gangireddy Sujeevan Reddy, Ampalam Venkata Snehalatha, Rebecca Kristina Edwin, Kazi Amirul Hossain, Varadaraj Bhat Giliyaru, Raghu Chandrashekhar Hariharapura, G. Gautham Shenoy, Parimal Misra, Manojit Pal

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number103155
JournalBioorganic Chemistry
Volume91
DOIs
Publication statusPublished - 01-10-2019

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

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