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 journalArticle

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

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Chorismate Mutase
Catalysis
Derivatives
Antitubercular Agents
Cyclization
Structure-Activity Relationship
Computer Simulation
Inhibitory Concentration 50
Toxicity
Bacteria
Animals
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Drug Discovery
  • Organic Chemistry

Cite this

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title = "Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM)",
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.",
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Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis : Identification of potent inhibitors of chorismate mutase (CM). / Reddy, Gangireddy Sujeevan; Snehalatha, Ampalam Venkata; Edwin, Rebecca Kristina; Hossain, Kazi Amirul; Giliyaru, Varadaraj Bhat; Hariharapura, Raghu Chandrashekhar; Gautham Shenoy, G.; Misra, Parimal; Pal, Manojit.

In: Bioorganic Chemistry, Vol. 91, 103155, 01.10.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis

T2 - Identification of potent inhibitors of chorismate mutase (CM)

AU - Reddy, Gangireddy Sujeevan

AU - Snehalatha, Ampalam Venkata

AU - Edwin, Rebecca Kristina

AU - Hossain, Kazi Amirul

AU - Giliyaru, Varadaraj Bhat

AU - Hariharapura, Raghu Chandrashekhar

AU - Gautham Shenoy, G.

AU - Misra, Parimal

AU - Pal, Manojit

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

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