InCl 3 mediated heteroarylation of indoles and their derivatization via C[sbnd]H activation strategy

Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis

Rajnikanth Sunke, Ramudu Bankala, B. Thirupataiah, E. V.V.Shivaji Ramarao, Jetta Sandeep Kumar, Hari Maduri Doss, Raghavender Medishetti, Pushkar Kulkarni, Ravi Kumar Kapavarapu, Mahaboobkhan Rasool, Jayesh Mudgal, Jessy E. Mathew, Gautham G. Shenoy, Kishore V.L. Parsa, Manojit Pal

Research output: Contribution to journalArticle

Abstract

A new class of PDE4 inhibitors were designed and synthesized via the InCl 3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed C[sbnd]H activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC 50 = 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively)showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE)model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints)as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity)in Zebrafish.

Original languageEnglish
Pages (from-to)198-215
Number of pages18
JournalEuropean Journal of Medicinal Chemistry
Volume174
DOIs
Publication statusPublished - 15-07-2019

Fingerprint

Indoles
Quinoxalines
Zebrafish
Multiple Sclerosis
Arthritis
Rats
Chemical activation
Phosphodiesterase 4 Inhibitors
Derivatives
Experimental Arthritis
Autoimmune Experimental Encephalomyelitis
Knee Joint
Gene expression
Toxicity
Disease Progression
Inflammation
Gene Expression
Messenger RNA
Cardiotoxicity
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Sunke, Rajnikanth ; Bankala, Ramudu ; Thirupataiah, B. ; Ramarao, E. V.V.Shivaji ; Kumar, Jetta Sandeep ; Doss, Hari Maduri ; Medishetti, Raghavender ; Kulkarni, Pushkar ; Kapavarapu, Ravi Kumar ; Rasool, Mahaboobkhan ; Mudgal, Jayesh ; Mathew, Jessy E. ; Shenoy, Gautham G. ; Parsa, Kishore V.L. ; Pal, Manojit. / InCl 3 mediated heteroarylation of indoles and their derivatization via C[sbnd]H activation strategy : Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 174. pp. 198-215.
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abstract = "A new class of PDE4 inhibitors were designed and synthesized via the InCl 3 mediated heteroarylation of indoles and their further derivatization through the Pd(II)-catalyzed C[sbnd]H activation strategy. This effort allowed us to discover a series of 2-(1H-indol-3-yl)-quinoxaline based inhibitors possessing PDE4B selectivity over PDE4D and PDE4C. One of these compounds i.e. 3b (PDE4B IC 50 = 0.39 ± 0.13 μM with ∼27 and > 250 fold selectivity for PDE4B over PDE4D and C, respectively)showed effects in Zebrafish experimental autoimmune encephalomyelitis (EAE)model of multiple sclerosis when dosed at 3, 10 and 30 mg/kg intraperitoneally. Indeed, it halted the progression of the disease across all these doses tested. At an intraperitoneal dose of 30 mg/kg the compound 3b showed promising effects in adjuvant induced arthritic rats. The compound reduced paw volume, inflammation and pannus formation (in the knee joints)as well as pro-inflammatory gene expression/mRNA levels significantly in arthritic rats. Moreover, this compound was found to be selective towards PDE4 over other families of PDEs in vitro and safe when tested for its probable toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity)in Zebrafish.",
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InCl 3 mediated heteroarylation of indoles and their derivatization via C[sbnd]H activation strategy : Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis. / Sunke, Rajnikanth; Bankala, Ramudu; Thirupataiah, B.; Ramarao, E. V.V.Shivaji; Kumar, Jetta Sandeep; Doss, Hari Maduri; Medishetti, Raghavender; Kulkarni, Pushkar; Kapavarapu, Ravi Kumar; Rasool, Mahaboobkhan; Mudgal, Jayesh; Mathew, Jessy E.; Shenoy, Gautham G.; Parsa, Kishore V.L.; Pal, Manojit.

In: European Journal of Medicinal Chemistry, Vol. 174, 15.07.2019, p. 198-215.

Research output: Contribution to journalArticle

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T1 - InCl 3 mediated heteroarylation of indoles and their derivatization via C[sbnd]H activation strategy

T2 - Discovery of 2-(1H-indol-3-yl)-quinoxaline derivatives as a new class of PDE4B selective inhibitors for arthritis and/or multiple sclerosis

AU - Sunke, Rajnikanth

AU - Bankala, Ramudu

AU - Thirupataiah, B.

AU - Ramarao, E. V.V.Shivaji

AU - Kumar, Jetta Sandeep

AU - Doss, Hari Maduri

AU - Medishetti, Raghavender

AU - Kulkarni, Pushkar

AU - Kapavarapu, Ravi Kumar

AU - Rasool, Mahaboobkhan

AU - Mudgal, Jayesh

AU - Mathew, Jessy E.

AU - Shenoy, Gautham G.

AU - Parsa, Kishore V.L.

AU - Pal, Manojit

PY - 2019/7/15

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