C-C bond formation at C-2 of a quinoline ring: synthesis of 2-(1H-indol-3-yl)quinoline-3-carbonitrile derivatives as a new class of PDE4 inhibitors

K Shiva Kumar; S Kiran Kumar; B Yogi Sreenivas; Dhilli Rao Gorja; Ravikumar Kapavarapu; D Rambabu; G Rama Krishna; C Malla Reddy; M V Basaveswara Rao; Kishore V L Parsa; Manojit Pal

doi:10.1016/j.bmc.2012.02.027

C-C bond formation at C-2 of a quinoline ring: synthesis of 2-(1H-indol-3-yl)quinoline-3-carbonitrile derivatives as a new class of PDE4 inhibitors

Bioorg Med Chem. 2012 Apr 1;20(7):2199-207. doi: 10.1016/j.bmc.2012.02.027. Epub 2012 Feb 16.

Authors

K Shiva Kumar¹, S Kiran Kumar, B Yogi Sreenivas, Dhilli Rao Gorja, Ravikumar Kapavarapu, D Rambabu, G Rama Krishna, C Malla Reddy, M V Basaveswara Rao, Kishore V L Parsa, Manojit Pal

Affiliation

¹ Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.

PMID: 22386978
DOI: 10.1016/j.bmc.2012.02.027

Abstract

A number of 2-(1H-indol-3-yl)quinoline-3-carbonitrile derivatives were synthesized via AlCl(3)-mediated C-C bond forming reaction between 2-chloroquinoline-3-carbonitrile and various indoles. The methodology does not require any N-protection of the indoles employed and provided the corresponding products in good yields. The molecular structure of a representative compound was established unambiguously by single crystal X-ray diffraction and structural elaboration of a compound synthesized has been demonstrated. Many of these compounds synthesized showed PDE4 inhibitory properties in vitro. A brief structure-activity relationship studies within the series along with docking results of a representative compound (EC(50) ∼0.89 μM) is presented.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aluminum Chloride
Aluminum Compounds / chemistry
Binding Sites
Carbon / chemistry
Cell Proliferation / drug effects
Chlorides / chemistry
Computer Simulation
Crystallography, X-Ray
Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry*
Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
HEK293 Cells
Humans
Indoles / chemistry
Molecular Conformation
Phosphodiesterase 4 Inhibitors / chemical synthesis*
Phosphodiesterase 4 Inhibitors / chemistry
Phosphodiesterase 4 Inhibitors / pharmacology
Quinolines / chemical synthesis
Quinolines / chemistry*
Quinolines / pharmacology

Substances

Aluminum Compounds
Chlorides
Indoles
Phosphodiesterase 4 Inhibitors
Quinolines
Aluminum Chloride
Carbon
quinoline
Cyclic Nucleotide Phosphodiesterases, Type 4
2-chloroquinoline