Issue 5, 2015
From the journal:

MedChemComm

Novel pyrrole derivatives as selective CHK1 inhibitors: design, regioselective synthesis and molecular modeling†

Taha M. A. Eldebss,a   Sobhi M. Gomha,a   Mohamed M. Abdullab  and  Reem K. Arafa*cd  

* Corresponding authors

a Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

b Research Unit, Saco Pharm. Co., 6th October City, Egypt

c Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, 11562 Giza, Egypt
E-mail: reem.arafa@pharma.cu.edu.eg
Tel: +2 0100 2074028

d Biomedical Sciences Department, University of Science and Technology, Zewail City of Science and Technology, 12588 Giza, Egypt

Abstract

An efficient synthesis of hitherto unreported 3-heteroaryl-pyrroles was described via regioselective 1,3-dipolar cycloaddition reactions of enaminone2 or 3 with nitrilimines 5a–j to afford the corresponding pyrazole derivatives 7a–j. Hydrazinolysis of 7a–f yielded the respective pyrazolo[3,4-d]pyridazines 10a–f. Furthermore, pyrrole analogs substituted on the 3-position with pyranone (14), benzofuran (16) or naphthofuran (18) were also synthesized. The structures of the synthesized compounds were determined by spectral, elemental analyses and alternative syntheses wherever possible. The synthesized compounds were evaluated for their protein kinase inhibitory activities against 25 kinases belonging to 4 kinase groups viz. AGC (5 kinases), CAMK (5 kinases), CMGC (4 kinases) and TK (11 kinases). While the tested compounds were found to be good inhibitors of VEGFR-2 and EGFR, exhibiting low micromolar IC50 values, they were selectively more potent against CHK1 eliciting a potent inhibitory effect with IC50 values in the submicromolar range. Finally, docking studies were performed to interpret the possible binding mode of the target compounds with CHK1.

Graphical abstract: Novel pyrrole derivatives as selective CHK1 inhibitors: design, regioselective synthesis and molecular modeling

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DOI
https://doi.org/10.1039/C4MD00560K
Article type
Concise Article
Submitted
14 Dec 2014
Accepted
17 Feb 2015
First published
17 Feb 2015

Med. Chem. Commun., 2015,6, 852-859

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Novel pyrrole derivatives as selective CHK1 inhibitors: design, regioselective synthesis and molecular modeling

T. M. A. Eldebss, S. M. Gomha, M. M. Abdulla and R. K. Arafa, Med. Chem. Commun., 2015, 6, 852 DOI: 10.1039/C4MD00560K

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