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Structure–Activity Relationship of N-Phenylthieno[2,3-b]pyridine-2-carboxamide Derivatives Designed as Forkhead Box M1 Inhibitors: The Effect of Electron-Withdrawing and Donating Substituents on the Phenyl Ring

Authors :
César Sebastian Huerta-García
David J. Pérez
Carlos A. Velázquez-Martínez
Seyed Amirhossein Tabatabaei Dakhili
Antonio Romo-Mancillas
Rafael Castillo
Alicia Hernández-Campos
Source :
Pharmaceuticals, Vol 15, Iss 3, p 283 (2022)
Publication Year :
2022
Publisher :
MDPI AG, 2022.

Abstract

We report synthesis, characterization, biological evaluation, and molecular-docking studies of 18 thieno[2,3-b]pyridines with a phenylacetamide moiety at position 2, which is disubstituted with F, Cl, Br, or I at position 4, and with electron-withdrawing and electron-donating groups (-CN, -NO2, -CF3, and -CH3) at position 2, to study how the electronic properties of the substituents affected the FOXM1-inhibitory activity. Among compounds 1–18, only those bearing a -CN (regardless of the halogen) decreased FOXM1 expression in a triple-negative breast cancer cell line (MDA-MB-231), as shown by Western blotting. However, only compounds 6 and 16 decreased the relative expression of FOXM1 to a level lower than 50%, and hence, we determined their anti-proliferative activity (IC50) in MDA-MB-231 cells using the MTT assay, which was comparable to that observed with FDI-6, in contrast to compound 1, which was inactive according to both Western blot and MTT assays. We employed molecular docking to calculate the binding interactions of compounds 1–18 in the FOXM1 DNA-binding site. The results suggest a key role for residues Val296 and Leu289 in this binding. Furthermore, we used molecular electrostatic potential maps showing the effects of different substituents on the overall electron density.

Details

Language :
English
ISSN :
14248247 and 12500070
Volume :
15
Issue :
3
Database :
Directory of Open Access Journals
Journal :
Pharmaceuticals
Publication Type :
Academic Journal
Accession number :
edsdoj.9b1f37ab697c41fdbe4b1250007097b7
Document Type :
article
Full Text :
https://doi.org/10.3390/ph15030283