1. Pharmacological Potential and Synthetic Approaches of Imidazo[4,5-b]pyridine and Imidazo[4,5-c]pyridine Derivatives
Malwina Krause, Henryk Foks, Katarzyna Gobis Molecules. 2017 Mar 4;22(3):399. doi: 10.3390/molecules22030399.
The structural resemblance between the fused imidazopyridine heterocyclic ring system and purines has prompted biological investigations to assess their potential therapeutic significance. They are known to play a crucial role in numerous disease conditions. The discovery of their first bioactivity as GABAA receptor positive allosteric modulators divulged their medicinal potential. Proton pump inhibitors, aromatase inhibitors, and NSAIDs were also found in this chemical group. Imidazopyridines have the ability to influence many cellular pathways necessary for the proper functioning of cancerous cells, pathogens, components of the immune system, enzymes involved in carbohydrate metabolism, etc. The collective results of biochemical and biophysical properties foregrounded their medicinal significance in central nervous system, digestive system, cancer, inflammation, etc. In recent years, new preparative methods for the synthesis of imidazopyridines using various catalysts have been described. The present manuscript to the best of our knowledge is the complete compilation on the synthesis and medicinal aspects of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines reported from the year 2000 to date, including structure-activity relationships.
2. New polyfunctional imidazo[4,5-C]pyridine motifs: synthesis, crystal studies, docking studies and antimicrobial evaluation
Gilish Jose, T H Suresha Kumara, Gopalpur Nagendrappa, H B V Sowmya, Jerry P Jasinski, Sean P Millikan, N Chandrika, Sunil S More, B G Harish Eur J Med Chem. 2014 Apr 22;77:288-97. doi: 10.1016/j.ejmech.2014.03.019. Epub 2014 Mar 11.
New antimicrobial agents, imidazo[4,5-c]pyridine derivatives have been synthesized. We have developed a new synthetic protocol for the final reaction, an efficient microwave-assisted synthesis of imidazo[4,5-c]pyridines from substituted 3,4-diaminopyridine and carboxylic acids in presence of DBU mediated by T3P. The chemical structures of the new compounds were characterized by IR, (1)H NMR, (13)C NMR, mass spectral analysis and elemental analysis. In addition, single crystal X-ray diffraction has also been recorded for compound 9c. The in vitro antimicrobial activities of the compounds were conducted against various Gram-negative, Gram-positive bacteria and fungi. Amongst the tested compounds 9c, 9e, 9g, 9k and 9l displayed promising antimicrobial activity. The molecular docking of GlcN-6-P synthase with newly synthesized compounds was carried out.
3. 1,4,6-Trisubstituted imidazo[4,5-c]pyridines as inhibitors of Bruton's tyrosine kinase
Soňa Krajčovičová, Radek Jorda, David Vanda, Miroslav Soural, Vladimír Kryštof Eur J Med Chem. 2021 Feb 5;211:113094. doi: 10.1016/j.ejmech.2020.113094. Epub 2020 Dec 9.
Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.
