Surrounding Chemical Space and Literature

SB-400868 (OSA_000812) fast facts

• First synthesized by GSK as a part of a series of ALK5 (TGFR1) inhibitors for fibrosis, Callahan et al., J. Med. Chem. 2002, 45, 999–1001 (DOI: 10.1021/jm010493y). The first author behind this original publication was able to make some comments about the project. Essentially the compounds were optimized for Alk-5 kinase inhibition, which quickly took the structures away (e.g. Gellibert et al., J. Med. Chem. 2004, 47, 4494–4506 (DOI: 10.1021/jm0400247)) from the starting point we are using in the OSA project (OSA_000812).
• Included in a computational study looking at a pharmacophore model for ALK inhibitors. Ren et al., Eur. J. Med. Chem. 2009, 44, 4259–4265 (DOI: 10.1016/j.ejmech.2009.07.008).
• This compound is included in the Published Kinase Inhibitor Set (PKIS).
• CHEMBL Compound Report Cards exist for the two relevant compounds (free amine and salt): CHEMBL1909377 and CHEMBL268889. The only kinases showing >30% inhibition are CK1a and (unsurprisingly) ALK5 (TGFR1).
• An easily-readable Google sheet containing kinase inhibition data for CHEMBL1909377 can be found here (all data exported from CHEMBL).

As synthetic chemistry proceeds, it is important to perform additional literature searches should we approach potential scaffold hops, and to re-evaluate kinase cross-reactivity.

Synthesis and Biological Activity of 4,5-Diaryl-imidazoles

1. Synthesis and biological activity of vicinal diaryl-substituted 1H-imidazoles - Bellina, F.; Cauteruccio, S.; Rossi, R. Tetrahedron, 2007, 63, 4571-4624.

Notes: Comprehensive review of the synthesis of all diaryl imidazole isomers and their biological activity. Most were active as kinase inhibitors, with some as COX-2 inhibitors. Only one paragraph reports antibacterial activity. The lead compound in this project came from one of the kinase projects out of SmithKline Beecham (SB) which later became GlaxoSmithKline (GSK). GSK has been active in tropical and neglected disease research- providing screens and libraries for some investigators. Other companies with examples in the chapter are Merck and RWJ.

2. Imidazoles as Promising Scaffolds for Antibacterial Activity: A Review - Rani, N.; Sharma, A.; Singh, R., Mini-Reviews in Medicinal Chemistry, 2013, 13, 1812-1835.

Notes: This review covers the field of substituted imidazoles as antibacterial agents, but it also includes the di(tri)aryl imidazoles as a subclass. In that regard, it intersects reference 1 and includes some of the compounds listed there, but also a number not covered by that review but which are still relevant. The review is limited sometimes by its references to levels of activity, i.e., not specific data.

3. Synthesis and antibacterial activity of novel and potent DNA gyrase inhibitors with azole ring - Tanitame, A.; Oyamada, Y.; Ofuji, K.; Fujimoto, M.; Suzuki, K.; Ueda, T.; Terauchi, H.; Kawasaki, M.; Nagai, K.; Wachi, M.; Yamagishi, J. Bioorg. Med. Chem., 2004, 12, 5515-5524.

Notes: This article describes the synthesis and evaluation of pyrazole, oxazole and imidazole derivatives as antibacterial agents. Of interest are the imidazole agents which are active at the 2-4µg/mL level against gram(-) and gram (+) bacteria as well as against MRSA and efflux pump mutants. A brief study suggests that these compounds may be inhibitors of DNA gyrase and/or Topoisomerase IV enzymes. The question is why no further studies were done if these compounds were easy to make and active.

4. Synthesis and antibacterial activity of a novel series of DNA gyrase inhibitors: 5-[(E)-2-arylvinyl]pyrazoles - Tanitame, A.; Oyamada, Y.; Ofuji, K.; Terauchi, H.; Kawasaki, M.; Wachi, M.; Yamaaguchi, J.-I., Bioorg. Med. Chem. Lett, 2005, 15, 4299-4303.

Notes: This is a follow-on to reference 3 using a similar scaffold but a different pendant group. Introduction of a vinyl group between the core heterocycle and the aromatic group gives compounds with similar but not significantly improved biological potency. Compounds are still moderately active against gram (-) and gram(+) organisms including resistant strains. Mechanism of action may be against DNA gyrase and Topoisomerase IV enzymes. This suggests that in exploring structural modifications based on the ALM technology, one could consider Arylvinyl boronic acids(esters) as well.

5. Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent - Velaparthi, U. et al, ACS Med. Chem. Lett. 2020, 11, 172−178.

Notes: Recent publication on TGF-R agents based on the diaryl imidazole motif. Contains relevant synthetic strategies and chemistry directed toward orally active drugs. Although this is targeted for eukaryotic cells, it may be possible to repurpose the scaffold by modifying the pendant groups. Screening this library for antibacterial activity may generate a lead.

Relevant Structures against other Pathogens

1. Collaborative virtual screening to elaborate an imidazo[1,2-a]pyridine hit series for visceral leishmaniasis, 2021

2. Synthesis and Structure−Activity Relationships of Imidazopyridine/Pyrimidine‐ and Furopyridine‐Based Anti‐infective Agents against Trypanosomiases, 2020

N-alkylated 2-(2-pyridyl)benzimidazoles (Chris Swain's Scaffold Hop described here)

Carbohydrate triazole tethered 2-pyridyl-benzimidazole ligands: Synthesis of their palladium (II) complexes and antimicrobial activities

"the ligands have displayed superior antimicrobial activity as compared to their corresponding metal complexes."