Synthesis and Evaluation of Chiral Rhodanine Derivatives Bearing Quinoxalinyl Imidazole Moiety as ALK5 Inhibitors.

BACKGROUND

TGF-β signaling pathway inhibition is considered an effective way to prevent the development of several diseases. In the design and synthesis of TGF-β inhibitors, a rhodanine compound containing a quinoxalinyl imidazole moiety was found to have strong antimicrobial activity.

OBJECTIVE

The purpose of this work was to investigate the antimicrobial activity of other chiral rhodanine TGF-β inhibitors synthesized.

METHODS

Two series of 3-substituted-5-(5-(6-methylpyridin-2-yl)-4-(quinoxalinyl-6-yl)- 1Himidazol- 2-yl)methylene)-2-thioxothiazolin-4-ones (12a-h and 13a-e) were synthesized and evaluated for their ALK5 inhibitory and antimicrobial activity. The structures were confirmed by their H NMR, C NMR and HRMS spectra. All the synthesized compounds were screened against Grampositive strains, Gram-negative strains, and fungi.

RESULTS

Among the synthesized compounds, compound 12h showed the highest activity (IC50 = 0.416 μM) against ALK5 kinase. Compound 12h exhibited a good selectivity index of >24 against p38α MAP kinase and was 6.0-fold more selective than the clinical candidate, compound 2 (LY- 2157299). Nearly all the compounds displayed high selectivity toward both Gram-positive and Gram-negative bacteria. They also showed similar or 2.0-fold greater antifungal activity (minimum inhibitory concentration [MIC] = 0.5 μg/mL) compared with the positive control compounds Gatifloxacin (MIC = 0.5 μg/mL) and fluconazole (MIC = 1 μg/mL).

CONCLUSION

The findings suggest that the synthesized rhodanine compounds have good ALK5 inhibitory activity, and merit further research and development as potential antifungal drugs.