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

Abstract

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)- 1H-imidazol-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 1H NMR, 13C NMR, and HRMS spectra. All the synthesized compounds were screened against Gram-positive 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 can be used for further research and development as potential antifungal drugs.

Discovery of Triazolyl Derivatives of Cucurbitacin B Targeting IGF2BP1 against Non-Small Cell Lung Cancer

“…21,22 In addition, the triazolyl group has been successfully applied in the development of selinexor (15), letrozole (16), and talzenna (17). 23,24 Furan and thiophene were used to develop tykerb (18) and orgovyx (19). 25,26 These drugs can be used effectively in cancer treatment (Figure 2).…”

“…Cinnamic acid, 14,15 pyridine/furan 16,17 and triazolyl moieties have been considered common structures in the design of anticancer drugs due to their dipolar interaction, hydrogen bond formation ability, rigidity, and solubility. 18,19 For instance, cinnamic acid was presented in many active molecules with good efficacy, such as (−)-Englerin A (12), which has been under intensive preclinical investigation at the NCI. 20 Orelabrutinib (13) and zytiga (14) containing a pyridine moiety have been approved for listing by the FDA.…”

“…Cinnamic acid, , pyridine/furan , and triazolyl moieties have been considered common structures in the design of anticancer drugs due to their dipolar interaction, hydrogen bond formation ability, rigidity, and solubility. , For instance, cinnamic acid was presented in many active molecules with good efficacy, such as (−)-Englerin A ( 12 ), which has been under intensive preclinical investigation at the NCI . Orelabrutinib ( 13 ) and zytiga ( 14 ) containing a pyridine moiety have been approved for listing by the FDA. , In addition, the triazolyl group has been successfully applied in the development of selinexor ( 15 ), letrozole ( 16 ), and talzenna ( 17 ). , Furan and thiophene were used to develop tykerb ( 18 ) and orgovyx ( 19 ). , These drugs can be used effectively in cancer treatment (Figure ).…”

Synthesis and Antibacterial Activity Evaluation of Imidazole Derivatives Containing 6‐Methylpyridine Moiety

“…In the current work, we prepared a number of activin receptor-like kinae 5 (ALK5) inhibitors bearing imidazole groups, [39][40][41][42] and found that compounds [43][44][45][46] (7) bearing imidazole and imidazo[2,1-b] [1,3,4]thiadiazole moiety showed a good antifungal activity and high selectivity against Grampositive and Gram-negative bacteria. We hypothesized that the high selectivity of compound 7 may be related to the insertion of a large active group at the 5-position of the imidazo[2,1-b][1,3,4]thiadiazole moiety.…”