Structural features and functional activities of benzimidazoles as NOD2 antagonists

Guzelj, Samo; Gobec, Martina; Urbančič, Dunja; Mlinarič-Raščan, Irena; Corsini, Emanuela

doi:10.1016/j.ejmech.2020.112089

Cited by 9 publications

(17 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 46 The NOD2 antagonist was synthesized as described. 77 The analytical data here were identical to those reported previously. The assembly of the final compounds was as described below, while the preparation of other precursors is given in the Supporting Information .…”

Section: Methodssupporting

confidence: 82%

“…Compounds 1 , 2 , 3 , 6 , 29 , 42 , 43 , 44 , 45 , and 46 were prepared as previously described by our group . The NOD2 antagonist was synthesized as described . The analytical data here were identical to those reported previously.…”

Section: Methodsmentioning

confidence: 79%

“…Furthermore, the specificities were determined by pretreating HEK-Blue NOD2 cells with a previously reported NOD2 antagonist 77 prior to stimulation with MDP (2 μM) or the desmuramylpeptides (2 μM). The resulting NF-κB-induced SEAP activities were compared to those of the controls without the NOD2 antagonist pretreatment.…”

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Structural Fine-Tuning of Desmuramylpeptide NOD2 Agonists Defines Their In Vivo Adjuvant Activity

et al. 2021

Self Cite

View full text Add to dashboard Cite

We report on the design, synthesis, and biological evaluation of a series of nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) desmuramylpeptide agonists with improved in vitro and in vivo adjuvant properties. We identified two promising compounds: 68 , a potent nanomolar in vitro NOD2 agonist, and the more lipophilic 75 , which shows superior adjuvant activity in vivo . Both compounds had immunostimulatory effects on peripheral blood mononuclear cells at the protein and transcriptional levels, and augmented dendritic-cell-mediated activation of T cells, while 75 additionally enhanced the cytotoxic activity of peripheral blood mononuclear cells against malignant cells. The C 18 lipophilic tail of 75 is identified as a pivotal structural element that confers in vivo adjuvant activity in conjunction with a liposomal delivery system. Accordingly, liposome-encapsulated 75 showed promising adjuvant activity in mice, surpassing that of muramyl dipeptide, while achieving a more balanced Th1/Th2 immune response, thus highlighting its potential as a vaccine adjuvant.

show abstract

Section: Methodssupporting

confidence: 82%

Section: Methodsmentioning

confidence: 79%

See 1 more Smart Citation

Structural Fine-Tuning of Desmuramylpeptide NOD2 Agonists Defines Their In Vivo Adjuvant Activity

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The specificities of all compounds were determined by pretreating HEK-Blue NOD2 cells with a known NOD2 antagonist (Figure S2A; see the SI ), 27 before the addition of desmuramylpeptides. The comparative reduction in measured activity in response to pretreatment with the NOD2 antagonist confirmed that the NF-κB transcriptional activity after stimulation with all compounds was reliant on the activation of NOD2 (Figure S2B; see the SI ).…”

mentioning

confidence: 99%

Discovery of Desmuramylpeptide NOD2 Agonists with Single-Digit Nanomolar Potency

Guzelj

Bizjak

2022

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

The innate immune receptor nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) represents an important target for the development of structurally defined small molecule immunomodulatory compounds that have great potential to be used either as vaccine adjuvants or as general immunostimulatory agents. We report here the investigation of the structure–activity relationship of a series of novel desmuramylpeptide NOD2 agonists. Extensive exploration of chemical space culminated in the discovery of a lipophilic adamantane-moiety-featuring compound 40 , the first single-digit nanomolar and the most potent NOD2 agonist in its structural class to date. Moreover, 40 acted synergistically with lipopolysaccharide and interferon-γ to induce the production of cytokines in human peripheral blood mononuclear cells and enhance their nonspecific cytotoxic activity against K562 cancer cells. These findings provide initial insight into its immunostimulatory potential, especially when used in combination with other immunopotentiators.

show abstract

“…In addition, benzimidazole target was described as inhibitors of the hepatitis C virus [15], indoleamine 2,3-dioxygenase-1 (IDO1) inhibitors from structurebased virtual screening to in Vivo pharmacodynamic activity [16], anti-hypertensive agent [17], Zika Virus Inhibitors [18], in vitro alpha-glucosidase inhibitory [19], NOD2 antagonists [20], antiglycation and antioxidant [21] and antileukemic agents [22]. Surineni G. et al considered that the benzimidazole core were used with excellent efficiency for the treatment of tuberculosis [23].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, Characterization and Anticancer Evaluation of Novel Mixed Complexes Derived from 2-(1H-Benzimizadol-2-yl)aniline Schiff base and 2-Mercaptobenzimidazole or 2-Aminobenzothiazole

Alminderej

Lotfi

2021

Egypt. J. Chem.

View full text Add to dashboard Cite

Two Schiff base ligands ((benzimidazol-2-phenyl)iminomethyl)phenol (HL1) (1) and 2-(1-H-benzimidazol-2yl)phenyl)imino)methyl) naphthol (HL2) (2) were synthesized via condensation of 2-(1H-benzimizadol-2-yl)aniline and respectively salicylaldehyde or naphtylaldehyde. The synthesis of mixed complexes (3)-(6) was realized by reacting ligands HL1 (1) and HL2 (2), copper salt (CuCl2.2H2O) and respectively one equivalent of 2-mercaptobenzothiazole or 2aminobenzothiazole. The ligands as well as the metal complexes have been identified with multiple spectroscopic techniques. The results data indicate that the copper is linked to ligands via deprotonated phenolic oxygen atom, nitrogen or sulphur atom of co-ligands and the coordination was realized through the azomethine group. X-ray powder diffraction analysis of complexes suggests that they posses monoclinic structure for complexes (3) and (4), while complex (5) has orthorhombic structure and rhombohedral structure for complex (6). The in vitro anticancer activities of the different complexes were evaluated and the results revealed an important cytotoxicity of complex (6) against lung human cancer A-549 and very good selectivity with 12.4 values of inhibitory concentration IC 50. The best result was described with complex (4) and present high activities on both A-549 and Caco-2 indicating good selectivity on lung human cancer A-549 and moderate selectivity on colorectal cell line Caco-2 with 10.9 and 15.7 respectively of IC 50.

show abstract

Structural features and functional activities of benzimidazoles as NOD2 antagonists

Cited by 9 publications

References 42 publications

Structural Fine-Tuning of Desmuramylpeptide NOD2 Agonists Defines Their In Vivo Adjuvant Activity

Structural Fine-Tuning of Desmuramylpeptide NOD2 Agonists Defines Their In Vivo Adjuvant Activity

Discovery of Desmuramylpeptide NOD2 Agonists with Single-Digit Nanomolar Potency

Design, Synthesis, Characterization and Anticancer Evaluation of Novel Mixed Complexes Derived from 2-(1H-Benzimizadol-2-yl)aniline Schiff base and 2-Mercaptobenzimidazole or 2-Aminobenzothiazole

Contact Info

Product

Resources

About