Anti-Inflammatory Trends of New Benzimidazole Derivatives

Bukhari, Syed Nasir Abbas; Lauro, Gianluigi; Jantan, Ibrahim; Chee, Chin Fei; Amjad, Muhammad Wahab; Bifulco, Giuseppe; Sher, Hassan; Abdullah, Iskandar; Rahman, Noorsaadah Abd.

doi:10.4155/fmc-2016-0062

Cited by 39 publications

(28 citation statements)

References 47 publications

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“…Concerning 5‐LO, the analysis of the only one human protein structure (wild‐type) available in the Protein Data Bank (PDB code: 3O8Y), not co‐complexed with an inhibitor, disclosed a partially accessible ligand binding site, thus not compatible for the semi‐rigid molecular docking procedure. For these reasons, in this specific case, Induced Fit experiments should be performed and, considering the high number of compounds to be tested, this should require high computational times.…”

Section: Resultsmentioning

confidence: 99%

A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4‐Thiazolidinedione‐Based Molecules as New Dual mPGES‐1/5‐LO Inhibitors

et al. 2020

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Dual inhibition of microsomal prostaglandin E2 synthase‐1 (mPGES‐1) and 5‐lipoxygenase (5‐LO), two key enzymes involved in pro‐inflammatory eicosanoid biosynthesis, represents a new strategy for treating inflammatory disorders. Herein we report the discovery of 2,4‐thiazolidinedione‐based mPGES‐1/5‐LO dual inhibitors following a multidisciplinary protocol, involving virtual combinatorial screening, chemical synthesis, and validation of the biological activities for the selected compounds. Following the multicomponent‐based chemical route for the decoration of the 2,4‐thiazolidinedione core, a large library of virtual compounds was built (∼2.0×104 items) and submitted to virtual screening. Nine selected molecules were synthesized and biologically evaluated, disclosing among them four compounds able to reduce the activity of both enzymes in the mid‐ and low‐ micromolar range of activities. These results are of interest for further expanding the chemical diversity around the 2,4‐thiazolidinedione central core, facilitating the identification of novel anti‐inflammatory agents endowed with a promising and safer pharmacological profile.

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Section: Resultsmentioning

confidence: 99%

A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4‐Thiazolidinedione‐Based Molecules as New Dual mPGES‐1/5‐LO Inhibitors

et al. 2020

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“…In contrast, there are few studies reporting the synthesis of 2-aminobenzimidazole derivatives. A variety of benzimidazole-based compounds have shown their potential use as antidiabetic, anti-ulcer, anti-convulsant (Shingalapur, Hosamani, Keri, & Hugar, 2010), anti-infectious (Ozkay, Tunali, Karaca, & Isikdag, 2011), or anti-inflammatory (Bukhari et al, 2016) agents. Recent studies demonstrated that benzimidazole derivatives also exhibit anti-angiogenesis (Huang, Lien, Kuo, & Huang, 2012) and anti-tumour (Chu et al, 2015) properties.…”

Section: Introductionmentioning

confidence: 99%

A novel 2‐aminobenzimidazole‐based compound Jzu 17 exhibits anti‐angiogenesis effects by targeting VEGFR‐2 signalling

Lien

Chung

Huang

et al. 2019

British J Pharmacology

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Background and Purpose Recent development in drug discovery have shown benzimidazole to be an important pharmacophore,. Benzimidazole derivatives exhibit broad‐spectrum pharmacological properties including anti‐microbial, anti‐diabetic and anti‐tumour activity. However, whether benzimidazole derivatives are effective in suppressing angiogenesis and its underlying mechanisms remain incompletely understood. In this study, we aim to characterize the anti‐angiogenic mechanisms of a novel 2‐aminobenzimidazole‐based compound, Jzu 17, in an effort to develop novel angiogenesis inhibitor. Experimental Approach Effects of Jzu 17 on endothelial cell proliferation, migration, invasion, and activation of signalling molecules induced by VEGF‐A, were analysed by immunoblotting, MTT, BrdU, migration, and invasion assays. We performed tube formation assay, aorta ring sprouting assay, matrigel plug assay, and a mouse model of metastasis to evaluate ex vivo and in vivo anti‐angiogenic effects of Jzu 17. Key Results Jzu 17 inhibited VEGF‐A‐induced cell proliferation, migration, invasion, and endothelial tube formation of HUVECs. Jzu 17 suppressed VEGF‐A‐induced microvessel sprouting ex vivo and attenuated VEGF‐A‐ or tumour cell‐induced neovascularization in vivo. Jzu 17 also reduced B16F10 melanoma lung metastasis. In addition, Jzu 17 inhibited the phosphorylation of VEGFR‐2 and its downstream signalling molecules in VEGF‐A‐stimulated HUVECs. Results from computer modelling further showed that Jzu 17 binds to VEGFR‐2 with high affinity. Conclusions and Implications Jzu 17 may inhibit endothelial remodelling and suppress angiogenesis through targeting VEGF‐A‐VEGFR‐2 signalling. These results also suggest Jzu 17 as a potential lead compound and warrant the clinical development of similar agents in the treatment of cancer and angiogenesis‐related diseases.

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“…We initially attempted the reactiono f2 -chloro-1H-benzo[d]imidazole with the in situ generated nitrile oxide,w hichw as pre-pared by the base-mediated dehydrochlorination of N-hydroximoyl chloride 1a.T he reactionw as carried out in the presence of organic and inorganic bases and in aprotic and protic solvents, such as EtOH, MeOH,t etrahydrofuran (THF), dichloromethane (DCM), N,N-dimethylformamide (DMF), isopropanol, 1,4-dioxane, and dimethylsulfoxide (DMSO,T able 1, entries [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. At race amounto ft he desired compound 3a (Table 1, entries 3, 4, 10, and 11)w as formed by employing tetra-n-butylammonium fluoride (TBAF)o r4 -(N,N-dimethylamino)pyridine (DMAP)a sb ases (detected by high resolution HPLC-MS and 1 HNMR analysis).…”

Section: Resultsmentioning

confidence: 99%

“…Benzimidazoles and imidazoles are important molecular frameworks that are found in alkaloids, and compounds that contain these structuresg enerally have important biological activity, [1][2][3] including antitumor, [4][5][6] antimicrobial, [7,8] anti-inflammatory, [9,10] and antiviral properties. [11,12] Many commercial drugs also contain this moleculars keleton, such as protonp ump-inhibitors (e.g.,o meprazole) [13,14] and antihelmintics (e.g.,a lbendazole).…”

Section: Introductionmentioning

confidence: 99%

1,3‐Dipolar Cycloaddition of Imidazole Derivatives with Nitrile Oxide: Synthesis of Imidazo[1,2,4]oxadiazole Derivatives

2017

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Ac oncise and efficient synthesis of imidazo [1,2,4]oxadiazole derivativest hat proceeds through the [3+ +2] cycloaddition of 2-chloro-1H-benzo[d]imidazole with nitrile oxides has been developed. This strategy can conveniently construct tricyclic imidazole heterocyclic derivatives that contain ab road range of functional groups. Compound 3p showede xcellent cytotoxic activity against the KYSE410 cell line (IC 50 = 0.26 mm). These tricyclicimidazole heterocyclic derivatives are promising candidates fordrug discovery.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under https://doi.

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Anti-Inflammatory Trends of New Benzimidazole Derivatives

Cited by 39 publications

References 47 publications

A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4‐Thiazolidinedione‐Based Molecules as New Dual mPGES‐1/5‐LO Inhibitors

A Combinatorial Virtual Screening Approach Driving the Synthesis of 2,4‐Thiazolidinedione‐Based Molecules as New Dual mPGES‐1/5‐LO Inhibitors

A novel 2‐aminobenzimidazole‐based compound Jzu 17 exhibits anti‐angiogenesis effects by targeting VEGFR‐2 signalling

1,3‐Dipolar Cycloaddition of Imidazole Derivatives with Nitrile Oxide: Synthesis of Imidazo[1,2,4]oxadiazole Derivatives

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