ABSTRACT
A series of novel pyrazolyl alcohols (5a-h), pyrazolyl azides (6a-h), and pyrazolyltriazoles (8a-h, 10a-p and 12a-l) were prepared and evaluated for their bioactivity (anti-bacterial and anti-inflammatory) profile. The compound 5c displayed the potent anti-bacterial activity against Micrococcus luteus (MIC 3.9 and MBC 7.81µg/mL). In vitro anti-inflammatory activity data denoted that compound 8b is effective among the tested compounds against IL-6 (IC50 6.23µM). Docking analysis of compounds 5f, 8a-b, 8e-f and 8h displayed high binding energies for the compounds 8a-b and 8h towards TNF-α dimer (2AZ5 protein) and IL-6 (1ALU protein). In vivo anti-inflammatory activity of compounds 8b and 8h with respect to LPS induced mice model indicated that compound 8h showed significant reduction in TNF-α.
Subject(s)
Molecular Docking Simulation , Triazoles/chemical synthesis , Triazoles/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Gene Expression Regulation/drug effects , Interleukin-6/genetics , Interleukin-6/metabolism , Mice , Microbial Sensitivity Tests , Micrococcus luteus/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Triazoles/chemistry , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Glycosidases play an important role in a wide range of physiological and pathological conditions, and have become potential targets for the discovery and development of agents useful for the treatment of diseases such as diabetes, cancer, influenza, and even AIDS. In this study, several benzimidazole derivatives were prepared from o-phenylenediamine and aromatic and heteroaromatic carboxaldehydes in very good yields, using PdCl2(CH3CN)2 as the most efficient catalyst. Synthesized compounds were assayed for their activity on yeast and rat intestinal alpha-glucosidase inhibition and cytotoxic activity against colon carcinoma cell line HT-29. Compound 3e exhibited 95.6% and 75.3% inhibition of yeast and rat intestinal alpha-glucosidase enzyme, while showing 74.8% cytotoxic activity against the HT-29 cell line at primary screening concentrations of 2.1 mM for yeast and rat intestinal alpha-glucosidase enzyme and 0.2 mM for cytotoxic activity against the HT-29 cell line, respectively. Compound 3c displayed 76% and 34.4% inhibition of yeast and rat intestinal alpha-glucosidase enzyme, and 80.4% cytotoxic activity against the HT-29 cell line at similar primary screening concentrations. The IC50 value for the most potent intestinal alpha-glucosidase inhibitor compound 3e was found to be 99.4 microM. The IC50 values for the most active cytotoxic compounds 3c and 3e were 82 microM and 98.8 microM, respectively. Both compounds displayed significant antihyperglycemic activity in starch-induced postprandial hyperglycemia in rats. This is the first report assigning yeast and rat intestinal alpha-glucosidase enzyme inhibition, cytotoxic activity against the HT-29 cell line, and antihyperglycemic activity to benzimidazole compounds 3c and 3e.
