piperidines and nitrobenzene

Mycobacterium tuberculosis (MTB) consumes nitrate as the alternate mechanism of respiration in the absence of oxygen, thus increasing its survival and virulence during latent stage of tuberculosis infection. NarL is a nitrate/nitrite response transcriptional regulatory protein of two-component signal transduction system which regulates nitrate reductase and formate dehydrogenase for MTB adaptation to anaerobic condition. Phosphorylation by sensor kinase (NarX) is the primary mechanism behind the activation of NarL although many response regulators get activated by small molecule phospho-donors in the absence of sensor kinase. Virtual screening was performed using Autodock suite for the compounds from ZINC database against NarL and potential inhibitors was identified to inhibit the activation of NarL by affecting its phosphorylation. Molecular dynamics simulation studies predicted the stability of 1-{1-[(3-nitrophenyl) methyl] piperidin-2-yl} ethan-1-amine in the active site of NarL over 10 ns simulation. Phosphorylation of NarL by small molecule phospho-donors is also investigated in the present study. Here we suggest that nitro benzene - amine piperidine moiety can be an effective lead candidate for developing novel anti-tuberculosis drugs.

Topics: Antitubercular Agents; Bacterial Proteins; Catalytic Domain; DNA-Binding Proteins; Formate Dehydrogenases; Humans; Molecular Docking Simulation; Mycobacterium tuberculosis; Nitrate Reductases; Nitrates; Nitrites; Nitrobenzenes; Nitrogen; Phosphorylation; Piperidines; Protein Kinases; Sequence Homology, Amino Acid; Signal Transduction; Transcription Factors; Tuberculosis

The mechanism of DNA damage induced by metabolites of nitrobenzene was investigated in relation to the carcinogenicity and reproductive toxicity of nitrobenzene. Nitrosobenzene, a nitrobenzene metabolite, induced NADH plus Cu(II)-mediated DNA cleavage frequently at thymine and cytosine residues. Catalase and bathocuproine inhibited the DNA damage, suggesting the involvement of H2O2 and Cu(I). Typical free hydroxyl radical scavengers showed no inhibitory effects on DNA damage. Nitrosobenzene caused the formation of 8-oxo-7, 8-dihydro-2'-deoxyguanosine in calf thymus DNA in the presence of NADH and Cu(II). ESR spectroscopic study has confirmed that nitrosobenzene is reduced by NADH to the phenylhydronitroxide radical even in the absence of Cu(II). These results suggest that nitrosobenzene can be reduced non-enzymatically by NADH, and the redox cycle reaction resulted in oxidative DNA damage due to the copper-oxygen complex, derived from the reaction of Cu(I) with H2O2.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Catalase; Cations; Cattle; Chelating Agents; Chromatography, High Pressure Liquid; Copper; Cytosine; Deoxyguanosine; DNA; DNA Damage; Electron Spin Resonance Spectroscopy; Free Radical Scavengers; Guanine; Humans; Hydrogen Peroxide; Metals; Models, Chemical; NAD; Nitrobenzenes; Nitroso Compounds; Oxidation-Reduction; Piperidines; Thymine