1-[(Aryloxy)alkyl]-1&lt;I&gt;H&lt;/I&gt;-imidazoles as Inhibitors of Neuronal Nitric Oxide Synthase

Salerno, Loredana; Sorrenti, Valeria; Guerrera, Francesco; Sarvà, M. C.; Siracusa, M. A.; Giacomo, Claudia Di; Vanella, A.

doi:10.1211/146080899128735225

Cited by 8 publications

(9 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, many of them show sufficient selectivity to warrant further investigation. Such compounds have been previously reported to inhibit nitric oxide synthase34 and thromboxane synthetase,35 as well as to possess anticonvulsant36 and metamorphosis-inducing37 activities; we have not found any reports of antimicrobial activities of this class.…”

Section: Discussionmentioning

confidence: 65%

High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv

et al. 2009

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 65%

High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv

et al. 2009

View full text Add to dashboard Cite

“…In recent years, our research group has conducted extensive investigations on a number of imidazole-based compounds designed as NOS inhibitors (37)(38)(39)(40)(41)(42). These molecules present an imidazole nucleus separated from a hydrophobic aryl moiety by different spacers such as an ethanone, an alkylene, an ethanol, or an alkoxy chain of different length, giving compounds of general formulae 4-7 ( Figure 2).…”

mentioning

confidence: 99%

Evaluation of Imidazole‐Based Compounds as Heme Oxygenase‐1 Inhibitors

et al. 2012

View full text Add to dashboard Cite

Imidazole-based compounds previously synthesized in our laboratory were selected and reconsidered as inhibitors of heme oxygenase-1 obtained from the microsomal fractions of rat spleens. Most of tested compounds were good inhibitors with IC 50 values in the low micromolar range. Compounds were also assayed on membrane-free fulllength recombinant human heme oxygenase-1; all tested compounds were unable to interact with human heme oxygenase-1 at 100 lM concentrations with the exception of compounds 11 and 13 that inhibited the enzyme of 54% and 20%, respectively. The binding of the most active compound 11 with heme or heme-conjugated human heme oxygenase-1 was also examined by spectral analyses. When heme was not conjugated to human heme oxygenase-1, compound 11 caused changes in the heme spectrum only at concentration 50-fold (100 lM) higher than that required to inhibit rat heme oxygenase-1; when heme was conjugated to human heme oxygenase-1, compound 11 was able to form a heme-compound 11 complex also at low micromolar concentrations. To obtain information on the binding mode of the tested compounds with enzyme, docking studies and pharmacophore analysis were performed. Template docking results were in agreement with experimental inhibition data and with a structure-based pharmacophoric model. These data may be exploitable to design new OH-1 inhibitors.Key words: docking studies, enzymatic and spectral analyses, HO-1 inhibitors, imidazole-based compounds, pharmacophoric model Heme oxygenase (HO) is a microsomal enzyme catalyzing the first, rate-limiting step in degradation of heme, yielding equimolar quantities of carbon monoxide (CO), Fe 2+ , and biliverdin (1). Finally, biliverdin is converted by biliverdin reductase to bilirubin (2), which can be oxidized by cytochrome P450 (CYP450) enzymes (3). Three distinct mammalian HO isoforms (HO-1, HO-2, and HO-3) have been identified, which are the products of different genes (4). HO-1, the inducible 32-kDa isoform, is highly expressed in the liver and spleen, but can be also detected in many other tissues. HO-2 is a constitutively expressed 36-kDa protein, present in high levels in the brain, testes, or endothelial cells. HO-3 was postulated as a 33-kDa protein expressed in different organs, very similar to HO-2, but with much lower catalytic activity (5). The HO system has been demonstrated to have a variety of cellular regulatory actions including anti-inflammatory, anti-apoptotic, anti-proliferative, and vasodilator effects, owing to contributing and complementary effects of each of the metabolites produced (6-9).Interestingly, expression of HO-1 is usually increased in tumors, compared with surrounding healthy tissues (10-13). It has been reported that the growth of a number of tumors is dependent on HO-1 activity (14). These results support the idea that HO-1 may be a potential target in antitumor therapy. Thus, pharmacologic inhibition of HO-1 has been suggested as a new therapeutic option and potential sensitizer to chemotherapy, radiotherapy, or photodynamic...

show abstract

“…Although NO has several important physiological functions, excessive levels are detrimental and have been implicated as a crucial factor in the pathogenesis of several diseases (6). Excessive activity of nNOS has been reported in a number of diseases including acute and chronic neurodegenerative disorders such as stroke, Alzheimer's, and Parkinson's as well as migraine headaches, convulsion, and pain (1,(6)(7)(8). Therefore, inhibition of the activities of nNOS may be used to prevent and/or treat pathological conditions that are due to uncontrolled production of NO.…”

mentioning

confidence: 99%

Mechanism of the inhibition of calmodulin‐dependent neuronal nitric oxide synthase by flaxseed protein hydrolysates

Omoni

Aluko

2006

J Americ Oil Chem Soc

View full text Add to dashboard Cite

This work was aimed at producing potential nutraceutical peptides from flaxseed protein hydrolysate that can bind to calmodulin (CaM) and inhibit the activity of CaM-dependent neuronal nitric oxide synthase (nNOS), an enzyme that has been implicated in some forms of human diseases. Flaxseed protein isolate was hydrolyzed with alcalase, and the resultant protein hydrolysate was passed through a 1000-Da M.W. cut-off membrane to isolate low-M.W. peptides. The permeate from the membrane was loaded onto a cation-exchange column, and adsorbed peptides were separated into fractions I and II that had a content of 42 and 51% basic amino acids, respectively. Kinetic analyses showed that both fractions were capable of binding to CaM, which led to reductions in the activity of nNOS; the inhibition constant (K i ) was 5.97 and 2.55 mg/mL for fractions I and II, respectively. Double reciprocal plots showed that the mode of enzyme inhibition was mostly noncompetitive. Estimation of nNOS structure by fluorescence spectroscopy indicated that binding of the peptides to CaM led to a gradual unfolding of enzyme structure as levels of the fractions were increased. We concluded that the flaxseed protein-derived peptides may be used as ingredients for the formulation of therapeutic foods.Paper no. J11220 in JAOCS 83, 335-340 (April 2006).

show abstract

1-[(Aryloxy)alkyl]-1<I>H</I>-imidazoles as Inhibitors of Neuronal Nitric Oxide Synthase

Cited by 8 publications

References 14 publications

High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv

High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv

Evaluation of Imidazole‐Based Compounds as Heme Oxygenase‐1 Inhibitors

Mechanism of the inhibition of calmodulin‐dependent neuronal nitric oxide synthase by flaxseed protein hydrolysates

Contact Info

Product

Resources

About