133512-93-3Relevant academic research and scientific papers
Dihydroquinazolines as a novel class of Trypanosoma brucei trypanothione reductase inhibitors: Discovery, synthesis, and characterization of their binding mode by protein crystallography
Patterson, Stephen,Alphey, Magnus S.,Jones, Deuan C.,Shanks, Emma J.,Street, Ian P.,Frearson, Julie A.,Wyatt, Paul G.,Gilbert, Ian H.,Fairlamb, Alan H.
, p. 6514 - 6530 (2011/12/02)
Trypanothione reductase (TryR) is a genetically validated drug target in the parasite Trypanosoma brucei, the causative agent of human African trypanosomiasis. Here we report the discovery, synthesis, and development of a novel series of TryR inhibitors based on a 3,4-dihydroquinazoline scaffold. In addition, a high resolution crystal structure of TryR, alone and in complex with substrates and inhibitors from this series, is presented. This represents the first report of a high resolution complex between a noncovalent ligand and this enzyme. Structural studies revealed that upon ligand binding the enzyme undergoes a conformational change to create a new subpocket which is occupied by an aryl group on the ligand. Therefore, the inhibitor, in effect, creates its own small binding pocket within the otherwise large, solvent exposed active site. The TryR-ligand structure was subsequently used to guide the synthesis of inhibitors, including analogues that challenged the induced subpocket. This resulted in the development of inhibitors with improved potency against both TryR and T. brucei parasites in a whole cell assay.
Micellar Catalysis of Organic Reactions. XXX A Study of the Mechanism of Hydrolysis of Oxazepam and 2'-Methyldiazepam in the Presence of Micelles and in Water
Broxton, Trevor J.,Wright, Sallyanne
, p. 103 - 111 (2007/10/02)
Acidic hydrolysis of oxazepam in water involved initial azomethine cleavage at low acid concentrations (0.1-0.2 M) with initial amide hydrolysis occurring concurrently at higher acid concentrations (0.3-0.6 M).In the presence of micelles of sodium dodecyl sulfate the percentage of initial amide cleavage increased.For the basic hydrolysis of oxazepam in water the rate was dependent on indicating at least some initial amide hydrolysis.At higher base concentrations the rate became independent of , because of the ionization of the NH group of oxazepam, producing an unreactive nitranion.In the presence of cetyltrimethylammonium bromide, the rate of basic hydrolysis was slower than in water, due to the increased amount of ionization in the presence of micelles.Acidic hydrolysis of 2'-methyldiazepam in water was independent of in the range 0.1-0.3 M, indicating initial azomethine hydrolysis.The rate was slower than for diazepam itself, indicating the existence of steric hindrance by the 2'-methyl group to water attack at C5.In basic solution, a biphasic reaction was observed.The rate of the first phase was dependent on , indicating the presence of initial amide hydrolysis for 2'-methyldiazepam, cf. initial azomethine hydrolysis for diazepam.At high base concentrations, a greater than first-order dependence on base concentration was observed.This was attributed to the formation of dianionic intermediates, as previously reported for the hydrolysis of similar anilides at high base concentrations.
