Intramolecular hydrogen bonding as a determinant of the inhibitory potency of N-unsubstituted imidazole derivatives towards mammalian hemoproteins
Literature Information
Lionel Perrin, François André, Caroline Aninat, Rémy Ricoux, Jean-Pierre Mahy, Ning Shangguan, Madeleine M. Joullié, Marcel Delaforge
Enzymes involved in the mammalian microsomal metabolism of drugs are, in numerous cases, inhibited by compounds bearing an imidazolyl scaffold. However, the inhibition potency is highly dependent upon the accessibility of the imidazolyl nitrogen lone pair. In order to highlight some structural parameters of inhibitors that control this phenomenon, a series of compounds containing a nitrogen unsubstituted imidazolyl moiety with varying degrees of nitrogen lone pair accessibility was tested on human and rat hepatic cytochromes P450 and microperoxidase 8, an enzymatically active peptide derived from cytochrome c. In each case, we have shown that the accessibility of the imidazole lone pair determined the extent of inhibition. Nitrogen accessibility was tuned not only by varying the steric hindrance in the vicinity of the imidazolyl ring but also by modifying its surrounding hydrogen bonding network. Compounds in which there exists intramolecular hydrogen bonding between the imidazole moiety and an H-bond acceptor, such as an appropriately positioned amidecarbonyl group, demonstrated enhanced inhibitory effects. Conversely, imidazole moieties which are in proximity to H-bond donors, such as an amide NH group, displayed reduced potency. This trend was observed in cyclo-peptide derivatives in which the intramolecular H-bond network was adjusted through the modification of the stereochemistry of a dehydrohistidine residue. It was observed that (Z)-isomers weakly bind heme, whereas (E)-isomers demonstrated higher degrees of metal binding. Therefore, enzymatic inhibition of heme-containing proteins by compounds bearing a dehydrohistidine motif seems to be closely related to its stereochemistry and hydrogen binding propensity. At neutral pH, these differences in binding affinities can be confidently attributed to the ambident H-bond properties of imidazole nitrogen atoms. This structure-activity relationship may be of use for the design of novel imidazolyl compounds as new P450 inhibitors or drug candidates.
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Metallomics

Metallomics publishes cutting-edge investigations aimed at elucidating the identification, distribution, dynamics, role and impact of metals and metalloids in biological systems. Studies that address the “what, where, when, how and why” of these inorganic elements in cells, tissues, organisms, and various environmental niches are welcome, especially those employing multidisciplinary approaches drawn from the analytical, bioinorganic, medicinal, environmental, biophysical, cell biology, plant biology and chemical biology communities. We are particularly interested in articles that enhance our chemical and/or physical understanding of the molecular mechanisms of metal-dependent life processes, and those that probe the common space between metallomics and other ‘omics approaches to uncover new insights into biological processes. Metallomics seeks to position itself at the forefront of those advances in analytical chemistry destined to clarify the enormous complexity of biological systems. As such, we particularly welcome those papers that outline cutting-edge analytical technologies, e.g., in the development and application of powerful new imaging, spectroscopic and mass spectrometric modalities. Work that describes new insights into metal speciation, trafficking and dynamics in complex systems or as a function of microenvironment are also strongly encouraged. Studies that examine the interconnectivity of metal-dependent processes with systems level responses relevant to organismal health or disease are also strongly encouraged, for example those that probe the effect of chemical exposure on metal homeostasis or the impact of metal-based drugs on cellular processes.














