Intramolecular hydrogen bonding as a determinant of the inhibitory potency of N-unsubstituted imidazole derivatives towards mammalian hemoproteins

Abstract

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 amide carbonyl 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.

Unconventional N-H…N Hydrogen Bonds Involving Proline Backbone Nitrogen in Protein Structures

“…Such H-bonds have been shown to be part of the pharmacophore and are important for binding to the target protein (23,24). Perrin et al (25) tested the capability of nitrogen atoms in the imidazole moiety to act as an H-bond acceptor or donor in cytochrome P450 using a series of compounds, and investigated their potential to be novel inhibitors.…”

Quantum Mechanical Assessment of Protein–Ligand Hydrogen Bond Strength Patterns: Insights from Semiempirical Tight-Binding and Local Vibrational Mode Theory

“…Although the majority (59.5%) of protein–ligand interactions do not form HB networks, 0-0-1 (17.4%), 1-0-0 (10.8%), 0-1-0 (9.0%), and 1-1-0 (3.3%) can be identified. The stability of such a hydrogen bond network can be quantified using the robustness, which is qualitatively expressed by Perrin et al [ 62 ] as the ratio of the strength of the network with one HB broken to that of the intact network. where is the Boltzmann constant, T is the absolute temperature, is the energy barrier of a single HB, and n is the number of HBs.…”

Stabilizing Bifurcated Hydrogen Bond in 8‐Aminoquinoline Appended Peptides

“…The presence of NÀ H i + 1 •••N i interaction was further proved using infrared stretching frequencies and the blue shifts of the absorptions. Perrin et al [18] recently designed and synthesized a series of compounds containing an imidazole moiety and identified them as potent novel inhibitors for cytochrome P450. Moreover, they illustrated that the nitrogen atoms within the imidazole scaffold are adept at serving as hydrogen bond acceptor or donor within the cytochrome P450 binding pocket.…”

“…The presence of N−H i+1 ⋅⋅⋅N i interaction was further proved using infrared stretching frequencies and the blue shifts of the absorptions. Perrin et al [18] . recently designed and synthesized a series of compounds containing an imidazole moiety and identified them as potent novel inhibitors for cytochrome P450.…”

“…recently designed and synthesized a series of compounds containing an imidazole moiety and identified them as potent novel inhibitors for cytochrome P450. Moreover, they illustrated that the nitrogen atoms within the imidazole scaffold are adept at serving as hydrogen bond acceptor or donor within the cytochrome P450 binding pocket [18] . To stabilize such unusual C 5a interaction in non‐prolyl residues, we hypothesized that introducing a bifurcated [19,20] hydrogen bond (N⋅⋅⋅H⋅⋅⋅N) may facilitate the amide N i+1 −H proximity to interact maximally with the amide N i electron density and also with the acceptor succeeding residue.…”