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Identification of N-Oxide-Containing Aromatic Heterocycles as Pharmacophores for Rumen Fermentation Modifiers.

ABSTRACT: Different strategies have been used to mitigate greenhouse gas emissions from domesticated ruminants, including the removal of protozoa (defaunation). The objective of the present work was to analyze the potential of different N-oxide-containing aromatic heterocycles with known antiprotozoal activity as rumen-gas-abating agents. Nineteen pure compounds, belonging to seven different N-oxide chemotypes from our chemo-library were studied together with monensin in an in vitro rumen simulation assay. Fermentation profiles, i.e., gas production, pH, and short carboxylic acid concentrations, were compared to an untreated control at 96 h post inoculation. In our study, we investigated whole-ruminal fluid, with and without compound treatments, by NMR spectroscopy focusing on concentrations of the metabolites acetate, propionate, butyrate, and lactate. From data analysis, three of the compounds from different N-oxide chemotypes, including quinoxaline dioxide, benzofuroxan, and methylfuroxan, were able to diminish the production of gases such as monensin with similar gas production lag times for each of them. Additionally, unlike monensin, one methylfuroxan did not decrease the rumen pH during the analyzed incubation time, shifting rumen fermentation to increase the molar concentrations of propionate and butyrate. These facts suggest interesting alternatives as feed supplements to control gas emissions from dairy ruminants.

SUBMITTER: Bonifacino C

PROVIDER: S-EPMC6523752 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Identification of N-Oxide-Containing Aromatic Heterocycles as Pharmacophores for Rumen Fermentation Modifiers.

Bonifacino Carla C Rodríguez Gonzalo G Pérez-Ruchel Analía A Repetto José Luis JL Cerecetto Hugo H Cajarville Cecilia C González Mercedes M

Metabolites 20190402 4

Different strategies have been used to mitigate greenhouse gas emissions from domesticated ruminants, including the removal of protozoa (defaunation). The objective of the present work was to analyze the potential of different N-oxide-containing aromatic heterocycles with known antiprotozoal activity as rumen-gas-abating agents. Nineteen pure compounds, belonging to seven different N-oxide chemotypes from our chemo-library were studied together with monensin in an in vitro rumen si ...[more]

PMID: 30986899

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Project description:Conformationally well-defined supramolecular complexes that can be studied in different solvents provide a platform for separating and quantifying free energy contributions due to functional group interactions and desolvation. Here 1:1 complexes formed between four different calix[4]pyrrole receptors and eleven different pyridine N-oxide guests have been used to dissect the factors that govern aromatic interactions with heterocycles in water and in chloroform solution. 1H NMR spectroscopy shows that the three-dimensional structures of the complexes are fixed by four H-bonding interactions between the pyrrole donors at the bottom of the receptor and the N-oxide acceptor on the guest, locking the geometrical arrangement of interacting functional groups in the binding pocket at the other end of the receptor. An aromatic heterocycle on the guest makes two stacking interactions and two edge-to-face interactions with the side walls of the receptor. Chemical double mutant cycles were used to measure the free energy contribution of these four aromatic interactions to the overall stability of the complex. In chloroform, the aromatic interactions measured with pyridine, pyrimidine, furan, thiophene and thiazole are similar to the interactions with a phenyl group, but the effect of introducing a heteroatom depends on where it sits with respect to the aromatic side-walls of the cavity. A nitrogen lone pair directed into a π-face of the side-walls of the binding site leads to repulsive interactions of up to 8 kJ mol-1. In water, the heterocycle aromatic interactions are all significantly more favourable (by up to 12 kJ mol-1). For the non-polar heterocycles, furan and thiophene, the increase in interaction energy correlates directly with hydrophobicity, as measured by the free energy of transfer of the heterocycle from n-hexadecane into water (ΔG°(water-hex)). For the heterocycles with polar nitrogen H-bond acceptors, water can access cracks in the walls of the receptor binding site to solvate the edges of the heterocycles without significantly affecting the geometry of the aromatic interactions, and these nitrogen-water H-bonds stabilise the complexes by about 15 kJ mol-1. The results highlight the complexity of the solvation processes that govern molecular recognition in water.

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Identification of N-Oxide-Containing Aromatic Heterocycles as Pharmacophores for Rumen Fermentation Modifiers.

Publications

Identification of <i>N</i>-Oxide-Containing Aromatic Heterocycles as Pharmacophores for Rumen Fermentation Modifiers.

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