Elucidation of the E-Amide Preference of N-Acyl Azoles

Abstract

The conformational properties of N-acyl azoles (imidazole, pyrazole, and triazole) were examined. The N-2',4',6'-trichlorobenzoyl azoles were stable in methanol at room temperature, and no hydrolyzed products were observed over 7 days in the presence of 5% trifluoroacetic acid or 5% triethylamine in CDCl. The high stability may be explained by the double-bond amide character caused by the steric hindrance due to the ortho-substituents in the benzoyl group. While specific E-amide preferences were observed in N-acyl pyrazoles/triazoles, the amides of the imidazoles gave a mixture of E and Z. One of the conceivable ideas to rationalize this conformational preference may be repulsive interaction between two sets of lone-pair electrons on the pyrazole 2-nitrogen (n) and the carbonyl oxygen atoms (n) in the Z-conformation of N-acyl pyrazoles/triazoles. However, analysis of orbital interactions suggested that in the case of the E-conformation of N-acyl pyrazoles, such electron repulsion is small because of distance. The interbond energy calculations suggested that the Z-conformer is involved in strong vicinal σ-σ repulsion along the amide linkage between the σ and σ orbitals in the anti-periplanar arrangement and between the σ and σ orbitals in the syn-periplanar arrangement, which lead to the overwhelming E-preference in N-acyl pyrazoles/triazoles. In the case of N-acyl imidazoles, similar vicinal σ-σ repulsions were counterbalanced, leading to a weak preference for the E-conformer over the Z-conformer. The chemically stable and E-preferring N-acyl azoles may be utilized as scaffolds in future drug design.

Comparison of quinazoline and benzoylpyrazoline chemotypes targeting the CaVα-β interaction as antagonists of the N-type CaV2.2 channel

“…The compound BTT-369 identified by Chen and coworkers contains aryldihydrobipyrazole chemotype [22]; a scaffold featuring multiple phenyl groups that are known to undergo significant metabolism resulting in a lower the systemic half-life and increase potential for toxicity. Furthermore, the benzoylpyrazoline skeleton found in BTT-369 is broadly patented across multiple therapeutic indications [23,24]. Moreover, the lead compound from this study [22] was not proved to be specific for CaV2.2 and only decreased total Ca 2+ currents at 50 µM after 48 h of incubation.…”

Comparison of quinazoline and benzoylpyrazoline chemotypes targeting the CaVα-β interaction as antagonists of the N-type CaV2.2 channel

“…The compound BTT-369 identified by Chen and coworkers contains aryldihydrobipyrazole chemotype [22]; a scaffold featuring multiple phenyl groups that are known to undergo significant metabolism resulting in a lower the systemic half-life and increase potential for toxicity. Furthermore, the benzoylpyrazoline skeleton found in BTT-369 is broadly patented across multiple therapeutic indications [23,24]. Moreover, the lead compound from this study [22] was not proved to be specific for CaV2.2 and only decreased total Ca 2+ currents at 50 µM after 48 h of incubation.…”

Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency

“…Calculations indicate that the ( E )-configuration is preferred by several kcal·mol –1 regardless the level of theory applied ( Figure 6 C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the ( Z )-configuration. 49 …”

“…Calculations indicate that the (E)-configuration is preferred by several kcal•mol −1 regardless the level of theory applied (Figure 6C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the (Z)-configuration. 49 The Michaelis complex of MGL with 4 in (E)-configuration was submitted to a 100 ns long MD simulation using AMBER force field (Figure 7A). 41 In this MD simulation, the catalytic triad maintains an arrangement close to the starting structure showing RMSD lower than 1.0 Å (Figure 7B).…”

“…To identify the preferred geometry for inhibitor 4 , the gas-phase energy for a piperazine triazole urea fragment, modeled in both ( E )- and ( Z ) - configurations (Figure B), was calculated with two different QM methods (DFTB3 and M06-2X-D3 with cc-PVDZ basis set). Calculations indicate that the ( E )-configuration is preferred by several kcal·mol –1 regardless the level of theory applied (Figure C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the ( Z )-configuration …”

Contribution of Solvents to Geometrical Preference in the Z/E Equilibrium of N-Phenylthioacetamide

“…To elucidate the origin of the effect of N -methylation on Z / E thioamide preference (Table ), we analyzed the electronic structures of the molecules in terms of the orbital interactions of thioacetamides ( 1a/3a and 1 b /3b ) by means of bond model analysis (BMA) (Tables S2–S4). , The interbond energies (IBEs), including both occupied-occupied orbitals and occupied-vacant orbitals, were used to evaluate the bond interactions in the molecules. The IBEs were calculated for (1) vicinal bond interactions with respect to the thioamide N–C­(S) bond, that is, between σ­(C1–C2)/σ­(C1–S) and σ­(N–H)/σ­(N–C­(Ar)) (they are in a vicinal relation; see Figure ), (2) conjugation between n (N) and CS, n (N) and Ar, and CS and Ar, and (3) repulsive interaction between two substituents attached to the thioamide bond, including all C–C and C–H σ bonds and π orbitals of the aromatic ring.…”

Comparison of quinazoline and benzoylpyrazoline chemotypes targeting the CaVα-β interaction as antagonists of the N-type CaV2.2 channel

“…The compound BTT-369 identified by Chen and coworkers contains aryldihydrobipyrazole chemotype [22]; a scaffold featuring multiple phenyl groups that are known to undergo significant metabolism resulting in a lower the systemic half-life and increase potential for toxicity. Furthermore, the benzoylpyrazoline skeleton found in BTT-369 is broadly patented across multiple therapeutic indications [23,24]. Moreover, the lead compound from this study [22] was not proved to be specific for CaV2.2 and only decreased total Ca 2+ currents at 50 µM after 48 h of incubation.…”

Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency

“…Calculations indicate that the ( E )-configuration is preferred by several kcal·mol –1 regardless the level of theory applied ( Figure 6 C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the ( Z )-configuration. 49 …”

“…Calculations indicate that the (E)-configuration is preferred by several kcal•mol −1 regardless the level of theory applied (Figure 6C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the (Z)-configuration. 49 The Michaelis complex of MGL with 4 in (E)-configuration was submitted to a 100 ns long MD simulation using AMBER force field (Figure 7A). 41 In this MD simulation, the catalytic triad maintains an arrangement close to the starting structure showing RMSD lower than 1.0 Å (Figure 7B).…”

“…To identify the preferred geometry for inhibitor 4 , the gas-phase energy for a piperazine triazole urea fragment, modeled in both ( E )- and ( Z ) - configurations (Figure B), was calculated with two different QM methods (DFTB3 and M06-2X-D3 with cc-PVDZ basis set). Calculations indicate that the ( E )-configuration is preferred by several kcal·mol –1 regardless the level of theory applied (Figure C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the ( Z )-configuration …”

Contribution of Solvents to Geometrical Preference in the Z/E Equilibrium of N-Phenylthioacetamide

“…To elucidate the origin of the effect of N -methylation on Z / E thioamide preference (Table ), we analyzed the electronic structures of the molecules in terms of the orbital interactions of thioacetamides ( 1a/3a and 1 b /3b ) by means of bond model analysis (BMA) (Tables S2–S4). , The interbond energies (IBEs), including both occupied-occupied orbitals and occupied-vacant orbitals, were used to evaluate the bond interactions in the molecules. The IBEs were calculated for (1) vicinal bond interactions with respect to the thioamide N–C­(S) bond, that is, between σ­(C1–C2)/σ­(C1–S) and σ­(N–H)/σ­(N–C­(Ar)) (they are in a vicinal relation; see Figure ), (2) conjugation between n (N) and CS, n (N) and Ar, and CS and Ar, and (3) repulsive interaction between two substituents attached to the thioamide bond, including all C–C and C–H σ bonds and π orbitals of the aromatic ring.…”

Comparison of quinazoline and benzoylpyrazoline chemotypes targeting the CaVα-β interaction as antagonists of the N-type CaV2.2 channel

“…The compound BTT-369 identified by Chen and coworkers contains aryldihydrobipyrazole chemotype [22]; a scaffold featuring multiple phenyl groups that are known to undergo significant metabolism resulting in a lower the systemic half-life and increase potential for toxicity. Furthermore, the benzoylpyrazoline skeleton found in BTT-369 is broadly patented across multiple therapeutic indications [23,24]. Moreover, the lead compound from this study [22] was not proved to be specific for CaV2.2 and only decreased total Ca 2+ currents at 50 µM after 48 h of incubation.…”

Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency

“…Calculations indicate that the ( E )-configuration is preferred by several kcal·mol –1 regardless the level of theory applied ( Figure 6 C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the ( Z )-configuration. 49 …”

“…Calculations indicate that the (E)-configuration is preferred by several kcal•mol −1 regardless the level of theory applied (Figure 6C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the (Z)-configuration. 49 The Michaelis complex of MGL with 4 in (E)-configuration was submitted to a 100 ns long MD simulation using AMBER force field (Figure 7A). 41 In this MD simulation, the catalytic triad maintains an arrangement close to the starting structure showing RMSD lower than 1.0 Å (Figure 7B).…”

“…To identify the preferred geometry for inhibitor 4 , the gas-phase energy for a piperazine triazole urea fragment, modeled in both ( E )- and ( Z ) - configurations (Figure B), was calculated with two different QM methods (DFTB3 and M06-2X-D3 with cc-PVDZ basis set). Calculations indicate that the ( E )-configuration is preferred by several kcal·mol –1 regardless the level of theory applied (Figure C and Table S1 in the Supporting Information), which may be explained by repulsive interactions between the lone pair electrons of the N2 and O atoms in the ( Z )-configuration …”

Contribution of Solvents to Geometrical Preference in the Z/E Equilibrium of N-Phenylthioacetamide

“…To elucidate the origin of the effect of N -methylation on Z / E thioamide preference (Table ), we analyzed the electronic structures of the molecules in terms of the orbital interactions of thioacetamides ( 1a/3a and 1 b /3b ) by means of bond model analysis (BMA) (Tables S2–S4). , The interbond energies (IBEs), including both occupied-occupied orbitals and occupied-vacant orbitals, were used to evaluate the bond interactions in the molecules. The IBEs were calculated for (1) vicinal bond interactions with respect to the thioamide N–C­(S) bond, that is, between σ­(C1–C2)/σ­(C1–S) and σ­(N–H)/σ­(N–C­(Ar)) (they are in a vicinal relation; see Figure ), (2) conjugation between n (N) and CS, n (N) and Ar, and CS and Ar, and (3) repulsive interaction between two substituents attached to the thioamide bond, including all C–C and C–H σ bonds and π orbitals of the aromatic ring.…”