Intramolecular hydrogen bonding: A potential strategy for more bioavailable inhibitors of neuronal nitric oxide synthase

Abstract

Selective neuronal nitric oxide synthase (nNOS) inhibitors have therapeutic applications in the treatment of numerous neurodegenerative diseases. Here we report the synthesis and evaluation of a series of inhibitors designed to have increased cell membrane permeability via intramolecular hydrogen bonding. Their potencies were examined in both purified enzyme and cell-based assays; a comparison of these results demonstrates that two of the new inhibitors display significantly increased membrane permeability over previous analogs. NMR spectroscopy provides evidence of intramolecular hydrogen bonding under physiological conditions in two of the inhibitors. Crystal structures of the inhibitors in the nNOS active site confirm the predicted non-intramolecular hydrogen bonded binding mode. Intramolecular hydrogen bonding may be an effective approach for increasing cell membrane permeability without affecting target protein binding.

It Is Important to Compute Intramolecular Hydrogen Bonding in Drug Design?

“…Furthermore, the accessibility of polar atoms in a molecule could be decreased if IMHBs are established. This may influence desolvation equilibria and facilitate the passage of molecules through low dielectric environments [216,217,218]. While geometric preferences for the formation of IMHBs have been described based on experimental evidence [67], the presence of stabilizing IMHBs are normally debated based on thermodynamics grounds, especially in high dielectric environments.…”

“…[209,217,247,399,400] The presence of IMHB has been shown to significantly alter molecular properties due to formation of various conformers that in turn influence solubility, permeability, PK/ PD processes, and protein binding affinity [207,210,401,402].…”

“…A hydrogen bond is strong enough to restrict rotation of fragments by forming most commonly [210,217,401,402] membered rings. Importantly, IMHBs are weak enough to allow these fragments to come apart and lose their orientational specificity in high dielectric media such as water.…”

Strategies for the synthesis of HBGl3 , a glutamic acid derived ligand bearing phenolic and azacarboxylate donor groups at the nitrogen atom

“…We reasoned that the structure of 9 could help us predict the hydrogen bonding behaviour of 10 because the hydroxybenzyl group is unchanged in going from 9 to 10 and intramolecular hydrogen bonding in other hydroxybenzylamines is known. 13,14 As a control, we therefore prepared a TBDMS-ether of 10, that is 10a (Scheme 3), which would be unable to form an intramolecular hydrogen bond like that seen in 9.…”

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

“…[1][2][3][4][5] The presence of IMHB has been shown to significantly alter molecular properties due to formation of various conformers that in turn influence solubility, permeability, PK/ PD processes, and protein binding affinity. [6][7][8][9] The IMHB as described by Desiraju 10 is an attractive interaction in which an electropositive hydrogen atom intercedes between two electronegative fragments of the same molecule and holds them together.…”