Molecular structure and gas-phase reactivity of clonidine and rilmenidine: Two-layered ONIOM calculations

Abstract

The geometries of various tautomers and rotamers of clonidine and rilmenidine in both anionic and protonated forms, were optimized using the two-layered ONIOM(B3LYP 6-311]G(d,p) : MNDO) method. The calculations showed that, in agreement with experiment, clonidine exists as the more stable imino tautomer. The tautomer containing the amino group is less stable by about 30 kJ mol~1. Rilmenidine also exists in two forms (amino and imino), the amino tautomer being more stable by 5 kJ mol~1. The computed stable conformation for the clonidine species is characterized by the phenyl and imidazolidine rings being perpendicular to each other. In the case of the rilmenidine tautomers and ionised forms, the oxazoline and dicyclopropyl moieties are in a mutual gauche conformation. In contrast to the parent neutral molecule of clonidine, ionization caused considerable geometric changes in the clonidine anions. The oxazoline derivative of rilmenidine is by about 50È60 kJ mol~1, a weaker acid than the imidazoline derivative clonidine. The primary protonation sites are the imidazolidine and oxazoline parts of the drugs. Rilmenidine is slightly less basic than clonidine. The proton affinities of clonidine and rilmenidine were computed to be [999 and [996 kJ mol~1, respectively. The clonidine base was found to be substantially more lipophilic than the base of rilmenidine.

Synthesis, Inhibition Properties, and Theoretical Study of the New Nanomolar Trehalase Inhibitor 1‐Thiatrehazolin: Towards a Structural Understanding of Trehazolin Inhibition

“…[26] The 2-aminooxazo(thiazo)line moiety, however, is perfectly suited to form a bidentate complex with the active site carboxylic acid, as shown in Figure 2 (or a salt bridge after net proton transfer from the catalytic acid to the heterocycle). Such a complex would be expected to be stronger for 5 than for its thiazoline analogue 11, as shown by DFT B3LYP/6-311 + G(d,p) quantum mechanical calculations performed on a simple model for this interaction in the gas phase.…”

“…In this theoretical study, we have used acetic acid to represent the enzyme cata- lytic acid group and 2-(methylamino)oxazoline or -thiazoline as models for 5 or 11, respectively. For the theoretical study we considered only the 2-(methylamino)-tautomer of the heterocycles, since previous calculations [26,27] at various levels of theory have shown that 2-aminooxazo(thiazo)line is more stable than the alternative 2-iminooxazo(thiazo)lidine tautomer by about 2 kcal mol…”

Multiple Binding Sites for Substrates and Modulators of Semicarbazide-Sensitive Amine Oxidases: Kinetic Consequences

“…Binding of CLON causes a displacement of TPQ, inducing a rotation of the TPQ side chain to the "on-copper" nonproductive orientation, in which the hydroxyl group of TPQ coordinates the copper ion, together with three histidine residues (His 519 , His 521 , and His 683 ). The phenyl ring of CLON is observed to lie almost perpendicular to the imidazolidine portion of the molecule, according to the more stable conformation optimized by Remko et al (2001), and it is clearly trapped by stacking interactions in a "sandwichlike" orientation within the aromatic side chains of TPQ 470 and Tyr 472 residues (Fig. 5).…”

Effect of the new centrally acting antihypertensive agent rilmenidine on endothelial and platelet function in essential hypertension

“…Rilmenidine is the first oxazoline derivative and its molecular structure differs from imidazoline derivative clonidine. 7 It acts preferably on the newly described I 1 -imidazoline receptor, also having a lesser effect on central ␣ 2 -adrenoceptors. 8 Rilmenidine, a selective I 1 imidazoline receptor binding agent, has been shown to bind to imidazoline receptor in the central nervous system (in the brain stem) and in the kidney.…”