Pyridin-2-yl Guanidine Derivatives: Conformational Control Induced by Intramolecular Hydrogen-Bonding Interactions

Abstract

The synthesis and conformational analysis of a series of pyridin-2-yl guanidine derivatives using NMR, X-ray crystallography and B3LYP/6-31+G** theoretical studies are reported. A remarkable difference was observed in the 1 H NMR spectra of the guanidinium salts compared with their N,N'-di-Boc protected and neutral analogues. This difference corresponds to a 180° change in the dihedral angle between the guanidine/ium moiety and the pyridine ring in the salts compared to the Boc protected derivatives; a conclusion which was supported by theoretical studies, X-ray data and NMR analysis. Moreover, our data sustains the existence of two intramolecular hydrogen bonding systems: (i) between the pyridine N1 atom and the guanidinium protons in the salts and (ii) within the tert-butyl carbamate groups of the Boc protected derivatives. To verify that the observed conformational control arises from these intramolecular interactions, a new series of N-Boc-N'-propyl substituted pyridin-2-yl guanidines was also prepared and studied.

Conformational equilibrium in supramolecular chemistry: Dibutyltriuret case

“…This observation gives the opportunity to control such processes [ 2 ] making conformational equilibrium [ 4 , 31 – 35 ] one of the factors, or a tool, that should be taken into account in molecular design. To the best of our knowledge there are only few publications focused on simple molecules capable to form two intramolecular HBs [ 36 – 37 ] that break upon association. This phenomenon is still under discussion [ 37 – 39 ].…”

α2-Adrenoceptor Antagonists: Synthesis, Pharmacological Evaluation, and Molecular Modeling Investigation of Pyridinoguanidine, Pyridino-2-aminoimidazoline and Their Derivatives

“…We have previously examined these conformations in a theoretical and spectroscopic study and predicted that these preferences will be maintained in the aqueous environment of the body. 16 Previous studies 6−11 have instructed that substitution of the aryl ring para to the cationic group is favored for α 2 -AR affinity and activity and that steric bulk in that position is not well tolerated. Thus, the para-substituents found in lead compounds 1 (-NHEt) and 2 [-(CH 2 ) 4 -] were prepared for all families (pyridin-2-yl and pyridin-3-yl; guanidines and 2-aminoimidazolines) because of their promising target engagement proved by microdialysis experiments 6,7 and their pharmacological profiles as antidepressants in animal models.…”

Exploring the Anti-Cancer Mechanism of Novel 3,4′-Substituted Diaryl Guanidinium Derivatives

“…Next, based on previous computational studies [9], the effect of the length of the molecule on its activity has been studied by replacing the disubstituted guanidinium in the "link" by a secondary amine (blue box in Figure 1). Additionally, we explored the effect of substituting one of the phenyl rings by a pyridine to lock the orientation of the guanidinium by means of intramolecular hydrogen bonds (IMHBs) [13]. Finally, in the "polar" region, different guanidine surrogates (i.e., isourea and sulfamide) have been tested (red box in Figure 1).…”