Abstract
Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use. In this paper, we describe the design concept of LASSBio-1835, a novel structural analogue of LASSBio-1359, planned by exploiting ring bioisosterism. Using X-ray powder diffraction, calorimetric techniques, and molecular modeling, we clearly indicate the presence of a preferred synperiplanar conformation at the amide function, which is fixed by an intramolecular 1,5-N∙∙∙S σ-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 (4) as a PDE4 inhibitor and as an A2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH.
Highlights
The conformational restriction of a flexible ligand can be used to fix a certain conformation capable of responding to molecular recognition by a particular receptor site with selectivity
The X-ray crystallography analysis, molecular modeling, and ultraviolet spectroscopy elucidated the bioactive conformations, revealing that the methylation of the N-acylhydrazone leads to an impressive conformational change that might be responsible for the different pharmacological properties of these two derivatives [4,5]
We described the development of two new thienyl-N-acylhydrazone derivatives, LASSBio-1834 (3) and LASSBio-1835 (4) [9], which were planned as multitarget vasodilator and anti-inflammatory prototypes, presenting an unprecedented structural pattern and bioactivity profile capable of being exploited in the treatment of pulmonary arterial hypertension [10]
Summary
The conformational restriction of a flexible ligand can be used to fix a certain conformation capable of responding to molecular recognition by a particular receptor site with selectivity. We have described earlier the participation of a new type of σ-hole intramolecular interaction between the sulfur atoms at the thiophene ring and the nitrogen atoms at the imine subunit of these N-acylhydrazone derivatives, which contribute to the stabilization of a particular molecular conformation and has an influence on its molecular properties [6]. This attractive interaction is based on the presence of positive electrostatic potential regions on the sides of the aromatic sulfur atom, that is, the σ-holes regions that are available for intramolecular interaction with Lewis basis, such as nitrogen and oxygen atoms [7,8] In this context, we described the development of two new thienyl-N-acylhydrazone derivatives, LASSBio-1834 (3) and LASSBio-1835 (4) [9], which were planned as multitarget vasodilator and anti-inflammatory prototypes, presenting an unprecedented structural pattern and bioactivity profile capable of being exploited in the treatment of pulmonary arterial hypertension [10]. HRMS (ESI, m/z): calculated for [M + Na] C15H16N2O3SNa, 327.0774, found 327.0778
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