Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-<i>N</i>-Acylhydrazone Derivative

• मुख्य लेखकों: Isadora T. S. Bastos (लेखक), Pedro de Sena M. Pinheiro (लेखक), Fanny N. Costa (लेखक), Miguel D. Rocha (लेखक), Carlos Mauricio R. Sant'Anna (लेखक), Delson Braz (लेखक), Everton T. Souza (लेखक), Marco A. Martins (लेखक), Eliezer J. Barreiro (लेखक), Fabio F. Ferreira (लेखक), Regina C. Barroso (लेखक), Carlos A. M. Fraga (लेखक)
• स्वरूप: पुस्तक
• प्रकाशित: MDPI AG, 2018-11-01T00:00:00Z.
• विषय: article
• ऑनलाइन पहुंच: Connect to this object online.

सारांश

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 <i>N</i>-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 A_2A 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 (<b>4</b>) as a PDE4 inhibitor and as an A_2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH.

वस्तु वर्णन

1424-8247
10.3390/ph11040119