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Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative.

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 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 ?-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 (4) 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.

SUBMITTER: Bastos ITS

PROVIDER: S-EPMC6316713 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative.

Bastos Isadora T S ITS Pinheiro Pedro de Sena M PSM Costa Fanny N FN Rocha Miguel D MD Sant'Anna Carlos Mauricio R CMR Braz Delson D Souza Everton T ET Martins Marco A MA Barreiro Eliezer J EJ Ferreira Fabio F FF Barroso Regina C RC Fraga Carlos A M CAM

Pharmaceuticals (Basel, Switzerland) 20181101 4

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 A ...[more]

PMID: 30388818

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Dataset Information

Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative.

Publications

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

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