Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative
AbstractPulmonary 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. View Full-Text
- Supplementary File 1:
PDF-Document (PDF, 1121 KB)
Share & Cite This Article
Bastos, I.T.S.; Pinheiro, P.S.M.; Costa, F.N.; Rocha, M.D.; Sant’Anna, C.M.R.; Braz, D.; Souza, E.T.; Martins, M.A.; Barreiro, E.J.; Ferreira, F.F.; Barroso, R.C.; Fraga, C.A.M. Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative. Pharmaceuticals 2018, 11, 119.
Bastos ITS, Pinheiro PSM, Costa FN, Rocha MD, Sant’Anna CMR, Braz D, Souza ET, Martins MA, Barreiro EJ, Ferreira FF, Barroso RC, Fraga CAM. Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative. Pharmaceuticals. 2018; 11(4):119.Chicago/Turabian Style
Bastos, Isadora T.S.; Pinheiro, Pedro S.M.; Costa, Fanny N.; Rocha, Miguel D.; Sant’Anna, Carlos M.R.; Braz, Delson; Souza, Everton T.; Martins, Marco A.; Barreiro, Eliezer J.; Ferreira, Fabio F.; Barroso, Regina C.; Fraga, Carlos A.M. 2018. "Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative." Pharmaceuticals 11, no. 4: 119.
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.