ABSTRACT
Among a small series of tested N-acylhydrazones (NAHs), the compound 8a was selected as a selective submicromolar phosphodiesterase-4 (PDE4) inhibitor associated with anti-TNF-α properties measured both in vitro and in vivo. The recognition pattern of compound 8a was elucidated through molecular modeling studies based on the knowledge of the 3D-structure of zardaverine, a PDE4 inhibitor resembling the structure of 8a, cocrystallized with the PDE4. Based on further conformational analysis dealing with N-methyl-NAHs, a quinazoline derivative (19) was designed as a conformationally constrained NAH analogue and showed similar in vitro pharmacological profile, compared with 8a. In addition 19 was found active when tested orally in LPS-evoked airway hyperreactivity and fully confirmed the working hypothesis supporting this work.
Subject(s)
Drug Design , Hydrazones/chemistry , Hydrazones/pharmacology , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Administration, Oral , Animals , Female , Humans , Hydrazones/chemical synthesis , Hydrazones/therapeutic use , Magnetic Resonance Spectroscopy , Mass Spectrometry , Mice , Models, Molecular , Molecular Conformation , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/therapeutic use , Pneumonia/drug therapyABSTRACT
This paper describes the synthesis, pharmacological evaluation and docking studies of a series of new sulindac analogues. Overall, the designed compounds revealed good, in vivo, antinociceptive activity and satisfactory anti-inflammatory profile. Flexible molecular docking with COX-1/COX-2 has shown putative binding modes of the designed compounds while the theoretical evaluation of cell permeability based on Lipinski's rule of five has helped rationalize the biological results.
