Design and Synthesis of Substituted Pyridazinone‐1‐Acetylhydrazones as Novel Phosphodiesterase 4 Inhibitors

Abstract

A series of novel pyridazin-6-one-1-acetylhydrazone hybrids were rationally designed to inhibit phosphodiesterase 4 (PDE4B). The prepared compounds were evaluated for their in vitro ability to inhibit the PDE4B enzyme; several of these compounds showed moderate activity compared to the reference drug, rolipram. Compounds 6, 12, and 14 emerged as the most potent inhibitors in this series. The [3-(4-methoxyphenyl)-6-oxo-5,6-dihydro-4H-pyridazin-1-yl]acetic acid [1-(3,4,5-trimethoxyphenyl)ethylidene]hydrazide (12) showed an IC50 value of 13 μM against PDE4B. Docking of 6, 12, and 14 into the active site of PDE4B illustrates their possible binding mode and provides insights for further optimization of this drug scaffold.

Structural design, synthesis and substituent effect of hydrazone-N-acylhydrazones reveal potent immunomodulatory agents

“…12,13 More specifically, N-acylhydrazone derivatives have been described as potential inhibitors of COX [14][15][16] , iNOS 17 and phosphodiesterases. 18,19 Lengthening the alkyl chain in the chemical structure of N-acylhydrazone-derived compounds has been identified as a strategy for https://doi.org/10.1016/j.bmc.2018.02.047 0968-0896/Ó 2018 Elsevier Ltd. All rights reserved. drug design and optimization.…”

Advances in the Development of Phosphodiesterase-4 Inhibitors

“…103,104 The combinatorial assembly of functional linkers led to compounds such as 55, in which a phenyl ring is connected to the C4 pyridazine atom. 105 5.g. Methoxy Heteroaromatic-Based PDE4 Inhibitors.…”

“…The ethyl branch at the 6-position of the benzene ring of 52 fits in the lipophilic pockets, while the benzoate extends into the outer solvated space. Replacement of the acetyl carbonyl group with a urea link between 3,5-dichloropyridine and pyridazinone led to compounds 53 and 54 (Figure ), which were shown to be potent, long-acting, and potentially safe inhaled PDE4 inhibitors. , The combinatorial assembly of functional linkers led to compounds such as 55 , in which a phenyl ring is connected to the C4 pyridazine atom …”

Synthesis, Characterization and computational study of N-Acylhydrazone derivatives.

“…Various drugs which have NAH structure which has a different activity [4][5][6] . In recent years, several studies have been published regarding the chemistry and bioactive lead scaffolds of N-acylhydrazones, and over time, this subject has grown in importance for the development of new, therapeutically useful bioactive NAH candidates [7][8][9][10][11] Scheme (1): General synthesis of N-Acylhydrazone derivatives ________________________________________________ Egypt. J. Chem.…”