Abstract

Background: Pyridazinone derivatives is considered a privileged structure that is currently experiencing a renewed interest in medicinal chemistry. Within this paper we studied the synthesis, structure and stereochemical aspects of some new Z-sinclinal/E-anticlinal acetylhydrazines isomers derived from pyridazin-3(2H)- ones.

Methods: The synthesis of the desired pyridazinones with acetylhydrazine skeleton have been done using a classical, straight and efficient method: reaction of the corresponding esters with hydrazine hydrate. The structure of compounds was proven by elemental and spectral analysis: IR, X-ray, NMR.

Results: The synthesis is leading to a mixture of Z-sinc (up to 90%) and E-antic (less than 10%) conformers, in a conformational equilibrium. The significant difference in chemical shift between the carbonyl in the Z-sc and in the E-ac (around 5 ppm), could be used as a facile and straight tools to discriminate Z-sc/Eac conformers in the 13C NMR spectra. The temperature dependence 1H NMR studies concerning conformational equilibrium indicating the presence of a single stereoisomer at temperatures higher to 80 °C, the Z-sc isomer. In the case of 4,5- dihydro-3(2H)-pyridazinones bearing a methyl substituent in the alfa position of N1-pyridazine heterocycles, a new class of fused heterocycle with 8,9-dihydropyridazino[1,2,4]triazine structure was obtained and fully characterized.

Conclusions: The present study sheds light concerning the synthesis, structure and stereochemical problems of some new Z-sinclinal/E-anticlinal acetylhydrazines isomers derived from pyridazin-3(2H)-ones. Also, a new class of fused heterocycle with 8,9-dihydropyridazino[1,2,4]triazine structure was obtained and fully characterized. A feasible reaction mechanism for cyclisation process is presented. The antimycobacterial activity of compounds was evaluated.

Keywords: Acetylhydrazine pyridazin-3(2H)-ones, conformational studies, variable temperature NMR, Z-sc and E-ac hydrazide stereoisomers, pyridazino[1, 2, 4]triazin-3(4H)-one, X-ray structure, antimycobacterial activity.

Graphical Abstract