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Synthesis, Stereochemical Studies and Antimycobacterial Activity of New Acetyl- Hydrazine Pyridazinones

[ Vol. 14 , Issue. 1 ]

Author(s):

Dorina Mantu, Vasilichia Antoci, Alina Nicolescu, Calin Deleanu, Violeta Vasilache and Ionel I. Mangalagiu*   Pages 112 - 119 ( 8 )

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.

Affiliation:

“Alexandru Ioan Cuza” University of Iasi, Faculty of Chemistry, “Alexandru Ioan Cuza” University of Iasi, Faculty of Chemistry, “Petru Poni” Institute of Macromolecular Chemistry, Grigore Ghica Voda 41-A Alley, RO-700487 Iasi, “Petru Poni” Institute of Macromolecular Chemistry, Grigore Ghica Voda 41-A Alley, RO-700487 Iasi, CERNESIM Research Center, Bd. Carol 11, RO-700506 Iasi, Department of Chemistry, Faculty of Chemistry, Al. I. Cuza University of Iasi, P.O. Box: RO-700506, Iasi, Romania.

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