Synthesis, structural characterisation and theoretical studies of a novel pyridazine derivative: Investigations of anti-inflammatory activity and inhibition of α-glucosidase

• Published in: Journal of molecular structure Vol. 1234; p. 130177
• Main Authors: Zaoui, Younes, Ramli, Youssef, Tan, Sang Loon, Tiekink, Edward R.T., Chemlal, Laila, Mague, Joel T., Taoufik, Jamal, Faouzi, M. E. Abbes, Ansar, M'Hammed
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.06.2021
• Subjects: Biological activities; DFT; Molecular packing; Pyridazinyl; Molecular packing; DFT; Biological activities; Pyridazinyl
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2021.130177

•Crystallography on 1 shows the N-bound ethylacetate to lie out of the central plane.•The methyl group in 1 effects the electronic structure compared to the H congener.•The methyl group in 1 forms only a weak non-covalent contact in the packing.•The calculated lattice energy for the methyl derivative is 4.1 kcal/mol greater.•Compound 1 has moderate inhibition against α-glucosidase. X-ray crystallography on pyridazine 1 (ethyl 2-(3-methyl-4-(4-methylbenzyl)-6-oxopyridazin-1(6H)-yl)acetate) shows the planar pyridazinyl ring to exhibit significant delocalisation of π-electron density over the constituent atoms and to be substituted with oxo, methyl, (4-methylphenyl)methyl and N-bound ethylacetate groups. While three of the ring-bound atoms are close to co-planar with the ring, the ethylacetate group is not; the latter exhibits a definitive kink in its conformation. In the molecular packing of 1, helical supramolecular chains along the b-axis are formed through O- and N-methylene-C–H…O(carbonyl) and O-methylene-C–H…π(pyridazinyl) interactions. The chains are connected into a supramolecular layer by π(pyridazinyl)…π(phenyl) interactions. The flat layers stacks along the c-axis without directional interactions between them. The geometry-optimisation of 1 resulted in the straightening of terminal ethylacetate group but no other substantial changes. Computational chemistry shows the most stabilising interactions in the crystal are due to the π(pyridazinyl)…π(phenyl) (-10.7 kcal/mol) followed by O- and N-methylene-C–H…O(carbonyl) (-9.5 and -9.0 kcal/mol, respectively). The most prominent identified inter-layer interaction is a weak methylene-C–H…N(pyridazinyl) contact. Throughout, comparisons are made with the phenyl analogue of 1, namely 2. Most notably, the lattice energy of 1 is approximately 4.1 kcal/mol more stable than that of 2, an observation related to the influence upon the molecular packing exerted by the methyl substituent of 1. Compound 1 exhibits moderate inhibition against α-glucosidase, compared to Acarbose, and weak heat-induced haemolysis inhibition. [Display omitted]