Synthesis and Antimicrobial Activity of Novel Hydrazone and 1,2,4-Triazole-3-thione Derivatives

Novel hydrazone and 1,2,4-triazole-3-thione derivatives were obtained via the reaction of N1,N3,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides with acid hydrazides and thiosemicarbazide, respectively. Structure of the products was proved using IR and 1H NMR spectroscopy methods. Some of the synthesized compounds were tested for antimicrobial activity

DOI: 10.1134/S1070363222020050 The synthesis and determination of the practical value of hydrazones are relevant, since a hydrazone fragment is present in the molecules of a number of biologically active compounds [1], which have antimicrobial [2][3][4][5], anti-inflammatory [6], analgesic [7], antiprotozoal [8], antituberculous [9], anticonvulsant [10], and cardioprotective activity [11]. The combination of different functional groups in hydrazones results in a large number of compounds with unique physical and chemical properties. Some of them can be used in the treatment of diseases of the central nervous system [12], as well as in molecular targeted therapy of drug treatment of cancer [13,14]. Structural analogs of hydrazones have shown good results in their study as growth promoters in plants of Nicotiana tabacum L. and Arabidopsis thaliana species [15].
In this regard, the synthesis of compounds with hydrazone and 1,2,4-triazole-3-thione fragments is promising for the preparation of biologically active compounds and for the creation of new drugs based on them.
Previously, we have obtained new oxocyclohexane-1,3-dicarboxamide derivatives by the condensation of acetoacetic acid amides with aromatic aldehydes in the presence of a basic piperidine catalyst in ethanol at room temperature [28][29][30][31]. The reactions of the obtained compounds with N-nucleophiles [29] and Baeyer-Villiger oxidation [33] have been studied.
The hydrazone form of compounds 7-9 is confirmed by the presence in the NMR spectra of the spin-spin coupling between the protons at the C 3 (3.65-4.42 ppm) C 2 atoms of the ring (3.12-4.04 ppm). The proton signal of the NH group not linked to the benzene ring also proves the proposed structure. The chemical shifts of the proton singlets of the two NH groups of the arylamide substituents are shifted to a stronger field compared to the chemical shifts of the starting compounds 6a-6o [28][29][30].
Existence of compounds 7-9 in the hydrazone form can be explained by its stabilization due to intermolecular hydrogen bonds. Heterocyclization apparently does not proceed due to the low nucleophilicity of nitrogen atoms in acid hydrazides.
In the IR spectra of compounds 10а-10d there are no stretching vibrations of the conjugated CO group of the alicycle and С=С bonds. The presence of stretching vibration bands of the N(C=S)N fragment at 1336-1360 cm -1 and the С=S moiety at 1592-1600 cm -1 , as well as the presence of proton signals of the NH groups at the C 1 and C 2 atoms (8.05-8.54 ppm), C 4 (10.33-10.46 ppm) and C 6 atoms (3.54-4.46 ppm) resonating with a proton at the C 7 atom (3.67-4.00 ppm) in the 1 H NMR spectra confirm the proposed structure of spiro compounds 10a-10d and excludes possible alternative enamine and imine structures. When comparing the spectral characteristics of spiro compounds 10a-10d with the starting cyclohexanones 6d, 6m-6o, it was found that the chemical shift of the proton doublet at the C 8 atom of the ring in the spectra of compounds 10a-10d is shifted to upfield region (2.78-3.12 ppm, J 11.4-12.0 Hz) [29,30].