Synthesis and Biological Screening of 2-Substituted 5,6-Dihydro-5-oxo- 4H-1,3,4-oxadiazine-4-propanenitriles and of Their Intermediates

Abstract

To evaluate the effect of substituents on biological activities of electron-rich N-containing heterocycles, the variably 2-substituted 5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitriles 26 ± 33 were synthesized and evaluated for antibacterial, antifungal, and enzyme-inhibition activities. The target compounds were obtained from alkyl 4-or 3-hydroxy benzoates 1 and 2, respectively, and from methyl indoleacetate 3. The phenolic OH group of benzoates 1 and 2 were substituted with p-toluenesulfonyl ( 3 4 and 5), benzoyl ( 3 6 and 7), and benzyl groups ( 3 8 and 9) and then converted to 5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitriles. To establish structure-activity relationships (SAR), a pharmacological screening of the intervening intermediates was also conducted, which revealed that the intermediate hydrazide 11 possesses significant antimicrobial and MAO-A inhibiting properties and intermediates 12, 24, 28, and 29 appreciable antifungal activities. Compound 7 inhibits a-chymotrypsin. Introduction. ± A diversity of biological effects is associated with 1,3,4-oxadiazine and its derivatives, they exhibit cardiovascular [1 ± 3], antibacterial [4], plant-growth regulating [5], miticidal and nematocidal [6], acricidal [7], and insecticidal activities [8]and monoamine-oxidase (MAO) inhibition [9]. The promising therapeutic potential of this class of compounds prompted us to synthesize and biologically screen a series of structural variants of 4H-1,3,4-oxidiazine-5(6H)-ones. To establish structure activity relationships (SAR), the activities of the intervening intermediates were also determined. Thus, the readily available alkyl benzoates 1, 2, and 4 ± 9 and the indoleacetate 3 were transformed to the target 5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitriles 26 ± 33 in excellent yields. The structures of 26 ± 33 were established by spectroscopic techniques, and their biological activities were determined.

Reaction Parameters for the Synthesis of N,N-Dimethyl Fatty Hydrazides from Oil

“…According to US Environmental Protection Agency 20 and International Agency for Research on Cancer 21 , dioxane is classified as a carcinogenic compound and it is a potential carcinogen to human. The result obtained for product prepared in ethanol is in agreement with the work by Khan et al 2002 which showed that alkylation of hydrazides at the N 1 or N 2 atom strongly dependent on the nature of the solvent 22 . In neutral medium, terminal N 2 atom is alkylated whereas, in the presence of a strong base such as sodium or sodium methoxide, alkylation at the internal N 1 atom is favored in aprotic solvents such as ether and benzene, while protic solvents such as ethanol will lead to N 2 substitution.…”

X-ray structure and vibrational spectroscopy of a cobalt(II) complex prepared with excess of 4-hydroxybenzhydrazide

“…Hydrazides are organic compounds primarily known for their medical applications in the treatment of tuberculosis [1,2] as well as antibacterial agents and fungicides [3,4]. Hydrazides are good ligands for binding metal ions and their coordination chemistry has grown since it was discovered that metal complexes have stronger antimicrobial action than pure ligand and metal salt [3][4][5].…”

“…Hydrazides are good ligands for binding metal ions and their coordination chemistry has grown since it was discovered that metal complexes have stronger antimicrobial action than pure ligand and metal salt [3][4][5]. The last possibility stimulates our efforts in the preparation of new metal complexes with 4-hydroxybenzhydrazide (4hbah), to be further tested for biological activity.…”

Vibrational spectroscopy of 4-hydroxybenzhydrazide and its O,N-deuterated isotopologue accompanied by X-ray structure refinement

“…It has been observed that 4-HBAH is able to induce resistance to tomato wilt disease [9]. The presented compound has also been used in syntheses of more complicated enzyme inhibitors [10].…”