Relying on a recently suggested protocol that furnishes convenient access to variously substituted 2-pyridyl ureas, twelve hitherto unknown Cu(II) complexes have been synthesized in the present work and their structures were evaluated by elemental analysis, HRMS, IR spectroscopy, and X-ray diffraction study. Two structural motifs ([Cu(L)₂Cl]⁺[Cl]⁻ or (Cu(L)₂Cl₂) depending on the substitution pattern on the 2-pyridine fragment were revealed. In addition, antiproliferative action of the obtained compounds have been investigated against lung cancer cell lines (A549, NCI-H460, NCI-H1975), and healthy WI-26 VA4 cells were used to monitor non-specific cytotoxicity. Two nitro-group substituted complexes Cu(U3)₂Cl₂ (IC₅₀ = 39.6 ± 4.5 μM) and Cu(U11)₂Cl₂ (IC₅₀ = 33.4 ± 3.8 μM) demonstrate enhanced activity against the drug resistant NCI-H1975 cells with moderate selectivity toward normal WI-26 VA4 cells. The antiproliferative mechanism of cell death underlying the growth inhibitory effect of the synthesized complexes was studied via additional experiments, including the cell cycle analysis and the apoptosis induction test. Reassuringly, certain 2-pyridyl urea-based Cu(II) complexes exerted cell line-specific antiproliferative effect which renders them valuable starting points for further unveiling the anticancer potential of this class of coordination compounds.

The cis- and trans-isomers of 6-(3-(3,4-dichlorophenyl)-1,2,4-oxadiazol-5-yl)cyclohex-3-ene-1-carboxylic acid (cis-A and trans-A) were obtained by the reaction of 3,4-dichloro-N′-hydroxybenzimidamide and cis-1,2,3,6-tetrahydrophthalic anhydride. Cocrystals of cis-A with appropriate solvents (cis-A‧½(1,2-DCE), cis-A‧½(1,2-DBE), and cis-A‧½C₆H₁₄) were grown from 1,2-dichloroethane (1,2-DCE), 1,2-dibromoethane (1,2-DBE), and a n-hexane/CHCl₃ mixture and then characterized by X-ray crystallography. In their structures, cis-A is self-assembled to give a hybrid 2D supramolecular organic framework (SOF) formed by the cooperative action of O–H⋯O hydrogen bonding, Cl⋯O halogen bonding, and π⋯π stacking. The self-assembled cis-A divides the space between the 2D SOF layers into infinite hollow tunnels incorporating solvent molecules. The energy contribution of each noncovalent interaction to the occurrence of the 2D SOF was verified by several theoretical approaches, including MEP and combined QTAIM and NCIplot analyses. The consideration of the theoretical data proved that hydrogen bonding (approx. −15.2 kcal/mol) is the most important interaction, followed by π⋯π stacking (approx. −11.1 kcal/mol); meanwhile, the contribution of halogen bonding (approx. −3.6 kcal/mol) is the smallest among these interactions. The structure of the isomeric compound trans-A does not exhibit a 2D SOF architecture. It is assembled by the combined action of hydrogen bonding and π⋯π stacking, without the involvement of halogen bonds. A comparison of the cis-A structures with that of trans-A indicated that halogen bonding, although it has the lowest energy in cis-A-based cocrystals, plays a significant role in the crystal design of the hybrid 2D SOF. The majority of the reported porous halogen-bonded organic frameworks were assembled via iodine and bromine-based contacts, while chlorine-based systems—which, in our case, are structure-directing—were unknown before this study.

We have developed a simple and convenient method for the synthesis of 3-aryl- and 3-hetaryl-1,2,4-oxadiazin-5-ones bearing an easily functionalizable (methoxycarbonyl)methyl group at position 6 via the reaction of aryl or hetaryl amidoximes with maleates or fumarates. The conditions for this reaction were optimized. Different products can be synthesized selectively in good yields depending on the base used and the ratio of reactants: substituted (1,2,4-oxadiazin-6-yl)acetic acids, corresponding methyl esters, or hybrid 3-(aryl)-6-((3-(aryl)-1,2,4-oxadiazol-5-yl)methyl)-4H-1,2,4-oxadiazin-5(6H)-ones. The reaction is tolerant to substituents’ electronic and steric effects in amidoximes. As a result, a series of 2-(5-oxo-3-(p-tolyl)-5,6-dihydro-4H-1,2,4-oxadiazin-6-yl)acetic acids, their methyl esters, and 1,2,4-oxadiazoles based on them were prepared and characterized by HRMS, ¹H, and ¹³C NMR spectroscopy. The structures of three of them were elucidated with X-ray diffraction.

Monoamine oxidase (MAO) plays a key role in the pathogenesis of central nervous system disorders, and MAO inhibitors have been used in the treatment of depression and Parkinson’s disease. In the search for new classes of MAO inhibitors, the present study investigated a series of 1,2,4-oxadiazin-5(6H)-one derivatives. This study provides the first optimization of the reaction conditions for the condensation of amidoximes with alkyl 2-halocarboxylates to yield the desired 1,2,4-oxadiazin-5(6H)-ones. The results of the in vitro MAO inhibition studies showed that the 1,2,4-oxadiazin-5(6H)-ones were indeed inhibitors of human MAO with the most potent inhibition observed for 5f (IC50 = 0.900 µM) and 7c (IC50 = 0.371 µM). It was concluded that, with appropriate substitution, 1,2,4-oxadiazin-5(6H)-one derivatives would act as good potency MAO-B inhibitors and lead compounds for the development of antiparkinsonian drugs. In Parkinson’s disease, MAO-B inhibitors enhance central dopamine levels and reduce MAO-mediated production of hydrogen peroxide and resultant oxidative injury. This study represents one of few works to investigate synthetic approaches and biological activities of the 1,2,4-oxadiazin-5(6H)-one class of heterocycles.

A preparative procedure has been developed for the synthesis of a series of new medicinally relevant 3-aryl-5-(aryloxymethyl)-1,2,4-oxadiazoles in 46–66% yields by alkylation of substituted phenols with 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles in the system K₂CO₃/KI/DMF. Poorly studied 3-R-4H-1,2,4-oxadiazin-5(6H)-ones were synthesized by a new method based on the reaction of methyl chloroacetate with amidoximes in the superbasic system t-BuONa/DMSO. The synthesized compounds at concentrations of up to 250 μg/mL showed no antibacterial activity against sensitive strains of Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas fluorescens, which supposedly suggests their low toxicity for human intestinal and mucous microflora.