Anastasia A. Zhukovets

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc amidase that catalyzes the second step of the biosynthesis of lipid A, which is an outer membrane essential structural component of Gram-negative bacteria. Inhibitors of this enzyme can be attributed to two main categories, non-hydroxamate and hydroxamate inhibitors, with the latter being the most effective given the chelation of Zn²⁺ in the active site. Compounds containing diacetylene or acetylene tails and the sulfonic head, as well as oxazoline derivatives of hydroxamic acids, are among the LpxC inhibitors with the most profound antibacterial activity. The present article describes the synthesis of novel functional derivatives of hydroxamic acids—bioisosteric to oxazoline inhibitors—containing 1,2,4- and 1,3,4-oxadiazole cores and studies of their cytotoxicity, antibacterial activity, and antibiotic potentiation. Some of the hydroxamic acids we obtained (9c, 9d, 23a, 23c, 30b, 36) showed significant potentiation in nalidixic acid, rifampicin, and kanamycin against the growth of laboratory-strain Escherichia coli MG1655. Two lead compounds (9c, 9d) significantly reduced Pseudomonas aeruginosa ATCC 27853 growth in the presence of nalidixic acid and rifampicin.

A series of phenylenediamines containing the NO₂ group and 3 to 0 fluorine atoms and 18-crown-6 ether were used to study the dependence of the stoichiometry and supramolecular structure of co-crystals on the degree of fluorination of the aromatic co-former. 2,4-Diamino-3,5,6-trifluoro- and -3,5-difluoronitrobenzenes form co-crystals of two stoichiometries: 2 : 1 (preferably) and 1 : 1. 2,4-Diamino-5-fluoronitrobenzene and the non-fluorinated analogue yield only 1 : 1 co-crystals. DSC analysis indicates complete regeneration of the stoichiometry and structure of the co-crystals in the melting–crystallization cycle. According to X-ray diffraction data, all the 1 : 1 co-crystals are built from the 1D assemblies in which N–H⋯O_cr H-bond is the only structure-directing interaction. The 2 : 1 co-crystals have a 3D or 2D supramolecular structure due to additional interactions formed by the aromatic co-formers, i.e. N–H⋯O_nitro H-bond and p⋯π electron contacts. Analysis of the structure of diaminonitrobenzene homocrystals showed that in di- and trifluorinated diaminonitrobenzenes, F atoms contribute to the formation of p⋯π electron interactions, while in mono- and non-fluorinated co-formers, the ability of NH₂ groups to form the H-bonds both as donors and as acceptors increases. Factors controlling the crystallization behaviour were rationalized using quantum-chemical computations of the packing and co-crystallization enthalpies, the energies of N–H⋯X (X = O_cr, O_nitro, N_amino) and p⋯π electron interactions, as well as the MEP and NCI analyses.