Design of novel water-soluble isoxazole-based antimicrobial agents and evaluation of their cytotoxicity and acute toxicity

[Display omitted] •Design and synthesis of novel water-soluble isoxazole-bearing antimicrobial agents.•Screening of substituents at positions 3 and 5 of the isoxazole ring.•Isoxazolyl amino acids show promising bacteriostatic activity (best MIC 0.06–2.5 µg/mL).•((3-Arylisoxazol-5-yl)methyl)-l-prolines 5c,d has wide spectrum of antimicrobial action.•Leading antibacterial compounds have both low cytotoxicity and low acute toxicity. Based on the readily available 3-organyl-5-(chloromethyl)isoxazoles, a number of previously unknown water-soluble conjugates of isoxazoles with thiourea, amino acids, some secondary and tertiary amines, and thioglycolic acid were synthesized. The bacteriostatic activity of aforementioned compounds has been studied against Enterococcus durans B-603, Bacillus subtilis B-407, Rhodococcus qingshengii Ac-2784D, and Escherichia coli B-1238 microorganisms (provided by All-Russian Collection of Microorganisms, VKM). The influence of the nature of the substituents in positions 3 and 5 of the isoxazole ring on the antimicrobial activity of the obtained compounds has been determined. It is found that the highest bacteriostatic effect is observed for compounds containing 4-methoxyphenyl or 5-nitrofuran-2-yl substituents in position 3 of the isoxazole ring as well as methylene group in position 5 bearing residues of l-proline or N-Ac-l-cysteine (5a–d, MIC 0.06–2.5 µg/ml). The leading compounds showed low cytotoxicity on normal human skin fibroblast cells (NAF1nor) and low acute toxicity on mice in comparison with the well-known isoxazole-containing antibiotic oxacillin.