Isoxazole derivatives of silatrane: synthesis, characterization, in silico ADME profile, prediction of potential pharmacological activity and evaluation of antimicrobial action

• Published in: Applied organometallic chemistry 2020-12, Vol.34 (12), p.n/a
• Main Authors: Adamovich, Sergey N., Kondrashov, Evgeniy V., Ushakov, Igor A., Shatokhina, Nina S., Oborina, Elizaveta N., Vashchenko, Alexander V., Belovezhets, Lydmila A., Rozentsveig, Igor B., Verpoort, Francis
• Format: Article
• Language: English
• Subjects: Adducts; Antiinfectives and antibacterials; antimicrobial activity; Antimicrobial agents; Chemical analysis; Chemical synthesis; Chemistry; E coli; Gentamicin; hybrids; Infrared analysis; isoxazole; Mass spectrometry; Microorganisms; NMR; Nuclear magnetic resonance; Pharmacology; Pseudomonas aeruginosa; Screening; silatrane; Substitutes; X‐ray crystallography
• ISSN: 0268-2605; 1099-0739
• DOI: 10.1002/aoc.5976

A new family of mono‐ (3a‐h) and bis‐ (4a‐g) isoxazole‐bridged silatranes has been synthesized by the reaction of 3‐aminopropylsilatrane (1) and 3‐substituted 5‐chloro‐methylisoxazoles (2a‐h). The structure of the isoxazole‐silatrane hybrids is characterized by elemental analysis, FT‐IR, UV, NMR (1H, 13C,29Si and 15N) spectroscopy, high‐resolution mass spectrometry, and X‐ray diffraction analysis. The in silico ADME (absorption, distribution, metabolism, excretion) assessment reveals that properties of mono‐adducts (3a‐h) are similar to those of drugs obeyed to the Lipinski's rule. The calculated screening of potential pharmacological activity profiles (in silico PASS program) of isoxazole‐silatranes shows that all synthesized compounds (both mono‐ and bis‐substituted) may have high antitumor action, unlike starting isoxazoles. The preliminary screening of the synthesized silatranes for antimicrobial activity against Enterococcus durans, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa indicates that all test samples are active only against gram‐positive microorganisms. Silatrane 3f displays minimal inhibitory concentration (MIC 12.5 and 6.2 μg ml−1) against E. durans and B. subtilis as compared with standard drug gentamicin (MIC 25 and 50 μg ml−1). A new family of mono‐and bis‐ isoxazole‐bridged silatranes has been synthesized. The in silico ADME (absorption, distribution, metabolism, excretion) assessment reveals that properties of mono‐adducts are like those of drugs obeyed to the Lipinski's rule. The preliminary screening of the synthesized silatranes for antimicrobial activity indicates that all test samples are active only against gram‐positive microorganisms.