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Molecules ; 26(4)2021 Feb 12.
Article in English | MEDLINE | ID: mdl-33673047

ABSTRACT

The analysis of stability of biologically active compounds requires an accurate determination of their structure. We have found that 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles are generally unstable in the presence of acids and bases and are rearranged into the salts of spiropyrazolinium compounds. Hence, there is a significant probability that it is the rearranged products that should be attributed to biological activity and not the primarily screened 5-aryl-3-(2-aminoethyl)-1,2,4-oxadiazoles. A series of the 2-amino-8-oxa-1,5-diazaspiro[4.5]dec-1-en-5-ium (spiropyrazoline) benzoates and chloride was synthesized by Boulton-Katritzky rearrangement of 5-substituted phenyl-3-[2-(morpholin-1-yl)ethyl]-1,2,4-oxadiazoles and characterized using FT-IR and NMR spectroscopy and X-ray diffraction. Spiropyrazolylammonium chloride demonstrates in vitro antitubercular activity on DS (drug-sensitive) and MDR (multidrug-resistant) of MTB (M. tuberculosis) strains (1 and 2 µg/mL, accordingly) equal to the activity of the basic antitubercular drug rifampicin; spiropyrazoline benzoates exhibit an average antitubercular activity of 10-100 µg/mL on MTB strains. Molecular docking studies revealed a series of M. tuberculosis receptors with the energies of ligand-receptor complexes (-35.8--42.8 kcal/mol) close to the value of intermolecular pairwise interactions of the same cation in the crystal of spiropyrazolylammonium chloride (-35.3 kcal/mol). However, only in complex with transcriptional repressor EthR2, both stereoisomers of the cation realize similar intermolecular interactions.


Subject(s)
Antitubercular Agents/chemistry , Benzoates/chemistry , Oxadiazoles/chemistry , Tuberculosis/drug therapy , Antitubercular Agents/pharmacology , Benzoates/pharmacology , Chlorides/chemistry , Humans , Microbial Sensitivity Tests , Molecular Docking Simulation , Molecular Structure , Mycobacterium tuberculosis/drug effects , Oxadiazoles/pharmacology , Spectroscopy, Fourier Transform Infrared , Stereoisomerism , Structure-Activity Relationship , Tuberculosis/microbiology
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