Boulton-katritzky rearrangement of 5-substituted phenyl-3-[2-(Morpholin-1-yl)ethyl]-1,2,4-oxadiazoles as a synthetic path to spiropyrazoline benzoates and chloride with antitubercular properties
Kayukova L. Vologzhanina A. Praliyev K. Dyusembaeva G. Baitursynova G. Uzakova A. Bismilda V. Chingissova L. Akatan K.
2 February 2021MDPI AG
Molecules
2021#26Issue 4
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.
1,2,4-oxadiazoles , In vitro antitubercular screening , Molecular docking , Spiropyrazolinium compounds , X-ray diffraction
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JSC A. B. Bekturov Institute of Chemical Sciences, 106 Shokan Ualikhanov St, Almaty, 050010, Kazakhstan
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilov St, B-334, Moscow, 119991, Russian Federation
National Scientific Center of Phthisiopulmonology of Ministry of Health of the Republic of Kazakhstan, 5 Bekkhozhin St, Almaty, 050010, Kazakhstan
National scientific laboratory, S. Amanzholov East Kazakhstan State University, 18/1 Amurskaya St, Ust-Kamenogorsk, 070002, Kazakhstan
JSC A. B. Bekturov Institute of Chemical Sciences
A. N. Nesmeyanov Institute of Organoelement Compounds
National Scientific Center of Phthisiopulmonology of Ministry of Health of the Republic of Kazakhstan
National scientific laboratory
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