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

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.

Redetermination of the structure of 2-amino-8-thia-1,5-diazaspiro[4.5]dec-1-en-5-ium chloride monohydrate

“…Their structures have been determined by the complex use of spectroscopic methods, as well as X-ray structural analysis (Kayukova, 2003;Beketov et al, 2004;Kayukova et al, 2010a). The dehydration of the products of the O-acylation of -aminopropioamidoximes allows for 3,5-disubstituted 1,2,4-oxadiazoles to be obtained, which under conditions of acid hydrolysis and in the presence of moisture are capable of undergoing a Boulton-Katritsky rearrangement to 2-amino-1,5-diazaspiro [4,5]dec-1-en-5-ium salts (Kayukova et al, 2010b(Kayukova et al, , 2018(Kayukova et al, , 2021a.…”

Reaction Products of β-Aminopropioamidoximes Nitrobenzenesulfochlorination: Linear and Rearranged to Spiropyrazolinium Salts with Antidiabetic Activity

“…Essentially, 1,2- and 2,3-spiro-1-pyrazolines exist as spiro-2-pyrazolines (∆2 isomers) [ 3 ], although, in solutions, they exhibit an equilibrium of the imine and enamine forms [ 4 ]. As we know, the spiropyrazolinium salts with a 1,5-diazaspiro-1-en-5-ium fragment that we obtained via the hydrolysis of 3-(β-heteroamino)ethyl-5-aryl-1,2,4-oxadiazoles and the arylsulfochlorination of β-aminopropioamidoximes exist, under standard conditions, as the ∆2 isomer [ 5 , 6 , 7 , 8 ]. The thermodynamic advantage of possible tautomers of the key pyrazoline moiety was estimated; it turns out that, in the case of pyrazolines, the ∆2 isomer is much more stable than the others [ 9 ].…”

“…Previously, we obtained new spiropyrazolium compounds via the hydrolysis of 3-(β-heteroamino)ethyl-5-aryl-1,2,4-oxadiazoles [ 5 , 6 ], by the arylsulfochlorination (Aryl: para -XC 6 H 4 SO 2 Cl; X=CH 3 O, CH 3 , H, Br, Cl, NO 2 ) of β-(morpholin-1-yl)aminopropioamidoxime [ 7 ] and by the tosylation of β-aminopropioamidoximes (β-amino group: piperidin-1-yl, morpholine-1-yl, thiomorpholin-1-yl, 4-phenylpiperazin-1-yl, benzimidazol-1-yl) at r.t. [ 8 ]. In the present study, we are interested in the regioselectivity of β-aminopropioamidoximes ortho -, para -nitrobenzenesulphochlorination at reaction conditions (chloroform (CHCl 3 ), diisopropylamine (DIPEA), room temperature and 70 °C).…”

Crystal structure and antidiabetic activity of 2-aminospiropyrazolinium tosylates and the product of O-tosylation of β-(benzimidazol-1-yl)propioamidoxime

“…Aminopyrazolinium-containing salts also possess inflammation, analgesic and antibacterial properties (Dusza et al, 1982a,b). Some of the authors found antitubercular activity for spiropyrazolinium benzoates and chlorides (Kayukova et al, 2021b), as well as antitubercular and antidiabetic activity in a series of -aminopropioamidoxime derivatives (Kayukova et al, 2018a(Kayukova et al, ,b, 2022a. Taking into account that the bioactivity of this family can be tuned by the nature of the parent -aminopropioamidoxime or the counter-ion in the reaction products, the screening of other derivatives of -aminopropioamidoximes for their antitubercular and antidiabetic activity is of practical interest.…”