Synthesis and antituberculosis activity of O-aroyl-β-(4-phenylpiperazin-1-yl)propioamidoximes

Abstract

The search for new tuberculostatics is an important task for medicinal chemistry. A series of new O-aroylb-(4-phenylpiperazin-1-yl)propioamidoximes were synthesized and tested in vitro for antituberculosis activity. The synthesis of the target substances consists of 3 -4 steps. In the first step, b-(4-phenylpiperazin-1-yl)propionitrile was obtained in 79% yield; the second step yields b-(4-phenylpiperazin-1-yl)propioamidoxime in 75% yield. Subsequent aroylation of this amidoxime by substituted benzoic acid chlorides in the presence of Et 3 N leads to the target O-aroyl-b-(4-phenylpiperazin-1-yl)propioamidoximes in 61 -93% yields. Hydrochlorides of the O-aroylated products were obtained in 72 -94% yields by the action of ethereal HCl on solutions of the bases. PMR spectra of hydrochlorides of the O-aroylated products show evidence of slow inversion of the heterocycle at the b-position and coordination of HCl at the N1 atom of the 4-phenylpiperazine fragment. Some bases and hydrochlorides of O-aroyl-b-(4-phenylpiperazin-1-yl)propioamidoximes exhibited interesting antituberculosis properties when tested in vitro on sensitive, resistant, and multi-drug resistant strains of M. tuberculosis.

Interaction of the O-Benzoyl--aminopropioamidoximes with Lawesson's Reagent and Spectral Characterization of the Products

“…Under cooling with ice water, stirring portions of Lawesson's reagent (0.14 g, 0.00035 mol) were added to a solution of O-benzoyl-( β -4-phenilpiperazin-1-yl)propioamidoxime ( 4 ) [19] (0.2 g, 0.00056 mol) in 15 mL of dry THF. The reaction mixture was stirred at room temperature for an hour and heated at 70°C with TLC monitoring.…”

“…A high anti-HIV activity of thion derivative of dibenzoyl substituted piperazine was revealed; thion derivative gives 100% inhibition of the HIV virus in comparison with 11% inhibition of the original carbonyl compounds [2]. In our group samples with high antitubercular activity were revealed within the row of β -aminopropioamides [3–5]. For us it was interesting to investigate the effect of replacing the oxygen atom in carbonyl group on a sulfur atom on the biological properties of studied compounds, primarily on the antitubercular properties.…”

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

“…Previously, in our studies of the acylation of -aminopropioamidoximes with acid chlorides of substituted benzoic acids, only O-acyl--aminopropioamidoximes were identified as acylation reaction products. 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.…”

Synthesis and In Vitro Antimycobacterial Activity of Novel N-Arylpiperazines Containing an Ethane-1,2-diyl Connecting Chain

“…An N -arylpiperazine privileged scaffold [ 1 ] has been found in the chemical structure of many effective antimycobacterial agents [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Some of these compounds have been characterized by a very typical structural arrangement [ 5 , 6 , 7 , 8 ], i.e., the N -aryl- or variously substituted N -phenylpiperazine moiety, connecting hydrocarbon chain and terminal heterocyclic fragment.…”

“…An N -arylpiperazine privileged scaffold [ 1 ] has been found in the chemical structure of many effective antimycobacterial agents [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Some of these compounds have been characterized by a very typical structural arrangement [ 5 , 6 , 7 , 8 ], i.e., the N -aryl- or variously substituted N -phenylpiperazine moiety, connecting hydrocarbon chain and terminal heterocyclic fragment. Efforts to combine the N -arylpiperazine and “ethambutol-like“ structural frameworks were supported by comprehensive structure–activity relationships ( SAR ) studies of homopiperazin-1,4-diyl-containing derivatives (e.g., a molecule SQ775 ; Figure 1 a), ethambutol (EMB; Figure 1 b) and the diamines structurally based on EMB [ 9 , 10 , 11 , 12 ].…”