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

Abstract

Novel 1-(2-{3-/4-[(alkoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)-piperazin-1-ium chlorides (alkoxy = methoxy to butoxy; 8a–h) have been designed and synthesized through multistep reactions as a part of on-going research programme focused on finding new antimycobacterials. Lipophilic properties of these compounds were estimated by RP-HPLC using methanol/water mobile phases with a various volume fraction of the organic modifier. The log kw values, which were extrapolated from intercepts of a linear relationship between the logarithm of a retention factor k (log k) and volume fraction of a mobile phase modifier (ϕM), varied from 2.113 (8e) to 2.930 (8h) and indicated relatively high lipophilicity of these salts. Electronic properties of the molecules 8a–h were investigated by evaluation of their UV/Vis spectra. In a next phase of the research, the compounds 8a–h were in vitro screened against M. tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794), M. kansasii CNCTC My 235/80 (identical with ATCC 12478), a M. kansasii 6 509/96 clinical isolate, M. avium CNCTC My 330/80 (identical with ATCC 25291) and M. avium intracellulare ATCC 13950, respectively, as well as against M. kansasii CIT11/06, M. avium subsp. paratuberculosis CIT03 and M. avium hominissuis CIT10/08 clinical isolates using isoniazid, ethambutol, ofloxacin, ciprofloxacin or pyrazinamide as reference drugs. The tested compounds 8a–h were found to be the most promising against M. tuberculosis; a MIC = 8 μM was observed for the most effective 1-(2-{4-[(butoxycarbonyl)amino]phenyl}-2-hydroxyethyl)-4-(2-fluorophenyl)piperazin-1-ium chloride (8h). In addition, all of them showed low (insignificant) in vitro toxicity against a human monocytic leukemia THP-1 cell line, as observed LD50 values > 30 μM indicated. The structure–antimycobacterial activity relationships of the analyzed 8a–h series are also discussed.

Dibasic Derivatives of Phenylcarbamic Acid against Mycobacterial Strains: Old Drugs and New Tricks?

“…Extrapolation of estimated solute retention (log k ) to elution with 100% water (calculation of log k w ) would definitely be much more precise approach than using of log k , because the k w parameters were independent of any effect of the organic modifier and relied on the SPh alone [ 45 ]. It has been recognized that the log k w descriptor was very efficient for anticipation of in vitro antimycobacterial properties of compounds [ 46 , 47 , 48 , 49 ].…”

“…The analyses were also focused on indication of a significance level of calculated F Ratio as follows: * (one star)—statistically significant; ** (two stars)—statistically very significant; *** (three stars)—statistically extremely significant. Detailed information regarding given statistical descriptors could be found in a research paper [ 47 ].…”

Recent applications of retention modelling in liquid chromatography

“…The extent to which a drug can penetrate biological membranes, such as the blood–brain barrier, cell membranes, and skin, depends heavily on the . A number of groups publish the lipophilicity parameters of many newly synthesized drug candidates [167–180]. In drug discovery research, the LSS model is often used to obtain the , but Hawrył et al.…”

Arylaminopropanone Derivatives as Potential Cholinesterase Inhibitors: Synthesis, Docking Study and Biological Evaluation

“…The target compounds were synthesized via two-step synthesis according to Scheme 1. The first step was the preparation of carbamates 1a-4a by slightly modified reaction described previously [25,26]. The starting compound, 4-aminoacetophenone, was treated with alkyl-chloroformate at the presence of pyridine in dichloromethane.…”