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@article{1836502,
author = {Curillova, Jana and Pechacova, Maria and Padrtová, Tereza and Pecher, Daniel and Mascaretti, Sarka and Jampílek, Josef and Paskova, Ludmila and Bilka, Frantisek and Kovac, Gustav and Malik, Ivan},
article_location = {Basel},
article_number = {1},
doi = {http://dx.doi.org/10.3390/app12010300},
keywords = {drug development; N-arylpiperazines; mycobacteria; electronic properties; lipophilicity; cytotoxicity; structure-activity},
language = {eng},
issn = {2076-3417},
journal = {Applied sciences},
title = {Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents},
url = {https://www.mdpi.com/2076-3417/12/1/300},
volume = {12},
year = {2021}
}
TY - JOUR
ID - 1836502
AU - Curillova, Jana - Pechacova, Maria - Padrtová, Tereza - Pecher, Daniel - Mascaretti, Sarka - Jampílek, Josef - Paskova, Ludmila - Bilka, Frantisek - Kovac, Gustav - Malik, Ivan
PY - 2021
TI - Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents
JF - Applied sciences
VL - 12
IS - 1
SP - 1-20
EP - 1-20
PB - MDPI
SN - 20763417
KW - drug development
KW - N-arylpiperazines
KW - mycobacteria
KW - electronic properties
KW - lipophilicity
KW - cytotoxicity
KW - structure-activity
UR - https://www.mdpi.com/2076-3417/12/1/300
N2 - This research focused on a three-step synthesis, analytical, physicochemical, and biological evaluation of hybrid molecules 6a-g, containing a lipophilic 3-trifluoromethylphenyl moiety, polar carbamoyloxy bridge, 2-hydroxypropan-1,3-diyl chain and 4-(substituted phenyl)-/4-diphenylmethylpiperazin-1-ium-1-yl fragment. The estimation of analytical and physicochemical descriptors (m/z(measured) via HPLC-UV/HR-MS, log epsilon(2 (Ch-T)) from UV/Vis spectrophotometry and log k(w) via RP-HPLC) as well as in vitro antimycobacterial and cytotoxic screening of given compounds were carried out (i.e., determination of MIC and IC50 values). These highly lipophilic molecules (log k(w) = 4.1170-5.2184) were tested against Mycobacterium tuberculosis H37Ra ATCC 25177 (Mtb H37Ra), M. kansasii DSM 44162 (MK), M. smegmatis ATCC 700084 (MS), and M. marinum CAMP 5644 (MM). The impact of the 6a-g set on the viability of human liver hepatocellular carcinoma (HepG2) cells was also investigated. 1-[2-Hydroxypropyl-{(3-trifluoromethyl)- phenyl}carbamoyloxy]-4-(3,4-dichlorophenyl)piperazin-1-ium chloride (6e) and 1-[2-hydroxy- propyl-{(3-trifluoromethyl)phenyl}carbamoyloxy]-4-(4-diphenylmethyl)piperazin-1-ium chloride (6g) most effectively inhibited the growth of Mtb H37Ra (MIC < 3.80 mu M). The substance 6g also showed interesting activity against MM (MIC = 8.09 mu M). All obtained data served as input values for structure-activity relationship evaluations using statistical principal component analysis. In fact, the toxicity of both 6e (IC50 = 29.39 mu M) and 6g (IC50 = 22.18 mu M) in HepG2 cells as well as selectivity index (SI) values (SI < 10.00) prevented to consider these promising antimycobacterials safe.
ER -
CURILLOVA, Jana, Maria PECHACOVA, Tereza PADRTOVÁ, Daniel PECHER, Sarka MASCARETTI, Josef JAMPÍLEK, Ludmila PASKOVA, Frantisek BILKA, Gustav KOVAC and Ivan MALIK. Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents. \textit{Applied sciences}. Basel: MDPI, 2021, vol.~12, No~1, p.~1-20. ISSN~2076-3417. Available from: https://dx.doi.org/10.3390/app12010300.
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