Synthesis and Critical View on the Structure-Activity
Relationships of N-(Substituted
phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as
Antimycobacterial Agents

J 2021

Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents

CURILLOVA, Jana, Maria PECHACOVA, Tereza PADRTOVÁ, Daniel PECHER, Sarka MASCARETTI et. al.

Basic information

Original name

Synthesis and Critical View on the Structure-Activity Relationships of N-(Substituted phenyl)-/N-Diphenylmethyl-piperazine-Based Conjugates as Antimycobacterial Agents

Authors

CURILLOVA, Jana (703 Slovakia), Maria PECHACOVA (703 Slovakia), Tereza PADRTOVÁ (203 Czech Republic, belonging to the institution), Daniel PECHER (703 Slovakia), Sarka MASCARETTI (203 Czech Republic), Josef JAMPÍLEK (203 Czech Republic), Ludmila PASKOVA (703 Slovakia), Frantisek BILKA (703 Slovakia), Gustav KOVAC (703 Slovakia) and Ivan MALIK (703 Slovakia, guarantor)

Edition

Applied sciences, Basel, MDPI, 2021, 2076-3417

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30107 Medicinal chemistry

Country of publisher

Switzerland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 2.838

RIV identification code

RIV/00216224:14160/21:00124261

Organization unit

Faculty of Pharmacy

DOI

http://dx.doi.org/10.3390/app12010300

UT WoS

000752599900001

Keywords in English

drug development; N-arylpiperazines; mycobacteria; electronic properties; lipophilicity; cytotoxicity; structure-activity

Abstract

V originále

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.

Citovat

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. Applied sciences. Basel: MDPI, 2021, vol. 12, No 1, p. 1-20. ISSN 2076-3417. Available from: https://dx.doi.org/10.3390/app12010300.

@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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