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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14160%2F21%3A00124261" target="_blank" >RIV/00216224:14160/21:00124261 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.mdpi.com/2076-3417/12/1/300" target="_blank" >https://www.mdpi.com/2076-3417/12/1/300</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/app12010300" target="_blank" >10.3390/app12010300</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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 &lt; 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 &lt; 10.00) prevented to consider these promising antimycobacterials safe.

Název v anglickém jazyce

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

Popis výsledku anglicky

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 &lt; 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 &lt; 10.00) prevented to consider these promising antimycobacterials safe.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Applied sciences

ISSN

2076-3417

e-ISSN

2076-3417

Svazek periodika

12

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

20

Strana od-do

1-20

Kód UT WoS článku

000752599900001

EID výsledku v databázi Scopus

2-s2.0-85122024992