Abstract
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/zmeasured via HPLC-UV/HR-MS, log ε2 (Ch–T) from UV/Vis spectrophotometry and log kw 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 kw = 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 μM). The substance 6g also showed interesting activity against MM (MIC = 8.09 μM). 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 μM) and 6g (IC50 = 22.18 μM) in HepG2 cells as well as selectivity index (SI) values (SI < 10.00) prevented to consider these promising antimycobacterials safe.
Highlights
N-containing heterocycles are exceptionally valuable structures that hold unique positions in the design and development of biologically active compounds
The equipment, employed software tools, and particular methods to measure and interpret properly infrared (IR) spectra, nuclear magnetic resonance (NMR) spectra (1 H NMR, 13 C NMR, and 19 F NMR), high-performance liquid chromatography high-resolution mass spectra (HPLC-UV/HR-M. smegmatis ATCC 700084 (MS)) as well as ultraviolet/visible (UV/Vis) spectra for all synthesized or analyzed molecules (i.e., 3, 5a–g, and 6a–g) can be found in [30]; in addition, they are provided in the Supplementary Materials
Different analytical and physicochemical properties of hybrid molecules containing an N-(substituted phenyl)-/N-diphenylmethylpiperazine privileged scaffold allowed for the modulation of their in vitro activity against several tuberculous and nontuberculous mycobacteria as well as a particular cancer cell line (HepG2)
Summary
N-containing heterocycles are exceptionally valuable structures that hold unique positions in the design and development of biologically active compounds. N-Arylpiperazines have been considered privileged scaffolds because they interact with multiple 2pharof 20 macological targets with (much) higher affinity and selectivity than other fragments [1–
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