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This research focused on a three-step synthesis, analytical, physicochemical, and biological evaluation of hybrid molecules <b>6a</b>–<b>g</b>, 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 (<i>m</i>/<i>z</i>_measured via HPLC-UV/HR-MS, log <i>ε</i>_{2 (Ch–T)} from UV/Vis spectrophotometry and log <i>k</i>_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 <i>k</i>_w = 4.1170–5.2184) were tested against <i>Mycobacterium tuberculosis</i> H₃₇R_a ATCC 25177 (<i>Mtb</i> H₃₇R_a), <i>M. kansasii</i> DSM 44162 (<i>MK</i>), <i>M. smegmatis</i> ATCC 700084 (<i>MS</i>), and <i>M. marinum</i> CAMP 5644 (<i>MM</i>). The impact of the <b>6a</b>–<b>g</b> 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 (<b>6e</b>) and 1-[2-hydroxy- propyl-{(3-trifluoromethyl)phenyl}carbamoyloxy]-4-(4-diphenylmethyl)piperazin-1-ium chloride (<b>6g</b>) most effectively inhibited the growth of <i>Mtb</i> H₃₇R_a (MIC < 3.80 μM). The substance <b>6g</b> also showed interesting activity against <i>MM</i> (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 <b>6e</b> (IC₅₀ = 29.39 μM) and <b>6g</b> (IC₅₀ = 22.18 μM) in HepG2 cells as well as selectivity index (SI) values (SI < 10.00) prevented to consider these promising antimycobacterials safe.