When replacing a benzyl group (\(W\) = benzyl) with the bulkier diphenylmethyl (\(W\) = dimethylphenyl) one, an extended geometry is provided at the binding site. This modification increases the compound's interactions with this site, as a docking study predicted, thus improving in vitro anti-_Mtb_ activity [15]. Other researchers suggested very precise modifications of fragment **A**, which can be made without the loss of in vitro antimycobacterial efficacy. For example, its replacement with a 3-/4-alkoxyphenyl group (alkoxy = methoxy to butoxy) was acceptable assuming simultaneous convenient structural changes within both **B** and **D** compartments. If such structural arrangement is established, the introduction of lipophilic substituents (3\({}^{\prime}\)-CF\({}_{3}\) or 4\({}^{\prime}\)-F) at a 4-(substituted)phenylpiperazine-1-ium-1-yl moiety improved in vitro activity against _Mtb_ H\({}_{37}\)R\({}_{\
u}\), _M. kansansii_ DSM 44162 (_MK_ DSM), and several other mycobacteria as well [18; 19]. In addition, the positive impact of increased lipophilicity on anti-tuberculosis (anti-TB) activity was also supported with the conclusions published in [20; 21; 22]. The replacement of a piperazin-1,4-diyl heterocycle with a piperidin-1,4-diyl moiety together with the introduction of a 4-OH group retained high in vitro anti-TB efficiency of the resulting compound **SD** (Figure 2) if both 4\({}^{\prime}\)-Cl-3\({}^{\prime}\)-CF\({}_{3}\)-phenyl and 4-Cl-phenyl groups were present. Interestingly, the replacement of the latter with phenyl, 3-CF\({}_{3}\)-phenyl, or a 3,4-diCl-phenyl fragment decreased anti-TB activity [23]. The OH group within compartment **C** (Figure 1) is important for the activity of the series of **RU** compounds against _Mtb_ H\({}_{37}\)R\({}_{\
u}\)[15]. Docking studies indicated hydrogen bonding interaction(s) between a given moiety and highly conserved and charged residues of particular amino acids localized at the pathogen's ATP synthase binding site. The synthase is an enzyme consisting of two functional domains, i.e., ATP-synthesizing F\({}_{1}\) unit and proton-translocating F\({}_{0}\) unit [24]. The research in [25] also confirmed that such structural arrangement of molecules, i.e., the combination of a lipophilic group, polar fragment (\(O\)-bridge), 2-hydroxypropan-1,3-diyl chain and 4-arylpiperazin-1-yl moiety, was favorable in order to interact with the synthase. The linker might also be modified precisely (Figure 3) to afford effective molecules from a series of **VN** compounds against multidrug-resistant TB (MDR-TB). The modification provided different mechanisms of anti-MDR-TB action, as the designed derivatives selectively targeted and inhibited DNA-dependent RNA polymerase enzymes of the pathogens. The keto-enol functional moiety (Figure 3) is responsible for chelating Mg\({}^{2+}\) ions located in the \(\beta^{\prime}\)-subunit of a given enzyme [26]. Figure 2: The highly lipophilic compound **SD** was efficient in vitro against _Mycobacterium tuberculosis_ H\({}_{37}\)R\({}_{\
u}\). (* = chiral center). The current research aimed at the synthesis of highly lipophilic racemates (Figure 4) structurally similar to those characterized in the literature [15; 18; 19] and estimation of the parameters describing their spectral, electronic, and lipohydphilic properties. The structural framework of designed 6a-g allowed for the assumption of their noticeable in vitro activity against some of the tested mycobacteria, i.e., an attenuated _Mtb_ H\({}_{37}\)Ra ATCC 25177, _MK_ DSM, _M. singematis_ ATCC 700084 (_MS_), and _M. marinum_ CAMP 5644 (_MM_). The impact of 6a-g on the viability of human liver hepatocellular carcinoma (HepG2) cells was also investigated in vitro. The cell line shows high proliferation rates and epithelial-like morphology [27], thus being used most commonly in drug metabolism and hepatotoxicity studies.