The \(N\)-arylpiperazine ligands can also bind to specific effector structures of mycobacteria affecting various biochemical processes within these pathogens. Overall, given scaffolds might serve as a very suitable structural platform to develop compounds with multiple pharmacological activities, including the antimycobacterial ones, or they might be involved in the construction of compound libraries [7; 8]. The search for effective antimycobacterials with favorable pharmacokinetic and toxicological properties is still challenging, because infections caused by tuberculous and non-tuberculous mycobacterial strains are responsible for significant morbidity and mortality worldwide. Moreover, current antibiotic treatment options often result in suboptimal outcomes [9]. [PERSON] et al. (2021) reported that quite a considerable number of the compounds containing an \(N\)-arylpiperazine structural motif showed remarkable activity against _Mycobacterium tuberculosis_\(\mathrm{H_{37}R_{v}}\), \(\mathrm{H_{37}R_{a}}\), \(\mathrm{\left({{Mtb}}\ {{\mathrm{H_{37}R_{a}}}}\right)}\), \(M\)-\(\mathrm{\left({{Mtb}}\ {{\mathrm{H_{37}R_{a}}}}\right)}\), \(M\)-\(\mathrm{\left({{M}S}\right)}\), and other mycobacterial strains. The authors also provided structure-activity relationships (SARs) for particular classes of these molecules divided according to their chemical structure. However, there is still room for the development of novel, fast-acting, potent, and safe antimycobacterial agents [10]. The design of antimycobacterial drugs via conjugation of efficacious drug fragments is well-known. Resulting compounds might be able to simultaneously affect different biological targets, exerting multiple biological actions, or one part of this molecule can offset adverse effects caused by the other one [11; 12; 13; 14]. [PERSON] et al. (2010) structurally combined a highly lipophilic 2-naphthyl(phenyl)methyl moiety (**A**) with a polar etheric bridge (**B**), 2-hydroxypropan-1,3-diyl chain (**C**) and N-aryl-/\(N\)-(substituted)phenyl-/\(N\)-benzyl-/\(N\)-diphenylmethylpiperazine group (**D**) [15] providing a series of **RU** compounds (Figure 1). The authors preliminary explored SARs and concluded that electron-withdrawing (EW) lipophilic substituents (i.e., \(R\) substituent or dissubstitution), attached to a phenyl ring of these molecules, decreased in vitro efficiency notably or even caused its loss against \(Mtb\)\(\mathrm{H_{37}R_{v}}\). Paradoxically, bulky lipophilic moieties at a piperazin-1,4-diyl heterocycle improved the activity. The most effective compounds containing a benzyl fragment (\(W\) = benzyl) or diphenylmethyl group (\(W\) = diphenylmethyl) inhibited the growth of \(Mtb\)\(\mathrm{H_{37}R_{v}}\) (the inhibition of 91% and 98%, respectively) showing the minimum inhibitory concentration (MIC) value of 13.41 and 11.53 \(\upmu\)M, respectively. The decrease in electron density on ring \(C\) atoms due to the replacement of phenyl with 2-pyridyl (Figure 1) caused the loss of the ability to inhibit the growth of given slow-growing pathogens [15]. The proper selection of these substituents is essential for interactions between resulting derivatives and particular amino acids localized at a binding site of adenosine-5'-triphosphate (ATP) synthase [15]. The enzyme is strongly evolutionarily conserved among prokaryotes and eukaryotes. Oxidative phosphorylation, as a crucial process for the existence of \(Mtb\)\(\mathrm{H_{37}R_{v}}\) obligate aerobic pathogens, leads to the ATP production necessary for growth and survival. Apart from replicating mycobacteria, ATP synthase is also  
Figure 1: General structure of naphthalene-based **RU** derivatives investigated in vitro as well as in silico against _Mycobacterium tuberculosis_\(\mathrm{H_{37}R_{v}}\). (* = chiral center). essential in the dormant state, because it carries specific features facilitating survival under nonreplicating conditions [16; 17].