Integrated Structural, Physicochemical, Pharmacokinetic and Pharmacodynamic Evaluation of Substituted Phenylcarbonyloxypiperazinopropanols as Antimycobacterial Agents

Abstract

This research aimed to evaluate structural, physicochemical and pharmacokinetic characteristics of racemic 2-hydroxy-3-(4-phenylpiperazin-1-yl)propyl 4-[(alkoxycarbonyl)amino]benzoates (Ib)–(IVb) and 2-hydroxy-3-[4-(R-substituted phenyl)piperazin-1-yl]propyl 4-[(alkoxycarbonyl)amino]benzoates (1b)–(12b), while further extending the in vitro screening of their racemic salts, 1-(3-{4-[(alkoxycarbonyl)amino]benzoyloxy}-2-hydroxypropyl)-4-(R-substituted phenyl)piperazin-1-ium chlorides (I)–(IV) and (1)–(12) (alkoxy = methoxy to butoxy in all of these series, and R = H, 4′-F, 2′-F or 2′-OCH3), against several mycobacterial species, including a slow-growing virulent Mycobacterium tuberculosis (Mtb) H37Rv strain. The values of structural, physicochemical and several pharmacokinetic descriptors of the compounds (Ib)–(IVb) and (1b)–(12b) were generated in silico, employing a palette of interactive web-based engines and standalone software packages. The obtained data allowed for exploration of their mutual relationships through a chemometric principal component analysis method. The predicted outputs were compared to the values of respective descriptors defining antimycobacterial drugs approved worldwide for therapeutic use in human medicine. Molecular docking (MD) analyses were carried out to explore the possibilities of whether particular (R)- and (S)-stereoisomers of non-protonated derivatives, as well as (R)- and (S)-stereoisomeric forms of their salts (I)–(IV) and (1)–(12) would effectively interact with a proposed pharmacological target, adenosine 5′-triphosphate (ATP) synthase. This membrane–protein complex was considered essential for energy metabolism and survival of various mycobacterial species. Respecting the fundamental structural arrangement of more efficient salts, the importance of their structural and spatial features was highlighted to achieve relative effective interactions with particular subunits of ATP synthase present in Mtb H37Rv. The results of the MD evaluations could contribute to the understanding of how these compounds inhibited growth of Mtb H37Rv. 1-(3-{4-[(Butoxycarbonyl)amino]benzoyloxy}-2-hydroxypropyl)-4-phenylpiperazin-1-ium chloride (IV) with a minimum inhibitory concentration (MIC) value of 62.5 μM estimated in vitro and 1-(3-{4-[(butoxycarbonyl)amino]benzoyloxy}-2-hydroxypropyl)-4-(2-methoxyphenyl)piperazin-1-ium chloride (12) with MIC = 16 μM, as the most effective anti-Mtb H37Rv agents of each series of the salts, were screened in vitro to investigate their antiproliferative or (eventual) cytotoxic properties using a normal human dermal fibroblast cell line. The derivative (IV) decreased cell viability slightly more compared to the molecule (12).