Authors: Ivan Malík | Jozef Csöllei | Ivan Solovič | Šárka Pospíšilová | Hana Michnová | Josef Jampílek | Alois Čížek | Iva Kapustíková | Jana Čurillová | Mária Pecháčová | Jiřina Stolaříková | Daniel Pecher | Michal Oravec
Source: Molecules (article, 2018-09-28)
Field: Chemistry — Organic Chemistry

Dibasic Derivatives of Phenylcarbamic Acid against Mycobacterial Strains: Old Drugs and New Tricks? In order to provide a more detailed view on the structure⁻antimycobacterial activity relationship (<i>SAR</i>) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (<b>1a</b>⁻<b>d</b>)/dichlorides (<b>1e</b>⁻<b>h</b>) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (<b>1i</b>⁻<b>l</b>)/dichlorides (<b>1m</b>⁻<b>p</b>; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube's stalagmometric method), electronic features (log <i>ε</i>; UV/Vis spectrophotometry) and lipophilic properties (log <i>k</i><sub>w</sub>; isocratic RP-HPLC) as well. The experimental log <i>k</i><sub>w</sub> dataset was studied together with computational logarithms of partition coefficients (log <i>P</i>) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and <i>in silico</i> lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The <i>in vitro</i> activity of compounds <b>1a</b>⁻<b>p</b> was inspected against <i>Mycobacterium tuberculosis</i> CNCTC My 331/88 (identical with H<sub>37</sub>R<sub>v</sub> and ATCC 2794, respectively), <i>M.</i> <i>tuberculosis</i> H<sub>37</sub>R<sub>a</sub> ATCC 25177, <i>M.</i> <i>kansasii</i> CNCTC My 235/80 (identical with ATCC 12478), the <i>M.</i> <i>kansasii</i> 6509/96 clinical isolate, <i>M.</i> <i>kansasii</i> DSM 44162, <i>M. avium</i> CNCTC My 330/80 (identical with ATCC 25291), <i>M.</i> <i>smegmatis</i> ATCC 700084 and <i>M. marinum</i> CAMP 5644, respectively. <i>In vitro</i> susceptibility of the mycobacteria to reference drugs isoniazid, ethambutol, ofloxacin or ciprofloxacin was tested as well. A very unique aspect of the research was that many compounds from the set <b>1a</b>⁻<b>p</b> were highly efficient almost against all tested mycobacteria. The most promising derivatives showed <i>MIC</i> values varied from 1.9 μM to 8 μM, which were lower compared to those of used standards, especially if concerning ability to fight <i>M.</i> <i>tuberculosis</i> H<sub>37</sub>R<sub>a</sub> ATCC 25177, <i>M.</i> <i>kansasii</i> DSM 44162 or <i>M. avium</i> CNCTC My 330/80. Current <i>in vitro</i> biological assays and systematic <i>SAR</i> studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds <b>1a</b>⁻<b>p</b> represented a very promising molecular framework for development of 'non-traditional' but effective antimycobacterial agents. Antimycobacterial ; Chemistry ; Mycobacterium kansasii ; Ethambutol ; Lipophilicity ; Isoniazid ; Alkoxy group ; Mycobacterium tuberculosis ; Stereochemistry ; Protonation ; Organic chemistry ; Biochemistry ; Streptomycin Synthesis and biological activity ; Phenothiazines and Benzothiazines Synthesis and Activities ; Tuberculosis Research and Epidemiology