In order to provide a more detailed view on the structure⁻antimycobacterial activity relationship (SAR) of phenylcarbamic acid derivatives containing two centers of protonation, 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(dipropylammonio)propyl]pyrrolidinium oxalates (1a⁻d)/dichlorides (1e⁻h) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1i⁻l)/dichlorides (1m⁻p; alkoxy = butoxy to heptyloxy) were physicochemically characterized by estimation of their surface tension (γ; Traube's stalagmometric method), electronic features (log ε; UV/Vis spectrophotometry) and lipophilic properties (log kw; isocratic RP-HPLC) as well. The experimental log kw dataset was studied together with computational logarithms of partition coefficients (log P) generated by various methods based mainly on atomic or combined atomic and fragmental principles. Similarities and differences between the experimental and in silico lipophilicity descriptors were analyzed by unscaled principal component analysis (PCA). The in vitro activity of compounds 1a⁻p was inspected against Mycobacterium tuberculosis CNCTC My 331/88 (identical with H37Rv and ATCC 2794, respectively), M.tuberculosis H37Ra ATCC 25177, M.kansasii CNCTC My 235/80 (identical with ATCC 12478), the M.kansasii 6509/96 clinical isolate, M.kansasii DSM 44162, M. avium CNCTC My 330/80 (identical with ATCC 25291), M.smegmatis ATCC 700084 and M. marinum CAMP 5644, respectively. In vitro 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 1a⁻p were highly efficient almost against all tested mycobacteria. The most promising derivatives showed MIC values varied from 1.9 μM to 8 μM, which were lower compared to those of used standards, especially if concerning ability to fight M.tuberculosis H37Ra ATCC 25177, M.kansasii DSM 44162 or M. avium CNCTC My 330/80. Current in vitro biological assays and systematic SAR studies based on PCA approach as well as fitting procedures, which were supported by relevant statistical descriptors, proved that the compounds 1a⁻p represented a very promising molecular framework for development of 'non-traditional' but effective antimycobacterial agents.

Clinic for Department of Infectious Diseases and Microbiology Faculty of Veterinary Medicine University of Veterinary and Pharmaceutical Sciences Palackého 1946 1 CZ 612 42 Brno Czech Republic

Clinic for Tuberculosis and Lung Diseases National Institute for Tuberculosis Lung Diseases and Thoracic Surgery Vyšné Hágy SK 059 84 Vysoké Tatry Slovakia Department of Public Health Faculty of Health Catholic University in Ružomberok Hrabovská cesta 1A SK 034 01 Ružomberok Slovakia

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences in Brno Palackého 1946 1 CZ 612 42 Brno Czech Republic

Department of Pharmaceutical Analysis and Nuclear Pharmacy Faculty of Pharmacy Comenius University in Bratislava Odbojárov 10 SK 832 32 Bratislava Slovakia Toxicological and Antidoping Center Faculty of Pharmacy Comenius University in Bratislava Odbojárov 10 SK 832 32 Bratislava Slovakia

Department of Pharmaceutical Chemistry Faculty of Pharmacy Comenius University in Bratislava Odbojárov 10 SK 832 32 Bratislava Slovakia

Global Change Research Institute CAS Belidla 986 4a CZ 603 00 Brno Czech Republic

Laboratory for Mycobacterial Diagnostics and Tuberculosis Regional Institute of Public Health Partyzánské náměstí 7 CZ 702 00 Ostrava Czech Republic

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