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Open AccessArticle

Dibasic Derivatives of Phenylcarbamic Acid against Mycobacterial Strains: Old Drugs and New Tricks?

1
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia
2
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences in Brno, Palackého 1946/1, CZ-612 42 Brno, Czech Republic
3
Clinic for Tuberculosis and Lung Diseases, National Institute for Tuberculosis, Lung Diseases and Thoracic Surgery, Vyšné Hágy, SK-059 84 Vysoké Tatry, Slovakia
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Department of Public Health, Faculty of Health, Catholic University in Ružomberok, Hrabovská cesta 1A, SK-034 01 Ružomberok, Slovakia
5
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
6
Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health, Partyzánské náměstí 7, CZ-702 00 Ostrava, Czech Republic
7
Department of Pharmaceutical Analysis and Nuclear Pharmacy, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia
8
Toxicological and Antidoping Center, Faculty of Pharmacy, Comenius University in Bratislava, Odbojárov 10, SK-832 32 Bratislava, Slovakia
9
Global Change Research Institute CAS, Belidla 986/4a, CZ-603 00 Brno, Czech Republic
*
Author to whom correspondence should be addressed.
Molecules 2018, 23(10), 2493; https://doi.org/10.3390/molecules23102493
Received: 5 September 2018 / Revised: 21 September 2018 / Accepted: 24 September 2018 / Published: 28 September 2018
(This article belongs to the Special Issue Heterocycles in Medicinal Chemistry)
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 (1ad)/dichlorides (1eh) as well as 1-[2-[({[2-/3-(alkoxy)phenyl]amino}carbonyl)oxy]-3-(di-propylammonio)propyl]azepanium oxalates (1il)/dichlorides (1mp; 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 1ap 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 1ap 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 1ap represented a very promising molecular framework for development of ‘non-traditional’ but effective antimycobacterial agents. View Full-Text
Keywords: dibasic phenylcarbamates; surface tension; electronic properties; lipophilicity; Mycobacterium spp. dibasic phenylcarbamates; surface tension; electronic properties; lipophilicity; Mycobacterium spp.
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MDPI and ACS Style

Malík, I.; Csöllei, J.; Solovič, I.; Pospíšilová, Š.; Michnová, H.; Jampílek, J.; Čížek, A.; Kapustíková, I.; Čurillová, J.; Pecháčová, M.; Stolaříková, J.; Pecher, D.; Oravec, M. Dibasic Derivatives of Phenylcarbamic Acid against Mycobacterial Strains: Old Drugs and New Tricks? Molecules 2018, 23, 2493.

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