A series of eighteen 4-chlorocinnamanilides and eighteen 3,4-dichlorocinnamanilides were designed, prepared and characterized. All compounds were evaluated for their activity against gram-positive bacteria and against two mycobacterial strains. Viability on both cancer and primary mammalian cell lines was also assessed. The lipophilicity of the compounds was experimentally determined and correlated together with other physicochemical properties of the prepared derivatives with biological activity. 3,4-Dichlorocinnamanilides showed a broader spectrum of action and higher antibacterial efficacy than 4-chlorocinnamanilides; however, all compounds were more effective or comparable to clinically used drugs (ampicillin, isoniazid, rifampicin). Of the thirty-six compounds, six derivatives showed submicromolar activity against Staphylococcus aureus and clinical isolates of methicillin-resistant S. aureus (MRSA). (2E)-N-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series 1. (2E)-N-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2E)-3-(3,4-dichlorophenyl)-N-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2E)-3-(3,4-dichloro- phenyl)-N-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2E)-3-(3,4-dichlorophenyl)- N-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series 2 and in addition to activity against S. aureus and MRSA were highly active against Enterococcus faecalis and vancomycin-resistant E. faecalis isolates and against fast-growing Mycobacterium smegmatis and against slow-growing M. marinum, M. tuberculosis non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.

Department of Analytical Chemistry Faculty of Natural Sciences Comenius University Ilkovicova 6 842 15 Bratislava Slovakia

Department of Biochemistry Faculty of Medicine Masaryk University Kamenice 5 625 00 Brno Czech Republic

Department of Infectious Diseases and Microbiology Faculty of Veterinary Medicine University of Veterinary Sciences Brno Palackeho 1946 1 612 42 Brno Czech Republic

Department of Infectious Diseases and Preventive Medicine Veterinary Research Institute Hudcova 296 70 621 00 Brno Czech Republic

Department of Pharmacology and Toxicology Veterinary Research Institute Hudcova 296 70 621 00 Brno Czech Republic

Global Change Research Institute CAS Belidla 986 4a 60300 Brno Czech Republic

Regional Centre of Advanced Technologies and Materials Czech Advanced Technology and Research Institute Palacky University Slechtitelu 27 783 71 Olomouc Czech Republic

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Chemistry towards Biology

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