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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 <i>Staphylococcus aureus</i> and clinical isolates of methicillin-resistant <i>S. aureus</i> (MRSA). (2<i>E</i>)-<i>N</i>-[3,5-bis(trifluoromethyl)phenyl]- 3-(4-chlorophenyl)prop-2-enamide was the most potent in series <b>1</b>. (2<i>E</i>)-<i>N</i>-[3,5-bis(Trifluoromethyl)phenyl]-3-(3,4-dichlorophenyl)prop-2-enamide, (2<i>E</i>)-3-(3,4-dichlorophenyl)-<i>N</i>-[3-(trifluoromethyl)phenyl]prop-2-enamide, (2<i>E</i>)-3-(3,4-dichloro- phenyl)-<i>N</i>-[4-(trifluoromethyl)phenyl]prop-2-enamide and (2<i>E</i>)-3-(3,4-dichlorophenyl)- <i>N</i>-[4-(trifluoromethoxy)phenyl]prop-2-enamide were the most active in series <b>2</b> and in addition to activity against <i>S. aureus</i> and MRSA were highly active against <i>Enterococcus faecalis</i> and vancomycin-resistant <i>E. faecalis</i> isolates and against fast-growing <i>Mycobacterium smegmatis</i> and against slow-growing <i>M. marinum</i>, <i>M. tuberculosis</i> non-hazardous test models. In addition, the last three compounds of the above-mentioned showed insignificant cytotoxicity to primary porcine monocyte-derived macrophages.