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Series of novel amides of isoferulic acid, where the phenolic hydroxyl was replaced by a difluoromethyl group, were synthesized and their in vitro antibacterial activities assayed against fourteen bacterial strains (six Gram-positive and eight Gram-negative). A one-pot methodology was developed to obtain the 3&#8242;-(difluoromethyl)-4&#8242;-methoxycinnamoyl amides using Deoxofluor^&#174; as a fluorinating agent. The <i>N</i>-isopropyl, <i>N</i>-isopentyl, and <i>N</i>-(2-phenylethyl) amides <b>11b</b>, <b>11d</b> and <b>11g</b> were the most active and selective against <i>Mycobacterium smegmatis</i> (MIC = 8 &#181;g/mL) with <b>11b</b> and <b>11g</b> displaying negligible or no cytotoxicity against HepG2 and A549 cells. Thirteen analogs of <i>N</i>-isopropylamide <b>11b</b> were also synthesized and their antibacterial activity assayed. Results show that the difluoromethyl moiety enhanced antibacterial activity and selectivity towards <i>M. smegmatis,</i> changing the microorganism inhibition profile of the parent compound. The selectivity exhibited by some of the compounds towards <i>M. smegmatis</i> makes them potential leads in the search for new narrow spectrum antibiotics against <i>M. tuberculosis</i>.