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The widespread incidence of antimicrobial resistance necessitates the discovery of new classes of antimicrobials as well as adjuvant molecules that can restore the action of ineffective antibiotics. Herein, we report the synthesis of a new class of indole-3-acetamido-polyamine conjugates that were evaluated for antimicrobial activities against a panel of bacteria and two fungi, and for the ability to enhance the action of doxycycline against <i>Pseudomonas aeruginosa</i> and erythromycin against <i>Escherichia coli</i>. Compounds <b>14b</b>, <b>15b</b>, <b>17c</b>, <b>18a</b>, <b>18b</b>, <b>18d</b>, <b>19b</b>, <b>19e</b>, <b>20c</b> and <b>20d</b> exhibited strong growth inhibition of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and <i>Cryptococcus neoformans</i>, with minimum inhibitory concentrations (MIC) typically less than 0.2 µM. Four analogues, including a 5-bromo <b>15c</b> and three 5-methoxyls <b>16d</b>–<b>f,</b> also exhibited intrinsic activity towards <i>E. coli</i>. Antibiotic kill curve analysis of <b>15c</b> identified it to be a bactericide. While only one derivative was found to (weakly) enhance the action of erythromycin against <i>E. coli</i>, three examples, including <b>15c</b>, were found to be strong enhancers of the antibiotic action of doxycycline against <i>P. aeruginosa</i>. Collectively, these results highlight the promising potential of α,ω-disubstituted indole-3-acetamido polyamine conjugates as antimicrobials and antibiotic adjuvants.