Synthesis, Antimicrobial Activity, Structure-Activity Relationship, and Molecular Docking Studies of Indole Diketopiperazine Alkaloids

Strategies for the synthesis of indole diketopiperazine alkaloids (indole DKPs) have been described and involve three analogs of indole DKPs. The antimicrobial activity and structure-activity relationship (SAR) of 24 indole DKPs were explored. Compounds <b>3b</b> and <b>3c</b> were found to be the most active, with minimum inhibitory concentrations (MIC) values in the range of 0.94-3.87 μM (0.39-1.56 μg/mL) against the four tested bacteria (<i>Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa</i>, and <i>Escherichia coli</i>). Furthermore, compounds <b>4a</b> and <b>4b</b> displayed broad-spectrum antimicrobial activity with MIC values of 1.10-36.9 μM (0.39-12.5 μg/mL) against all tested bacteria and plant pathogenic fungi (<i>Colletotrichum gloeosporioides, Valsa mali, Alternaria alternata</i> and <i>Alternaria brassicae</i>). According to the <i>in silico</i> study, compounds <b>3c</b> showed significant binding affinity to the FabH protein from <i>Escherichia coli</i>, which has been identified as the key target enzyme of fatty acid synthesis (FAS) in bacteria. Therefore, these compounds are not only promising new antibacterial agents but also potential FabH inhibitors.