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

Abstract

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 3b and 3c 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 (Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli). Furthermore, compounds 4a and 4b 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 (Colletotrichum gloeosporioides, Valsa mali, Alternaria alternata and Alternaria brassicae). According to the in silico study, compounds 3c showed significant binding affinity to the FabH protein from Escherichia coli, 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.

Design, Synthesis, Antimicrobial Evaluation and in Silico Studies of Eugenol‐Sulfonamide Hybrids

“…It is worth noting that although we are comparing data from cell‐based experimental biological activities with theoretical enzyme‐based studies (which do not take into account physico‐chemical properties, membrane transposition capacity or the differences between Gram‐positive and Gram‐negative bacteria), previously published studies show a good correlation between MIC‐based experimental trends and theoretical ones [39–41] . From the results shown in Table 2, the comparison between the binding energies of the enzyme‐ligand complexes and the MIC data in the in vitro assays shows a partial correlation between the experimental antibacterial activity and the in silico enzyme inhibition potential.…”

Quinazoline Derivatives Designed as Efflux Pump Inhibitors: Molecular Modeling and Spectroscopic Studies

“…BG1189 and BG1190 lipophilicity or hydrophobicity evaluation indicate a LogP( o/w ) predicted value close to 1. This suggests a high antimicrobial activity of these compounds [ 20 ]. Values are presented in Table 1 as MlogP o/w and WlogP o/w .…”

“…Besides importance in “drug-like”, lipophilicity can be an indicator of antimicrobial activity. A coefficient of partition between octanol and water (log P o / w ) with values between 1 and 2 is associated with high antimicrobial activity [ 20 ]. Pharmacokinetics of the two quinazoline derivatives were also predicted using in silico approaches.…”

Analysis of molecular interactions of 8-gingerol compounds in Ginger (Zingiber officinale) as ACE Inhibitor

“…Van der Waals forces formed on eleven amino acids (THR302, ALA170, PRO163, LYS511, TRP279, GLN369, ASP377, GLU376, ASN374, ASN285, and THR171) provide additional strength, which affects the energy of the bonds formed. Efficient binding of ligand-protein is supported by various binding types and binding energy (Choi et al, 2000;Jia et al, 2019;Krisnamurti et al, 2021).…”