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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 ?M (0.39-1.56 ?g/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 ?M (0.39-12.5 ?g/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.

SUBMITTER: Jia B

PROVIDER: S-EPMC6897290 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Jia Bin B Ma Yang-Min YM Liu Bin B Chen Pu P Hu Yan Y Zhang Rui R

Frontiers in chemistry 20191129

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, Pseudomona ...[more]

PMID: 31850323

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Project description:Background:In search of effective antimicrobial and cytotoxic agents, a series of indole hybridized diazenyl derivatives (DS-1 to DS-21) was efficiently prepared by condensation of diazotized p-aminoacetophenone with indole or nitroindole followed by reaction with different aromatic/heteroaromatic amines of biological significance. The synthesized derivatives were characterized by various spectroscopic techniques. Methodology:The antimicrobial evaluation of DS-1 to DS-23 was done by tube dilution method against various pathogenic bacterial and fungal strains. The active antimicrobial derivatives were further evaluated for cytotoxicity against human lung carcinoma cell line (HCT-116), breast cancer cell line (MDAMB231), leukemic cancer cell line (K562), and normal cell line (HEK293) by MTT assay using doxorubicin as the standard drug. The test derivatives were additionally docked for the B-subunit of enzyme DNA gyrase from E. coli at the ATPase binding site to study the molecular interactions using Schrodinger maestro v11.5 software. Results and discussion:Most of the synthesized derivatives have shown high activity against Gram-negative bacteria particularly E. coli and K. pneumonia with MIC ranging from 1.95 to 7.81 ?g/ml. The derivatives have demonstrated very less activity against tested Gram positive bacterial and fungal strains. The derivatives DS-14 and DS-20 have been found to active against breast cancer cell line and human colon carcinoma cell line having IC50 in the range of 19-65 µg/ml. All the derivatives were found to less potent against leukemic cancer cell line. The synthesized derivatives have revealed their safety by exhibiting very less cytotoxicity against the normal cell line (HEK-293) with IC50?>?100 µg/ml. Most of the active derivatives have shown good docking scores in comparison to the standard drugs against DNA gyrase from E. coli. Further ADME predictions by Qikprop module of the Schrodinger confirmed these molecules have drug like properties. Conclusion:The derivatives DS-14 and DS-20 have shown potential against Gram-negative bacteria and breast cancer cell line and can be used as a lead for rational drug designing of the antimicrobial and cytotoxic agents..

Dataset Information

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

Publications

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

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