Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria

In an effort to gain more understanding on the structure activity relationship of pseudoceratidine 1, a di-bromo pyrrole spermidine alkaloid derived from the marine sponge Pseudoceratina purpurea that has been shown to exhibit potent biofouling, anti-fungal, antibacterial, and anti-malarial activities, a large series of 65 compounds that incorporated several aspects of structural variation has been synthesised through an efficient, divergent method that allowed for a number of analogues to be generated from common precursors. Subsequently, all analogues were assessed for their antibacterial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. Overall, several compounds exhibited comparable or better activity than that of pseudoceratidine 1, and it was found that this class of compounds is generally more effective against Gram-positive than Gram-negative bacteria. Furthermore, altering several structural features allowed for the establishment of a comprehensive structure activity relationship (SAR), where it was concluded that several structural features are critical for potent anti-bacterial activity, including di-halogenation (preferable bromine, but chlorine is also effective) on the pyrrole ring, two pyrrolic units in the structure and with one or more secondary amines in the chain adjoining these units, with longer chains giving rise to better activities.

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Variability of the antibacterial potential among analogue diterpenes against Gram-positive bacteria: considerations on the structure–activity relationship

Canadian Journal of Chemistry ◽

10.1139/cjc-2018-0369 ◽

2019 ◽

Vol 97 (7) ◽

pp. 568-575 ◽

Cited By ~ 1

Author(s):

Ana Carolina Ferreira Soares ◽

Priscilla Mendonça Matos ◽

Herbert Júnior Dias ◽

Gabriela de Paula Aguiar ◽

Eliene Silvério dos Santos ◽

...

Keyword(s):

Antimicrobial Agents ◽

Public Health Problem ◽

Antibacterial Activities ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Gram Positive ◽

Structure Activity ◽

Esterification Reactions ◽

Relationship Of ◽

Synthetic Derivatives

The search for new antibacterial agents and a better comprehension of substances with antimicrobial behavior is mandatory nowadays due to the serious public health problem of infection diseases. In the present work, 30 diterpenes were studied, with 2 natural derivatives, named ent-16-kauren-19-oic acid and ent-pimara-8(14),15-dien-19-oic acid, and 28 semi-synthetic derivatives. The natural diterpenes were isolated from Mikania glomerata and Viguiera arenaria, respectively. All diterpenes were submitted to antimicrobial assays against six different Gram-positive microorganisms to better understand the structure–activity relationship of antimicrobial diterpenes. The semi-synthetic derivatives were all obtained from the two natural derivatives by structural modifications, mainly esterification reactions. Both natural derivatives, together with the derivative ent-8(14)-pimaren-19-oic acid, displayed the most relevant antibacterial activities, with minimal inhibitory concentration (MIC) values that were less than 10 μg mL–1 for most pathogens; thus, they were considered promising antimicrobial agents. Moreover, in light of the hypothesis of Urzúa and colleagues, several considerations about the structure–activity relationship of antimicrobial diterpenes could be stated.

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Photosensitizer-peptoid conjugates for photoinactivation of gram-negative bacteria: structure-activity relationship and mechanistic studies

Organic & Biomolecular Chemistry ◽

10.1039/d1ob00926e ◽

2021 ◽

Author(s):

Woojin Yang ◽

Younggun Yoon ◽

Yunjee Lee ◽

Hyeongyeol Oh ◽

Jieun Choi ◽

...

Keyword(s):

Bacterial Infection ◽

Structure Activity Relationship ◽

Mechanisms Of Action ◽

Activity Relationship ◽

Gram Negative Bacteria ◽

Effective Strategy ◽

Mechanistic Studies ◽

Gram Negative ◽

Structure Activity

Multitarget engagement is considered an effective strategy to overcome the threat of bacterial infection, and antimicrobials with multiple mechanisms of action have been successful as natural chemical weaponry. Here, we...

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Development of a competitive binding assay for the Burkholderia cenocepacia lectin BC2L-A and structure activity relationship of natural and synthetic inhibitors

MedChemComm ◽

10.1039/c5md00557d ◽

2016 ◽

Vol 7 (3) ◽

pp. 519-530 ◽

Cited By ~ 14

Author(s):

Ghamdan Beshr ◽

Roman Sommer ◽

Dirk Hauck ◽

David Chan Bodin Siebert ◽

Anna Hofmann ◽

...

Keyword(s):

Cystic Fibrosis ◽

Binding Assay ◽

Structure Activity Relationship ◽

Competitive Binding ◽

Burkholderia Cenocepacia ◽

Activity Relationship ◽

Competitive Binding Assay ◽

Gram Negative ◽

Structure Activity ◽

Relationship Of

Burkholderia cenocepacia is an opportunistic Gram-negative pathogen and especially hazardous for cystic fibrosis patients.

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Comprehensive 2D-Quantitative Structure-Activity Relationship Study on Monobactam Analogues Against Gram-Negative Bacteria

Journal of Biomedical Nanotechnology ◽

10.1166/jbn.2020.2931 ◽

2020 ◽

Vol 16 (6) ◽

pp. 941-953

Author(s):

Dousheng Zhang ◽

Xia Zhang ◽

Zhiwen Li ◽

Sheng Tang ◽

Zhihao Guo ◽

...

Keyword(s):

Bacterial Infections ◽

Rational Design ◽

Quantitative Structure Activity Relationship ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Klebsiella Pneumonia ◽

Gram Negative Bacteria ◽

Quantitative Structure ◽

Gram Negative ◽

Structure Activity

Human health has been severely affected by infections resulting from multidrug-resistant (MDR) gram-negative bacteria (GNB). Monobactam antibiotics are known to be effective against such infections. This study aimed to construct a predictive two-dimensional quantitative structure-activity relationship (2D-QSAR) model for the rational design of new monobactams based on the 65 known monobactams against Escherichia coli (Eco) and Klebsiella pneumonia (Kpn) strains using the kernel partial least squares regression (KPLS) algorithm. The total performance of Eco and Kpn KPLS modes was shown as RMSE: 0.681/0.596, R2: 0.946/0.882, Q2: 0.922/0.877, and RMSU: 0.625/0.593. Thirty-four monobactams reported in our lab were chosen as external data to predict their activities against Eco and Kpn using the newly established models, by which the R2 between the experimental and predicted values was 0.878 and 0.871, respectively. The models developed and verified in this study provide a powerful design strategy for novel monobactams that are effective against MDR gram-negative bacterial infections.

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Chemical Synthesis and Structure-Activity Relationship Study Yield Desotamide a Analogues with Improved Antibacterial Activity

Marine Drugs ◽

10.3390/md19060303 ◽

2021 ◽

Vol 19 (6) ◽

pp. 303

Author(s):

Run Xu ◽

Yongxiang Song ◽

Jun Li ◽

Jianhua Ju ◽

Qinglian Li

Keyword(s):

Staphylococcus Aureus ◽

Antibacterial Activity ◽

Fold Increase ◽

Antibacterial Activities ◽

Structure Activity Relationship ◽

Activity Relationship ◽

Gram Positive ◽

Methicillin Resistant ◽

Structure Activity ◽

Relationship Of

Desotamides A, a cyclohexapeptide produced by the deep-sea-derived Streptomyces scopuliridis SCSIO ZJ46, displays notable antibacterial activities against strains of Streptococcus pnuemoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus epidermidis (MRSE). In this study, to further explore its antibacterial potential and reveal the antibacterial structure-activity relationship of desotamides, 13 cyclopeptides including 10 new synthetic desotamide A analogues and wollamides B/B1/B2 were synthesized and evaluated for their antibacterial activities against a panel of Gram-positive and -negative pathogens. The bioactivity data reveal that residues at position II and VI greatly impact antibacterial activity. The most potent antibacterial analogues are desotamide A4 (13) and A6 (15) where l-allo-Ile at position II was substituted with l-Ile and Gly at position VI was simultaneously replaced by d-Lys or d-Arg; desotamides A4 (13) and A6 (15) showed a 2–4-fold increase of antibacterial activities against a series of Gram-positive pathogens including the prevalent clinical drug-resistant pathogen methicillin-resistant Staphylococcus aureus (MRSA) with MIC values of 8–32 μg/mL compared to the original desotamide A. The enhanced antibacterial activity, broad antibacterial spectrum of desotamides A4 and A6 highlighted their potential as new antibiotic leads for further development.

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