scholarly journals Syntheses and Biological Activity of Some Derivatives of C-9154 Antibiotic

2012 ◽  
Vol 2012 ◽  
pp. 1-7
Author(s):  
Isaac Asusheyi Bello ◽  
George Iloegbulam Ndukwe ◽  
Joseph Olorunju Amupitan ◽  
Rachael Gbekele Ayo ◽  
Francis Oluwole Shode
Keyword(s):  
Biological Activity ◽  
Functional Group ◽  
Marked Effect ◽  
2D Nmr ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
New Antibiotics ◽  
Agricultural Use ◽  
Derivatives Of

This research was undertaken to design several new antibiotics, by structurally modifying the C-9154 antibiotic, simultaneously improving its activity and lowering toxicity. This was achieved by synthesizing an analogue to the C-9154 antibiotic and seven derivatives of this analogue. The approach was to significantly reduce the polarity of the synthesized analogue in the derivatives to achieve increased permeability across cell membranes by conversion of the highly polar carboxylic group to an ester functional group. The compounds were fully characterized using infrared, GC-MS, and 1D and 2D NMR experiments. The in vitro biological activity of the compounds showed that the derivatives were more active than the analogue as was anticipated and both were more active than the standard drugs used for comparison. Work is ongoing to establish applications for the compounds as antiplasmodials, antivirals, anticancers/tumours, antitrypanosomiasis, anthelminthic, and as general antibiotics for human, veterinary, and even agricultural use as they had marked effect on both Gram-positive and Gram-negative bacteria and some fungi.

scholarly journals Syntheses and In Vitro Biological Activity of Some Derivatives of C-9154 Antibiotic

2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Isaac Asusheyi Bello ◽  
George Iloegbulam Ndukwe ◽  
Joseph Olorunju Amupitan ◽  
Rachael Gbekele Ayo ◽  
Francis Oluwole Shode
Keyword(s):  
Biological Activity ◽  
Minimum Inhibitory Concentration ◽  
Functional Group ◽  
Inhibitory Concentration ◽  
2D Nmr ◽  
Esterification Reaction ◽  
New Antibiotics ◽  
Derivatives Of ◽  
Better Than

In our continued attempts at designing new antibiotics based on the structure of the C-9154 antibiotic, to simultaneously improve activity and lower toxicity, an analogue to the C-9154 antibiotic and six derivatives of this analogue were synthesized. The approach was to significantly reduce the polarity of the synthesized analogue in the derivatives to achieve increased permeability across cell membranes by conversion of the highly polar carboxylic group to an ester functional group. The compounds were synthesized using a two-step reaction which involved an additional reaction between benzyl amine and maleic anhydride and then conversion of the terminal carboxylic acid functional group to an ester functional group using a thionyl chloride mediated esterification reaction. The compounds were fully characterized using Infrared, GC-MS, and 1D and 2D NMR experiments. The in vitro biological activity of the compounds showed that the derivatives were more active than the analogues as was anticipated with minimum inhibitory concentration in the range 0.625–5 μg/mL. The analogue had minimum inhibitory concentration in the range 2.5–10 μg/mL. These values are significantly better than that obtained for the original C-9154 antibiotic which had activity in the range 10–>100 μg/mL.

Antibiotic potential of some synthesized derivatives of C-9154 antibiotic

2020 ◽  
Vol 15 (2) ◽  
pp. 52-58
Author(s):  
Isaac Asusheyi Bello ◽  
Isaac Asusheyi Bello ◽  
George Iloegbulam Ndukwe ◽  
Joseph Olorunju Amupitan ◽  
Rachael Gbekele Ayo ◽  
...  
Keyword(s):  
Structural Modification ◽  
Functional Group ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
Gram Positive Bacteria ◽  
Derivatives Of ◽  
Acid Functional Group ◽  
Better Than

Structural modification of the C-9154 antibiotic in an attempt to simultaneously improve its activity and lower its toxicity led to the synthesis of an analogue of the C-9154 antibiotic and six derivatives of this analogue. The significant reduction of the polarity of the synthesized analogue in the derivatives to increase permeability across cell membranes was achieved by conversion of the highly polar carboxylic group to the nonpolar ester functional groups. The compounds were synthesized by condensation of 4-nitroaniline with maleic anhydride and then conversion of the terminal carboxylic acid functional group to an ester functional group using a thionyl chloride-mediated esterification. The in vitro biological activity using gram positive bacteria (MRSA, S. pyogenes, B. subtilis, and C. ulcerans), gram negative bacteria (E. coli, P. mirabilis, P. aeruginosa, S. typhii, S. dysenteriae, and K. pneumonia and some fungi (C. albicans, A. nigre and T. rubrum), showed that the derivatives were more active than their respective analogue and significantly better than the standard antibiotics (Sparfloxacin and Fluconazole) used for comparison, establishing their potential or use as antibiotics. The derivatives exhibited activity at concentrations as low as 0.625μg/mL while the analogue was active at 2.5μg/mL. These values were higher than results obtained for the standard drugs which showed activity at concentrations of 5 μg/mL. The derivatives however did not show activity against A. nigre whereas the analogue was active against it. Keywords: C-9154 Antibiotic, Bioactivity, Fumaramidmycin, antibacterial, antifungal

Synthesis and in vitro Biological Activity of New 4,6-Disubstituted 3(2H)-Pyridazinone-acetohydrazide Derivatives

2012 ◽  
Vol 67 (5-6) ◽  
pp. 257-265
Author(s):  
Murat Sukuroglu ◽  
Tijen Onkol ◽  
Fatma Kaynak Onurdağ ◽  
Gulsen Akalın ◽  
M. Fethi Şahin
Keyword(s):  
Biological Activity ◽  
Antimicrobial Activities ◽  
Cytotoxic Activities ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
E Coli ◽  
Preliminary Results ◽  
H Nmr ◽  
Pyridazinone Derivatives

New 3(2H)-pyridazinone derivatives containing a N’-benzyliden-acetohydrazide moiety at position 2 were synthesized. The structures of these newly synthesized compounds were confi rmed by IR, 1H NMR, and MS data. These compounds were tested for their antibacterial, antifungal, antimycobacterial, and cytotoxic activities. The compounds 2-[4-(4-chlorophenyl)- 6-(morpholin-4-yl)-3-oxo-(2H)-pyridazin-2-yl]-N’-(4-tert-butylbenzyliden)acetohydrazide and 2-[4-(4-chlorophenyl)-6-(morpholin-4-yl)-3-oxo-(2H)-pyridazin-2-yl]-N’-(4-chlorobenzyliden) acetohydrazide exhibited activity against both Gram-positive and Gram-negative bacteria. Most of the compounds were active against E. coli ATCC 35218. The preliminary results of this study revealed that some target compounds exhibited promising antimicrobial activities

scholarly journals Inhibition of the β-barrel assembly machine by a peptide that binds BamD

2015 ◽  
Vol 112 (7) ◽  
pp. 2011-2016 ◽  
Author(s):  
Christine L. Hagan ◽  
Joseph S. Wzorek ◽  
Daniel Kahne
Keyword(s):  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Outer Membranes ◽  
Essential Proteins ◽  
Growth Defects ◽  
Substrate Protein ◽  
Assembly Mechanism ◽  
New Antibiotics

The protein complex that assembles integral membrane β-barrel proteins in the outer membranes of Gram-negative bacteria is an attractive target in the development of new antibiotics. This complex, the β-barrel assembly machine (Bam), contains two essential proteins, BamA and BamD. We have identified a peptide that inhibits the assembly of β-barrel proteins in vitro by characterizing the interaction of BamD with an unfolded substrate protein. This peptide is a fragment of the substrate protein and contains a conserved amino acid sequence. We have demonstrated that mutations of this sequence in the full-length substrate protein impair the protein’s assembly, implying that BamD’s interaction with this sequence is an important part of the assembly mechanism. Finally, we have found that in vivo expression of a peptide containing this sequence causes growth defects and sensitizes Escherichia coli to antibiotics to which they are normally resistant. Therefore, inhibiting the binding of substrates to BamD is a viable strategy for developing new antibiotics directed against Gram-negative bacteria.

scholarly journals An Update on Eight “New” Antibiotics against Multidrug-Resistant Gram-Negative Bacteria

2021 ◽  
Vol 10 (5) ◽  
pp. 1068
Author(s):  
Erlangga Yusuf ◽  
Hannelore I. Bax ◽  
Nelianne J. Verkaik ◽  
Mireille van Westreenen
Keyword(s):  
Drug Administration ◽  
Food And Drug Administration ◽  
Treatment Options ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Beta Lactamases ◽  
New Antibiotics ◽  
Tract Infections ◽  
The U.S

Infections in the ICU are often caused by Gram-negative bacteria. When these microorganisms are resistant to third-generation cephalosporines (due to extended-spectrum (ESBL) or AmpC beta-lactamases) or to carbapenems (for example carbapenem producing Enterobacteriales (CPE)), the treatment options become limited. In the last six years, fortunately, there have been new antibiotics approved by the U.S. Food and Drug Administration (FDA) with predominant activities against Gram-negative bacteria. We aimed to review these antibiotics: plazomicin, eravacycline, temocillin, cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem/vaborbactam, and imipenem/relebactam. Temocillin is an antibiotic that was only approved in Belgium and the UK several decades ago. We reviewed the in vitro activities of these new antibiotics, especially against ESBL and CPE microorganisms, potential side effects, and clinical studies in complicated urinary tract infections (cUTI), intra-abdominal infections (cIAI), and hospital-acquired pneumonia/ventilator-associatedpneumonia (HAP/VAP). All of these new antibiotics are active against ESBL, and almost all of them are active against CPE caused by KPC beta-lactamase, but only some of them are active against CPE due to MBL or OXA beta-lactamases. At present, all of these new antibiotics are approved by the U.S. Food and Drug Administration for cUTI (except eravacycline) and most of them for cIAI (eravacycline, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam) and for HAP or VAP (cefiderocol, ceftazidime/avibactam, ceftolozane/tazobactam, and imipenem/relebactam).

scholarly journals Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin

2021 ◽  
Vol 12 ◽  
Author(s):  
Danyel Ramirez ◽  
Liam Berry ◽  
Ronald Domalaon ◽  
Yanqi Li ◽  
Gilbert Arthur ◽  
...  
Keyword(s):  
Amino Acid ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Fatty Acyl ◽  
Gram Negative Bacteria ◽  
Wild Type ◽  
Gram Negative ◽  
Proteolytic Stability ◽  
Derivatives Of

Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resulting in three dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs). The nonhemolytic dUSTBβP 3, comprised of three β3-homoarginine residues and two fatty acyl tails eight carbons long, enhanced the antibacterial activity of various antibiotics from different classes. Notably, compound 3 retained the ability to potentiate novobiocin and rifampicin in wild-type Gram-negative bacteria against MDR clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved in vitro stability (86.8 ± 3.7% remaining) relative to its α-amino acid-based counterpart (39.5 ± 7.4% remaining) after a 2 h incubation in human plasma.

scholarly journals Microbial Enzymatic Synthesis of Amikacin Analogs With Antibacterial Activity Against Multidrug-Resistant Pathogens

2021 ◽  
Vol 12 ◽  
Author(s):  
Yeon Hee Ban ◽  
Myoung Chong Song ◽  
Joong Ho Jeong ◽  
Min Seok Kwun ◽  
Chang Rae Kim ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Resistance Mechanism ◽  
Multidrug Resistant ◽  
Amino Group ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Structural Modifications ◽  
New Antibiotics ◽  
Pharmacological Potential

With the constant emergence of multidrug-resistant gram-negative bacteria, interest in the development of new aminoglycoside (AG) antibiotics for clinical use has increased. The regioselective modification of AG scaffolds could be an efficient approach for the development of new antibiotics with improved therapeutic potency. We enzymatically synthesized three amikacin analogs containing structural modifications in the amino groups and evaluated their antibacterial activity and cytotoxicity. Among them, 6′-N-acyl-3″-N-methylated analogs showed improved antibacterial activity against the multidrug-resistant gram-negative bacteria tested, while exhibiting reduced in vitro nephrotoxicity compared to amikacin. This study demonstrated that the modifications of the 6′-amino group as well as the 3″-amino group have noteworthy advantages for circumventing the AG-resistance mechanism. The regiospecific enzymatic modification could be exploited to develop novel antibacterial agents with improved pharmacological potential.

Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

2020 ◽  
Vol 20 (3) ◽  
pp. 192-208 ◽  
Author(s):  
Talita Odriane Custodio Leite ◽  
Juliana Silva Novais ◽  
Beatriz Lima Cosenza de Carvalho ◽  
Vitor Francisco Ferreira ◽  
Leonardo Alves Miceli ◽  
...  
Keyword(s):  
In Silico ◽  
Bacterial Infections ◽  
Antimicrobial Agents ◽  
Mass Spectrometry Analysis ◽  
World Health ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Dione Derivative ◽  
In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

Structure-Activity Relationship and Antimicrobial Evaluation of N-Phenylpyrazole Curcumin Derivatives

2020 ◽  
Vol 16 (4) ◽  
pp. 481-488
Author(s):  
Heli Sanghvi ◽  
Satyendra Mishra
Keyword(s):  
Antibacterial Activity ◽  
Gram Negative Bacteria ◽  
Pyrazole Derivatives ◽  
Gram Positive ◽  
Gram Negative ◽  
E Coli ◽  
Curcumin Derivatives ◽  
Structure Activity ◽  
Electron Donating Groups ◽  
Derivatives Of

Background: Curcumin, one of the most important pharmacologically significant natural products, has gained significant consideration among scientists for decades since its multipharmacological activities. 1, 3-Dicarbonyl moiety of curcumin was found to be accountable for the rapid degradation of curcumin molecule. The aim of present work is to replace 1, 3-dicarbonyl moiety of curcumin by pyrazole and phenylpyrazole derivatives with a view to improving its stability and to investigate the role of substitution in N-phenylpyrazole curcumin on its antibacterial activity against both Gram-positive as well as Gram-negative bacteria. Methods: Pyrazole derivatives of curcumin were prepared by heating curcumin with phenyhydrazine/ substituted phenyhydrazine derivatives in AcOH. The residue was purified by silica gel column chromatography. Structures of purified compounds were confirmed by 1H NMR and Mass spectroscopy. The synthesized compounds were evaluated for their antibacterial activity by the microdilution broth susceptibility test method against gram positive (S. aureus) and gram negative (E. coli). Results: Effects of substitution in N-phenylpyrazole curcumin derivatives against S. aureus and E. coli were studied. The most active N-(3-Nitrophenylpyrazole) curcumin (12) exhibits twenty-fold more potency against S. aureus (MIC: 10μg/mL)) and N-(2-Fluoroophenylpyrazole) curcumin (5) fivefold more potency against E. coli (MIC; 50 μg/mL) than N-phenylpyrazole curcumin (4). Whereas, a remarkable decline in anti-bacterial activity against S. aureus and E. coli was observed when electron donating groups were incorporated in N-phenylpyrazole curcumin (4). Comparative studies of synthesized compounds suggest the effects of electron withdrawing and electron donating groups on unsubstituted phenylpyrazole curcumin (4). Conclusion: The structure-activity relationship (SAR) results indicated that the electron withdrawing and electron donating at N-phenylpyrazole curcumin played key roles for their bacterial inhibitory effects. The results of the antibacterial evaluation showed that the synthesized pyrazole derivatives of curcumin displayed moderate to very high activity in S. aureus. In conclusion, the series of novel curcumin derivatives were designed, synthesized and tested for their antibacterial activities against S. aureus and E. coli. Among them, N-(3-Nitrophenylpyrazole curcumin; 12) was most active against S. aureus (Gram-positive) and N-(2-Fluoroophenylpyrazole) curcumin (5) against E. coli (Gram-negative) bacteria.

scholarly journals Coumarin Exhibits Broad-Spectrum Antibiofilm and Antiquorum Sensing Activity against Gram-Negative Bacteria: In Vitro and In Silico Investigation

ACS Omega ◽  
2021 ◽  
Author(s):  
Faizan Abul Qais ◽  
Mohammad Shavez Khan ◽  
Iqbal Ahmad ◽  
Fohad Mabood Husain ◽  
Rais Ahmad Khan ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
In Silico ◽  
Gram Negative Bacteria ◽  
Gram Negative
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