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Conclusions Introduction Acknowledgements Synthesis and Antimicrobial Studies of Pyrazole Derivatives as Potent Anti-Methicillin-Resistant Staphylococcus aureus Agents Hydrazone Derivatives References Synthesis Future Directions Results Abstract Microbial resistance to antibiotics is a global concern. Without urgent and coordinated action, the world is moving toward a post-antibiotic era, in which normal infections or minor injuries may become fatal. In an effort to find new agents to combat this resistance, we report the synthesis and antimicrobial activities of new pyrazole derivatives. No work up and no column purification 10 g scale synthesis Easily available and inexpensive reagents Two dynamic functional groups for further derivatization Zone of Inhibition Testing Testing performed against multiple bacteria to evaluate growth inhibition. Discs treated with 10 µL of 0.1 M compound Bacteria used: Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Enterobacter aerogenes This work was supported by College of Science and Mathematics Arkansas State University, Jonesboro. Arkansas Statewide MS facility, Grant Number P30 GM103450 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) for recording mass spectrometry. This publication was made possible by the Arkansas INBRE program, supported by grant funding from the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) (P20 GM103429). Derivati ve S. Aureus B. subtilis Derivati ve S. Aureus B. subtilis 1 7 7.5 6 12 12 2 No Activity No Activity 7 10 8.5 3 10 11.5 8 10 11.5 4 13 16.5 9 No Activity 7.5 5 17.5 18 10 No Activity 8.5 C+ 26 29 C- No Activity No Activity Values reported in millimeters Values are averages of two trials with deviations < 4mm Molecules showed no inhibition to Gram- negative bacteria C+ = Chloramphenicol (30 µg) Figure 2: Synthesis of pyrazole base compound Figure 4: Synthesis of hydrazone derivatives Figure 3: 1 H NMR spectrum of pyrazole base compound Kucukguzel, S. G.; Senkardes, S. Eur. J. Med. Chem. 2015, 97, 786-815. Further testing will be performed to determine the minimum inhibitory concentration (MIC) of the active molecules. These results will indicate if further attention is warranted. Additional derivatives are also being synthesized to expand our library of new molecules. Figure 1: Pyrazole derived drugs Many pyrazole derivatives have been approved as drugs to treat various kinds of diseases. 1 Using efficient synthesis methods, we have synthesized ten pyrazole derivatives to test against various bacteria. The ten new molecules were tested against both Gram-positive and Gram-negative bacteria. All molecules, with the exception of derivatives 2, 9, and 10, showed inhibition to both S. aureus and B. subtilis, both Gram-positive bacteria. Zone averages as large as 17.5 mm for S. aureus and 18.0 mm for B. subtilis were seen. No inhibition was noted against Gram-negative bacteria. Figure 5: Zone of inhibition results Trent Rowe, Devin Allison, Evan Delaney, Adam Gottsponer, Danielle Gibler, Michael Branscum, David Gilmore, Allyn Ontko, Mohammad A Alam* Department of Chemistry and Physics, and the Department of Biological Sciences, Arkansas State University, PO Box 409, State University, AR 72467 1 . 2 . 3 . 4 . 5 . 6. 7. 8. 9. 10 . N N NH N N H 2 O Cl Cl F R uxolitin ib (T rea ts in term ed ia te o r h ig h -risk m y elofib ro sis) C rizotin ib (T rea ts n o n -sm all c ell lu n g cancer) N N CN N N N H N N F 3 C S NH 2 O O CH 3 Celecoxib ( nonsteroidal anti-inflam m atory drug) N O H O NH 2 H acetophenone A cO H , 2 4 h N O H O N H Ph N N O H O O H Ph POCl 3 , D M F 0 to 7 0 °C , 5 h
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Transcript of Rowe-Create@State-poster (1)
Conclusions
Introduction
Acknowledgements
Synthesis and Antimicrobial Studies of Pyrazole Derivatives as Potent Anti-Methicillin-Resistant Staphylococcus aureus Agents
Hydrazone Derivatives
References
Synthesis
Future Directions
Results
Abstract Microbial resistance to antibiotics is a global
concern. Without urgent and coordinated action, the world
is moving toward a post-antibiotic era, in which normal infections or minor injuries may become fatal.
In an effort to find new agents to combat this resistance, we report the synthesis and antimicrobial activities of new pyrazole derivatives.
No work up and no column purification 10 g scale synthesis Easily available and inexpensive reagents Two dynamic functional groups for further
derivatization
Zone of Inhibition Testing
Testing performed against multiple bacteria to evaluate growth inhibition.
Discs treated with 10 µL of 0.1 M compound Bacteria used: Staphylococcus aureus, Bacillus
subtilis, Pseudomonas aeruginosa, Enterobacter aerogenes
This work was supported by College of Science and Mathematics Arkansas State University, Jonesboro. Arkansas Statewide MS facility, Grant Number P30 GM103450 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) for recording mass spectrometry. This publication was made possible by the Arkansas INBRE program, supported by grant funding from the National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) (P20 GM103429).
Derivative S. Aureus B. subtilis Derivative S. Aureus B. subtilis
1 7 7.5 6 12 12
2 No Activity No Activity 7 10 8.5
3 10 11.5 8 10 11.5
4 13 16.5 9 No Activity 7.5
5 17.5 18 10 No Activity 8.5
C+ 26 29 C- No Activity No Activity
Values reported in millimeters Values are averages of two trials with deviations < 4mm Molecules showed no inhibition to Gram-negative bacteria C+ = Chloramphenicol (30 µg)
Figure 2: Synthesis of pyrazole base compound
Figure 4: Synthesis of hydrazone derivatives
Figure 3: 1H NMR spectrum of pyrazole base compound
Kucukguzel, S. G.; Senkardes, S. Eur. J. Med. Chem. 2015, 97, 786-815.
Further testing will be performed to determine the minimum inhibitory concentration (MIC) of the active molecules. These results will indicate if further attention is warranted. Additional derivatives are also being synthesized to expand our library of new molecules.
NN
NHNNH2
O
Cl
Cl
F
R uxo litin ib (T rea ts in term edia te o r h igh-r isk m yelofib ros is )
C rizo tinib (T rea ts non-sm a ll cell lu ng ca ncer )
NN
CN
NN
NH
NN
F3CS NH2
O
O
CH3
Celecoxib (nonsteroidal anti-inflammatory drug)
Figure 1: Pyrazole derived drugs
Many pyrazole derivatives have been approved as drugs to treat various kinds of diseases.1
Using efficient synthesis methods, we have synthesized ten pyrazole derivatives to test against various bacteria.
The ten new molecules were tested against both Gram-positive and Gram-negative bacteria.
All molecules, with the exception of derivatives 2, 9, and 10, showed inhibition to both S. aureus and B. subtilis, both Gram-positive bacteria.
Zone averages as large as 17.5 mm for S. aureus and 18.0 mm for B. subtilis were seen.
No inhibition was noted against Gram-negative bacteria.
Figure 5: Zone of inhibition results
Trent Rowe, Devin Allison, Evan Delaney, Adam Gottsponer, Danielle Gibler, Michael Branscum, David Gilmore, Allyn Ontko, Mohammad A Alam*Department of Chemistry and Physics, and the Department of Biological Sciences, Arkansas State University, PO Box 409, State University, AR 72467
N
OH
O
NH2
H
a c e to p h e n o n eA c O H , 2 4 h
N
OH
O
N
H Ph
NN
OH
O
OH PhP O C l3 , D M F0 to 7 0 °C , 5 h
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