Synthesis and characterization of pyrrolylated-chalcones as anti methicillin-resistant Staphylococcus aureus agents
A bacterial infection is well recognized as one of the leading causes of fatal morbidity and death in patients infected with diseases, hence are immune compromised. Although some molecules including vancomycin and linezolid, the standard drugs used for the treatment of methicillin-resistant Staph...
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| Main Author: | |
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| Format: | Thesis |
| Language: | English |
| Published: |
2020
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| Subjects: | |
| Online Access: | http://psasir.upm.edu.my/id/eprint/92791/1/FS%202021%2011%20-%20IR.pdf |
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| Summary: | A bacterial infection is well recognized as one of the leading causes of fatal
morbidity and death in patients infected with diseases, hence are immune
compromised. Although some molecules including vancomycin and linezolid, the
standard drugs used for the treatment of methicillin-resistant Staphylococcus aureus
(MRSA), have been successfully developed over the years, the ability of
microorganisms to develop resistance to these drugs during treatments has evoked
the need for a continuous search for new drugs with better efficacies. Chalcone has
been one of the most studied class of molecules possessing variety of remarkable
bioactivities, including anti-bacterial, anti-parasitic and anti-inflammatory. Due to
the ease of preparation and numerous pharmacological activities involving the
chalcone motifs, therefore, it is worth to further study the anti-bacteria activity,
specifically related to the multidrug-resistant methicillin-resistant Staphylococcus
aureus (MDR-MRSA) on the new analogs of the pyrrolylated-chalcones.
In this study, a series of pyrrolylated-chalcone analogs (compounds 1-15) were
synthesized by treating 2-acetylpyrrole with respectively substituted benzaldehydes
via a base-catalyzed Claisen-Schmidt condensation reaction. The purified final
compounds were subjected for confirmatory structural elucidation by established
spectroscopic techniques comprising of 1H, 19F- and 13C- high field nuclear magnetic
resonance (NMR), direct injection-mass spectroscopy (DI-MS), and Fourier
transform infrared (FTIR) spectroscopy. The purified pyrrolylated-chalcones were
then assayed for anti-MRSA activity through the disk diffusion (DDA, for a
preliminary screening), in vitro minimal inhibitory concentration (MIC), minimum
bactericidal concentration (MBC), and killing time curve assays. Based on the
results, the hydroxyl-containing compounds (8, 9, and 10) showed the most
significant anti-MRSA property, with range of inhibition zone diameters between 7.5 to 10 mm and the MIC and MBC values ranged of 0.08 to 0.70 mg/ml and 0.16
to 1.88 mg/ml, respectively. In comparison, the inhibition zone for the standard drug,
chlorhexidine (CHX) was 14 to 15 mm in diameter with a respective MIC and MBC
values of 0.03 to 0.12 mg/ml and 0.07 to 0.23 mg/ml. The time-kill curve plots
showed that MRSA strains to a concentration of 4× MIC for four hours resulted in
the death of all cells. Furthermore, ligand 9 was chosen for docking analyses with
penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) and the results showed a
similar bonding interaction to the specific docking of the CHX with the respective
binding affinity scores of -7.0 kcal/ mol and -8.2 kcal/mol. Following that, the
morphology of compound 9 was further confirmed by the scanning electron microscopy
(SEM) technique. Overall results suggested that the pyrrolylated-chalcones,
particularly compound 9 may be considered as potential inhibitor in the design of new
anti-MRSA agents. |
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