Our search for new antibiotics led to the syntheses and biological evaluation of new classes of dicarboxylic acid analogues. The syntheses involve nucleophilic addition of different substituted benzylamine, aniline, alkylamine, and 4-hydroxyl-L-proline with carbamoylbenzoic acid. The results of the antimicrobial activity as indicated by the zone of inhibition (ZOI) showed that
Development of novel bioactive drugs in chemical warfare against bacteria, fungi, and other infectious diseases has become an important and challenging task for the synthetic and medicinal chemists. Many research programs are tailored towards the design and synthesis of new drugs, for their chemotherapeutic application. The emergence of antimicrobial resistance threatens the effective prevention and treatment of an ever increasing range of infections caused by bacteria, parasites, virus, and fungi. New resistance mechanisms are emerging and spreading globally; the appearance and widespread use of fake and substandard drugs have further compounded the problem [
Currently, there are more than 450 clinically approved drugs containing a free carboxylic acid group [
All chemicals and solvents were purchased from Sigma-Aldrich (Germany) and used as purchased without further purification. Thin-layer chromatography was performed using precoated silica gel 60 (F254) from MERCK (Germany). Spots on the TLC plates were visualized under UV light (254 nm and 366 nm) and by heating with 10% sulphuric acid in MeOH. The melting point was recorded using a Gallenkamp melting point apparatus. The UV-VIS analysis was carried out on a Perkin Elmer Lambda 35 UV/VIS Spectrometer, scanning from 200 to 400 nm. Absorbance was measured with a 1 cm quartz cell. The infrared spectra of the solid products were recorded on a Perkin Elmer Spectrum 100 FTIR spectrometer using ATR sampling accessory. 1H and 13C-NMR spectra were recorded using Bruker
A solution of 1,3-dioxo-2-benzofuran-5-carbonyl chloride (5 g, 23.8 mmol) was weighed into a round bottom flask containing 100 mL of
The synthesised compounds and their percentage yield (%).
Sample | R | Product | Yield (%) |
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99 |
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55 |
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35 |
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78 |
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90 |
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54 |
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24 |
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65 |
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79 |
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36 |
Preparation of carbamoylbenzoic and carbamoyldibenzoic acid.
The test compounds (
The cork and bore diffusion method as reported by Karou et al. [
The MIC was determined for the compounds using microbroth dilution method in accordance with National Committee for Clinical Laboratory Standard [
The MBC/MFC was determined by aseptically inoculating aliquots of culture, from the minimum inhibition concentration (MIC) tubes that showed no growth, on sterile nutrient Agar (OXOID) plates incubated at 38°C for bacteria and 34°C for fungi for 48 h. The MBC/MFC was recorded as the lowest concentration of compounds showing no bacterial/fungal growth at all.
Our synthetic approach involved two steps (Scheme
The structures of the compounds were confirmed by the use of 1H and 13C NMR with application of 2D NMR where necessary.
The synthesised compounds were tested against eleven bacteria including two resistance bacteria, Methicillin Resistant
Zone of inhibition (mm).
Test organism |
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Sp | Fl |
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26 | 28 | — | — | 22 | 28 | — | 29 | 28 | — | 35 | — |
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— | 24 | — | 29 | — | 24 | 20 | 27 | — | 24 | — | — |
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27 | 29 | 24 | — | 24 | 27 | — | 29 | 29 | 26 | 37 | — |
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25 | — | 27 | 27 | — | — | 24 | — | — | 24 | 34 | — |
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— | 24 | 23 | — | 26 | 24 | 28 | 30 | — | — | 32 | — |
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29 | 27 | 26 | 29 | 26 | — | — | — | 27 | 25 | 37 | — |
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— | — | 26 | 28 | — | — | 25 | — | 25 | 27 | — | — |
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— | 24 | — | 24 | 30 | 31 | 28 | 32 | — | 24 | 35 | — |
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27 | 29 | 28 | — | — | — | 25 | 29 | 30 | 27 | 39 | — |
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— | 27 | 26 | — | 29 | 26 | 26 | 30 | — | 24 | 42 | — |
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29 | — | — | 29 | 25 | — | 27 | — | 24 | — | 40 | — |
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24 | — | 27 | 24 | — | 28 | 24 | 29 | 29 | 27 | — | 35 |
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27 | 28 | — | 26 | 25 | 24 | 22 | 28 | 24 | 27 | — | 35 |
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— | 26 | — | 24 | — | 26 | 26 | 29 | 23 | 24 | — | 30 |
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26 | 27 | 28 | 29 | 27 | 28 | 24 | 27 | 27 | 23 | — | 34 |
—: not determined.
Minimum inhibitory concentration (MIC) results (Table
Minimum inhibitory concentration (MIC) (
Test organism |
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12.50 | 6.2 | — | — | 6.2 | 6.2 | — | 6.2 | 6.2 | — |
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— | 6.2 | — | 6.2 | — | 12.5 | 12.5 | 6.2 | — | 12.5 |
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6.2 | 12.5 | 12.5 | — | 6.2 | 6.2 | — | 6.2 | 6.2 | 12.5 |
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12.5 | 6.2 | 6.2 | 6.2 | — | — | 12.5 | — | — | 12.5 |
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— | 12.5 | 12.5 | — | 12.5 | — | 6.2 | 6.2 | — | — |
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6.2 | 6.2 | 12.5 | 6.2 | 12.5 | 12.5 | 6.2 | — | 6.2 | 12.5 |
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— | — | 12.5 | 6.2 | 12.5 | — | — | — | 12.5 | 6.2 |
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— | 12.5 | — | 12.5 | — | — | 12.5 | 6.2 | — | 12.5 |
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6.2 | 6.2 | 6.2 | — | 6.2 | 6.2 | 6.2 | 6.2 | 6.2 | 6.2 |
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— | — | 12.5 | — | — | — | 12.5 | 6.2 | — | 12.5 |
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6.2 | 6.2 | — | 6.2 | 6.2 | 12.5 | 12.5 | — | 12.5 | — |
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12.5 | — | 6.2 | 12.5 | 12.5 | 6.2 | 12.5 | 6.2 | 6.2 | 6.2 |
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6.2 | 6.2 | — | 12.5 | — | 12.5 | 12.5 | 6.2 | 12.5 | 6.2 |
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— | 12.5 | — | 12.5 | 6.2 | 12.5 | 12.5 | 6.2 | 12.5 | 12.5 |
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12.5 | 6.2 | 6.2 | 6.2 | — | 6.2 | 12.5 | 6.2 | 6.2 | 12.5 |
—: no MIC.
Minimum bactericidal/fungicidal concentration (MBC/MFC) (
Test organism |
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25 | 12.5 | — | — | 50 | 12.5 | — | 12.5 | 12.5 | — |
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— | 50 | — | 12.5 | — | 50 | 50 | 25 | — | 50 |
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25 | 12.5 | 50 | — | 50 | 25 | — | 12.5 | 12.5 | 25 |
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25 | — | 25 | 25 | — | — | 25 | — | — | 25 |
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— | 25 | 50 | — | 25 | — | 25 | — | — | — |
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12.5 | 25 | 25 | 12.5 | 25 | 50 | 12.5 | 12.5 | 25 | 25 |
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— | — | 25 | 12.5 | 25 | — | — | — | 25 | 25 |
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— | 25 | — | 50 | — | — | 25 | — | — | 25 |
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25 | 12.5 | 12.5 | — | 12.5 | 12.5 | 12.5 | 12.5 | 12.5 | 25 |
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— | — | 25 | — | — | — | 25 | 12.5 | — | 50 |
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12.5 | 25 | — | 12.5 | 12.5 | 25 | 25 | 12.5 | 25 | — |
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50 | — | 25 | 25 | — | 12.5 | 50 | 12.5 | 12.5 | 25 |
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25 | 12.5 | — | 25 | 25 | 25 | 50 | 12.5 | 50 | 25 |
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— | 25 | — | 50 | — | 25 | 25 | 12.5 | 50 | 50 |
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25 | 25 | 12.5 | 12.5 | 25 | 12.5 | 50 | 25 | 25 | 50 |
—: no MBC/MFC.
The different substituted test compounds were successfully synthesised and their structures were confirmed by NMR analysis. Generally,
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors wish to thank the School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa, for providing facilities to carry out this research.