Design, Synthesis and In Vitro Characterization of Novel Antimicrobial Agents Based on 6-Chloro-9<i<H</i<-carbazol Derivatives and 1,3,4-Oxadiazole Scaffolds
In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to <i<N</i<-[(2<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propanoil]-<i<N</i<′-<i<R</i<-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (<i<RS</i<)-1-(6-chloro-9<i<H</i<-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (<i<RS</i<)-1-(6-chloro-9<i<H</i<-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, <sup<1</sup<H-NMR and <sup<13</sup<C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on <i<E. coli</i<, while others on <i<C. albicans</i<. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the <i<P. aeruginosa</i< biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 μg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
|---|---|
| Enthalten in: |
Molecules - 25(2020), 2, p 266 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Alexandra T. Bordei Telehoiu [VerfasserIn] |
|---|
| Links: |
doi.org [kostenfrei] |
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| Themen: |
Antimicrobial |
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| doi: |
10.3390/molecules25020266 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
DOAJ074564900 |
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| 520 | |a In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to <i<N</i<-[(2<i<RS</i<)-2-(6-chloro-9<i<H</i<-carbazol-2-yl)propanoil]-<i<N</i<′-<i<R</i<-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (<i<RS</i<)-1-(6-chloro-9<i<H</i<-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (<i<RS</i<)-1-(6-chloro-9<i<H</i<-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, <sup<1</sup<H-NMR and <sup<13</sup<C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on <i<E. coli</i<, while others on <i<C. albicans</i<. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the <i<P. aeruginosa</i< biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 μg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity. | ||
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