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Design, Synthesis and In Vitro Characterization of Novel Antimicrobial Agents Based on 6-Chloro-9H-carbazol Derivatives and 1,3,4-Oxadiazole Scaffolds.


ABSTRACT: 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) (RS)-2-(6-chloro-9H-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (RS)-2-(6-chloro-9H-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N-[(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoil]-N'-R-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (RS)-1-(6-chloro-9H-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 (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, 1H-NMR and 13C-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 E. coli, while others on C. albicans. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the P. aeruginosa biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 ?g/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.

SUBMITTER: Bordei Telehoiu AT 

PROVIDER: S-EPMC7024163 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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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.

Bordei Telehoiu Alexandra T AT   Nuță Diana C DC   Căproiu Miron T MT   Dumitrascu Florea F   Zarafu Irina I   Ioniță Petre P   Bădiceanu Carmellina D CD   Avram Speranța S   Chifiriuc Mariana C MC   Bleotu Coralia C   Limban Carmen C  

Molecules (Basel, Switzerland) 20200109 2


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  ...[more]

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