Design, Synthesis and In Vitro Characterization of Novel Antimicrobial Agents Based on 6-Chloro-9-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) ()-2-(6-chloro-9-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl ()-2-(6-chloro-9-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to ()-2-(6-chloro-9-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to -[(2)-2-(6-chloro-9-carbazol-2-yl)propanoil]-'--substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the ()-1-(6-chloro-9-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 ()-1-(6-chloro-9-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, H-NMR and 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 , while others on . The most significant result is represented by their exceptional anti-biofilm activity, particularly against the 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.