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) (<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, 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 <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.