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

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 2; p. 266
• Main Authors: Bordei Telehoiu, Alexandra T., Nuță, Diana C., Căproiu, Miron T., Dumitrascu, Florea, Zarafu, Irina, Ioniță, Petre, Bădiceanu, Carmellina D., Avram, Speranța, Chifiriuc, Mariana C., Bleotu, Coralia, Limban, Carmen
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 09.01.2020; MDPI
• Subjects: Adenosine triphosphatase; Anticonvulsants; Antihypertensives; Antiinfectives and antibacterials; antimicrobial; Antimicrobial activity; Antimicrobial agents; Biofilms; Biological activity; Blood-brain barrier; Cancer; Carbazole; Carbazoles; carprofen; Cell cycle; Cyclic compounds; Cytotoxicity; Drug dosages; E coli; Ethane; Gram-negative bacteria; Hepatotoxicity; Hydrazine; Hydrazines; in silico; Isoniazid; oxadiazole; Oxadiazoles; Permeability; Pharmacophores; Phosphorus
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25020266

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 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.