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

Alexandra T Bordei Telehoiu,Miron T Căproiu,Carmen Limban,Speranța Avram,Mariana C Chifiriuc,Florea Dumitrascu,Coralia Bleotu,Diana C Nuță,Carmellina D Bădiceanu,Irina Zarafu,Petre Ioniță

doi:10.3390/molecules25020266

Alexandra T Bordei Telehoiu, Miron T Căproiu + Show 9 more

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https://doi.org/10.3390/molecules25020266

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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 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.

Highlights

Carbazole and its derivatives represent an important group of aromatic heterocyclic compounds containing a nitrogen atom
We aimed to combine in the same molecular framework the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives
The chemical structures of the novel compounds and the carprofen methyl ester were confirmed on the basis of spectral studies

Summary

Introduction

Carbazole and its derivatives represent an important group of aromatic heterocyclic compounds containing a nitrogen atom. Compounds containing this scaffold have important electronic and charge-transport properties, as well as a conjugated pi-electron system, which facilitate the easy introduction of various functional groups into the structurally rigid carbazole ring [1]. These properties result in the extensive applications of carbazole derivatives in the medical field, such as antitumor, antimicrobial, antihistaminic, antioxidant, anti-inflammatory, and psychotropic agents [2]. The carbazole acid ring is present in many drugs, such as olivacine (antimalarial), rimcazole (antipsychotic and anticonvulsant), carvedilol (antihypertensive) [1,2] (Figure 1)

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