In Silico and Experimental Investigation of the Biological Potential of Some Recently Developed Carprofen Derivatives

Dumitraşcu, Florea; Udrea, Ana-Maria; Caira, Mino R.; Nuță, Diana Camelia; Limban, Carmen; Chifiriuc, Mariana Carmen; Popa, Marcela; Bleoţu, Coralia; Hanganu, Anamaria; Dumitrescu, Dan; Avram, Speranța

doi:10.3390/molecules27092722

Cited by 6 publications

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“…New carbazole derivatives 1a-i and III were synthesized by nitration, halogenation, N-alkylation followed by subsequent halogenation, starting from the NSAID carprofen and its esters I and II ( Scheme 1 ). Esters I and II were obtained by esterification of commercial carprofen with methanol and ethanol in the presence of H 2 SO 4 ( Avram et al., 2002 ; Favia et al., 2012 ; Dumitrascu et al., 2022 ).…”

Section: Resultsmentioning

confidence: 99%

Repurposing anti-inflammatory drugs for fighting planktonic and biofilm growth. New carbazole derivatives based on the NSAID carprofen: synthesis, in silico and in vitro bioevaluation

Dumitrascu,

Caira,

Avram

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionOne of the promising leads for the rapid discovery of alternative antimicrobial agents is to repurpose other drugs, such as nonsteroidal anti-inflammatory agents (NSAIDs) for fighting bacterial infections and antimicrobial resistance.MethodsA series of new carbazole derivatives based on the readily available anti-inflammatory drug carprofen has been obtained by nitration, halogenation and N-alkylation of carprofen and its esters. The structures of these carbazole compounds were assigned by NMR and IR spectroscopy. Regioselective electrophilic substitution by nitration and halogenation at the carbazole ring was assigned from H NMR spectra. The single crystal X-ray structures of two representative derivatives obtained by dibromination of carprofen, were also determined. The total antioxidant capacity (TAC) was measured using the DPPH method. The antimicrobial activity assay was performed using quantitative methods, allowing establishment of the minimal inhibitory/bactericidal/biofilm eradication concentrations (MIC/MBC/MBEC) on Gram-positive (Staphylococcus aureus, Enterococcus faecalis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) strains. Computational assays have been performed to assess the drug- and lead-likeness, pharmacokinetics (ADME-Tox) and pharmacogenomics profiles.Results and discussionThe crystal X-ray structures of 3,8-dibromocarprofen and its methyl ester have revealed significant differences in their supramolecular assemblies. The most active antioxidant compound was 1i, bearing one chlorine and two bromine atoms, as well as the CO2Me group. Among the tested derivatives, 1h bearing one chlorine and two bromine atoms has exhibited the widest antibacterial spectrum and the most intensive inhibitory activity, especially against the Gram-positive strains, in planktonic and biofilm growth state. The compounds 1a (bearing one chlorine, one NO2 and one CO2Me group) and 1i (bearing one chlorine, two bromine atoms and a CO2Me group) exhibited the best antibiofilm activity in the case of the P. aeruginosa strain. Moreover, these compounds comply with the drug-likeness rules, have good oral bioavailability and are not carcinogenic or mutagenic. The results demonstrate that these new carbazole derivatives have a molecular profile which deserves to be explored further for the development of novel antibacterial and antibiofilm agents.

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Section: Resultsmentioning

confidence: 99%

Repurposing anti-inflammatory drugs for fighting planktonic and biofilm growth. New carbazole derivatives based on the NSAID carprofen: synthesis, in silico and in vitro bioevaluation

Dumitrascu,

Caira,

Avram

et al. 2023

Front. Cell. Infect. Microbiol.

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“…The chemical structure of the compounds influences their pharmacological activity [ 80 ]. The three-dimensional arrangement of the atoms in the molecule can play an important role in the activity of the compounds both in the accessibility to the active sites and for the interaction of the drug with the targeted receptor [ 18 ].…”

Section: Methodsmentioning

confidence: 99%

“…A significant number of items representing toxicity were analyzed for natural compounds—Ames (mutagenesis), carcinogenicity, toxicity to different species (crustacea, bees, fish), nephrotoxicity, hepatotoxicity, cardiotoxicity, mitochondrial toxicity, toxicity to nuclear receptors, and so on [ 80 ].…”

Section: Methodsmentioning

confidence: 99%

“…Aquatic toxicity for fish and crustaceans is also a common indicator for toxicity, with positive compounds for this category inhibiting the growth of half of the studied fish/crustacean population. This type of toxicity refers to the toxicity of the environment, with some drugs not being completely metabolized, being eliminated in their active state or their active metabolites and ending up in domestic water through excretion and in the soil, thus affecting the balance of the environment [ 80 , 86 ].…”

Section: Methodsmentioning

confidence: 99%

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Bioinformatics Tools for the Analysis of Active Compounds Identified in Ranunculaceae Species

et al. 2023

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The chemical compounds from extracts of three Ranunculaceae species, Aconitum toxicum Rchb., Anemone nemorosa L. and Helleborus odorus Waldst. & Kit. ex Willd., respectively, were isolated using the HPLC purification technique and analyzed from a bioinformatics point of view. The classes of compounds identified based on the proportion in the rhizomes/leaves/flowers used for microwave-assisted extraction and ultrasound-assisted extraction were alkaloids and phenols. Here, the quantifying of pharmacokinetics, pharmacogenomics and pharmacodynamics helps us to identify the actual biologically active compounds. Our results showed that (i) pharmacokinetically, the compounds show good absorption at the intestinal level and high permeability at the level of the central nervous system for alkaloids; (ii) regarding pharmacogenomics, alkaloids can influence tumor sensitivity and the effectiveness of some treatments; (iii) and pharmacodynamically, the compounds of these Ranunculaceae species bind to carbonic anhydrase and aldose reductase. The results obtained showed a high affinity of the compounds in the binding solution at the level of carbonic anhydrases. Carbonic anhydrase inhibitors extracted from natural sources can represent the path to new drugs useful both in the treatment of glaucoma, but also of some renal, neurological and even neoplastic diseases. The identification of natural compounds with the role of inhibitors can have a role in different types of pathologies, both associated with studied and known receptors such as carbonic anhydrase and aldose reductase, as well as new pathologies not yet addressed.

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“…The tested essential oils were achieved from commercial producers, according to Table 2. In order to determine the effect of the tested suspensions on the adhesion capacity to the inert substrate, we have used the crystal (purple) violet assay [8][9][10]. For this purpose, serial two-fold microdilutions were performed in 96 well plates in tryptic soy broth (TSB) liquid medium, starting from 1% oil in the first well, in a final volume of 150 μl liquid medium.…”

Section: Methodsmentioning

confidence: 99%

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2022

Biointerface Res Appl Chem

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Biofilms are the structure microbial that attach to different surfaces and enclave microorganisms in a matrix composed, protecting them from harsh conditions, including immune effectors and antibiotics. Therefore, this study aimed to assess the anti-biofilm activity of lavender, cloves, eucalyptus, rosemary, thyme, and oregano commercial essential oils, known for their biocidal properties against Gram-positive and Gram-negative ESKAPE isolates, exhibiting multiple drug resistance. The most efficient proved to be the oregano, thyme, and clove essential oils, which exhibited the lowest minimal biofilm eradication concentrations values against all bacterial species. Although lavender, eucalyptus, and rosemary had a weaker effect than the first three oils, they have also inhibited biofilm development at concentrations low enough to be considered effective. This experimental approach may open new perspectives for developing efficient strategies to combat the emergent threat of antibiotic resistance and to control the formation of microbial biofilms, being also a valuable source of bioactive compounds and new anti-biofilm drugs.

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In Silico and Experimental Investigation of the Biological Potential of Some Recently Developed Carprofen Derivatives

Cited by 6 publications

References 42 publications

Repurposing anti-inflammatory drugs for fighting planktonic and biofilm growth. New carbazole derivatives based on the NSAID carprofen: synthesis, in silico and in vitro bioevaluation

Repurposing anti-inflammatory drugs for fighting planktonic and biofilm growth. New carbazole derivatives based on the NSAID carprofen: synthesis, in silico and in vitro bioevaluation

Bioinformatics Tools for the Analysis of Active Compounds Identified in Ranunculaceae Species

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