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Carmen Limban,1 Alexandru Vasile Missir,1 Khairi Mustafa Salem Fahelelbom,2 Moawia Mohammad Al-Tabakha,2 Miron Teodor Caproiu,3 Bassem Sadek4 1Department of Pharmaceutical Chemistry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; 2Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University of Science and Technology, Al Ain, United Arab Emirates; 3Costin D Nenitescu Center of Organic Chemistry Romanian Academy, Bucharest, Romania; 4Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates Abstract: A number of 2-((4-ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl)benzamides (1a–h) were synthesized via reaction of 2-((4-ethylphenoxy)methyl)benzoyl isothiocyanate (2) as a key intermediate with several substituted primary aromatic amines. The new compounds were characterized by proton nuclear magnetic resonance (1H-NMR), carbon-13 nuclear magnetic resonance (13C-NMR), infrared spectrometry (IR), mass spectrometry (MS), and elemental analysis. The anti-inflammatory activity of 1a–h was investigated by acute carrageenan-induced paw edema in mice using the reference drug indomethacin. The results obtained indicated that, of the derivatives developed, 1a and 1d–h exhibited significantly higher anti-inflammatory activity (26.81%–61.45%) when compared with the reference drug indomethacin (22.43%) (P = 0.0490 for 1a, 0.0015 for 1d, 0.0330 for 1f, and P < 0.001 for 1e and 1h). Moreover, the ulcer incidence of 20% for 1e and 1h was clearly lower when compared with the indomethacin group (in which the ulcer incidence was 80%). Of particular note, the ulcer index of 0.2 for 1e was significantly less than that in the indomethacin group (0.6, P = 0.014). Additionally, prostaglandin E2 (PGE2) inhibitory properties were found to be high with 1e (68.32 pg/mL), significantly different from those of the placebo group (530.13 pg/mL, P < 0.001), and equipotent to the effect observed in the indomethacin-pretreated group (96.13 pg/mL, P > 0.05). Moreover, the PGE2 level of 54.15 pg/mL with 1h was also significantly different from that of the placebo group (P > 0.001) and of the indomethacin group (P > 0.05). The significant inhibition of PGE2 observed with 1e (68.32 pg/mL) and 1h (54.15 pg/mL) agree with their observed ulcer incidences. Our overall findings for N-phenylcarbamothioylbenzamides 1a–h clearly suggest that the compounds exhibit an anti-inflammatory effect, potently inhibit PGE2 synthesis, and markedly demonstrate low ulcer incidence. Keywords: PGE2, inhibitory properties, N-phenylcarbamothioylbenzamides, indomethacin, gastric ulcer, ulcerogenic

One of the biggest health challenges of today's world is the emergence of antimicrobial resistance (AMR), which renders conventional therapeutics insufficient and urgently demands the generation of novel antimicrobial strategies. Mycobacterium tuberculosis (M. tuberculosis), the pathogen causing tuberculosis (TB), is among the most successful bacteria producing drug-resistant infections. The versatility of M. tuberculosis allows it to evade traditional anti-TB agents through various acquired and intrinsic mechanisms, rendering TB among the leading causes of infectious disease-related mortality. In this context, researchers worldwide focused on establishing novel approaches to address drug resistance in M. tuberculosis, developing diverse alternative treatments with varying effectiveness and in different testing phases. Overviewing the current progress, this paper aims to briefly present the mechanisms involved in M. tuberculosis drug-resistance, further reviewing in more detail the under-development antibiotics, nanotechnological approaches, and natural therapeutic solutions that promise to overcome current treatment limitations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Growing resistance to antimicrobials, combined with pathogens that form biofilms, presents significant challenges in healthcare. Modifying current antimicrobial agents is an economical approach to developing novel molecules that could exhibit biological activity. Thus, five sulfanilamide Schiff bases were synthesized under microwave irradiation and characterized spectroscopically and in silico. They were evaluated for their antimicrobial and antibiofilm activities against both Gram-positive and Gram-negative bacterial strains. Their cytotoxic potential against two cancer cell lines was also determined. Gram-positive bacteria were susceptible to the action of these compounds. Derivatives 1b and 1d inhibited S. aureus 's growth (MIC from 0.014 mg/mL) and biofilm (IC from 0.029 mg/mL), while compound 1e was active against E. faecalis' s planktonic and sessile forms. Two compounds significantly reduced cell viability at 5 μg/mL after 24 h of exposure ( 1d -HT-29 colorectal adenocarcinoma cells, 1c -LN229 glioblastoma cells). A docking study revealed the increased binding affinities of these derivatives compared to sulfanilamide. Hence, these Schiff bases exhibited higher activity compared to their parent drug, with halogen groups playing a crucial role in both their antimicrobial and cytotoxic effects.

N-acyl hydrazone (NAH) is recognized as a promising framework in drug design due to its versatility, straightforward synthesis, and attractive range of biological activities, including antimicrobial, antitumoral, analgesic, and anti-inflammatory properties. In the global context of increasing resistance of pathogenic bacteria to antibiotics, NAHs represent potential solutions for developing improved treatment alternatives. Therefore, this research introduces six novel derivatives of ( EZ )-N'-benzylidene-2-(6-chloro-9 H -carbazol-2-yl)propanehydrazide, synthesized using a microwave-assisted method. In more detail, we joined two pharmacophore fragments in a single molecule, represented by an NSAID-type carprofen structure and a hydrazone-type structure, obtaining a new series of NSAID-N-acyl hydrazone derivatives that were further characterized spectrally using FT-IR, NMR, and HRMS investigations. Additionally, the substances were assessed for their tuberculostatic activity by examining their impact on four strains of M. tuberculosis , including two susceptible to rifampicin (RIF) and isoniazid (INH), one susceptible to RIF and resistant to INH, and one resistant to both RIF and INH. The results of our research highlight the potential of the prepared compounds in fighting against antibiotic-resistant M. tuberculosis strains.

Microorganisms participating in the development of biofilms exhibit heightened resistance to antibiotic treatment, therefore infections involving biofilms have become a problem in recent years as they are more difficult to treat. Consequently, research efforts are directed towards identifying novel molecules that not only possess antimicrobial properties but also demonstrate efficacy against biofilms. While numerous investigations have focused on antimicrobial capabilities of Schiff bases, their potential as antibiofilm agents remains largely unexplored. Thus, the objective of this article is to present a comprehensive overview of the existing scientific literature pertaining to small molecules categorized as Schiff bases with antibiofilm properties. The survey involved querying four databases (Web of Science, ScienceDirect, Scopus and Reaxys). Relevant articles published in the last 10 years were selected and categorized based on the molecular structure into two groups: classical Schiff bases and oximes and hydrazones. Despite the majority of studies indicating a moderate antibiofilm potential of Schiff bases, certain compounds exhibited a noteworthy effect, underscoring the significance of considering this type of molecular modeling when seeking to develop new molecules with antibiofilm effects.

The present study aimed to synthesize, characterize, and validate a separation and quantification method of new N -acyl thiourea derivatives ( 1a - 1o ), incorporating thiazole or pyridine nucleus in the same molecule and showing antimicrobial potential previously predicted in silico. The compounds have been physiochemically characterized by their melting points, IR, NMR and MS spectra. Among the tested compounds, 1a , 1g , 1h , and 1o were the most active against planktonic Staphylococcus aureus and Pseudomonas aeruginosa , as revealed by the minimal inhibitory concentration values, while 1e exhibited the best anti-biofilm activity against Escherichia coli (showing the lowest value of minimal inhibitory concentration of biofilm development). The total antioxidant activity (TAC) assessed by the DPPH method, evidenced the highest values for the compound 1i, followed by 1a . A routine quality control method for the separation of highly related compounds bearing a chlorine atom on the molecular backbone ( 1g , 1h , 1i , 1j , 1m , 1n ) has been developed and validated by reversed-phase high-performance liquid chromatography (RP-HPLC), the results being satisfactory for all validation parameters recommended by the ICH guidelines (i.e., system suitability, specificity, the limits of detection and quantification, linearity, precision, accuracy and robustness) and recommending it for routine separation of these highly similar compounds.

Introduction: One 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., Methods: A 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 Discussion: The 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dumitrascu, Caira, Avram, Buiu, Udrea, Vlad, Zarafu, Ioniță, Nuță, Popa, Chifiriuc and Limban.)

New N-acyl thiourea derivatives with heterocyclic rings have been synthesized by first obtaining isothiocyanate, which further reacted with a heterocyclic amine, characterized by (FT-IR, NMR spectroscopy and FT-ICR) and tested for their in vitro antimicrobial, anti-biofilm and antioxidant activities to obtain a drug candidate in a lead-optimization process. From the tested compounds, those bearing benzothiazole ( 1b ) and 6-methylpyridine ( 1d ) moieties revealed anti-biofilm activity against E. coli ATCC 25922 at MBIC values of 625 µg/mL. Compound 1d exhibited the highest antioxidant capacity (~43%) in the in vitro assay using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Considering the in vitro results, the highest anti-biofilm and antioxidant activities were obtained for compound 1d . Therefore, a reversed-phase high-performance liquid chromatography (RP-HPLC) method has been optimized and validated for the quantitative determination of compound 1d . The detection and quantitation limits were 0.0174 μg/mL and 0.0521 μg/mL, respectively. The R 2 correlation coefficient of the LOQ and linearity curves were greater than 0.99, over the concentration range of 0.05 μg/mL-40 μg/mL. The precision and accuracy of the analytical method were within 98-102%, confirming that the method is suitable for the quantitative determination of compound 1d in routine quality control analyses. Evaluating the results, the promising potential of the new N-acyl thiourea derivatives bearing 6-methylpyridine moiety will be further investigated for developing agents with anti-biofilm and antioxidant activities.

The unprecedented increase in microbial resistance rates to all current drugs raises an acute need for the design of more effective antimicrobial strategies. Moreover, the importance of oxidative stress due to chronic inflammation in infections with resistant bacteria represents a key factor for the development of new antibacterial agents with potential antioxidant effects. Thus, the purpose of this study was to bioevaluate new O-aryl-carbamoyl-oxymino-fluorene derivatives for their potential use against infectious diseases. With this aim, their antimicrobial effect was evaluated using quantitative assays (minimum inhibitory/bactericidal/biofilms inhibitory concentrations) (MIC/MBC/MBIC), the obtained values being 0.156-10/0.312-10/0.009-1.25 mg/mL), while some of the involved mechanisms (i.e., membrane depolarization) were investigated by flow cytometry. The antioxidant activity was evaluated by studying the scavenger capacity of DPPH and ABTS•+ radicals and the toxicity was tested in vitro on three cell lines and in vivo on the crustacean Artemia franciscana Kellog. The four compounds derived from 9 H -fluoren-9-one oxime proved to exhibit promising antimicrobial features and particularly, a significant antibiofilm activity. The presence of chlorine induced an electron-withdrawing effect, favoring the anti- Staphylococcus aureus and that of the methyl group exhibited a +I effect of enhancing the anti- Candida albicans activity. The IC50 values calculated in the two toxicity assays revealed similar values and the potential of these compounds to inhibit the proliferation of tumoral cells. Taken together, all these data demonstrate the potential of the tested compounds to be further used for the development of novel antimicrobial and anticancer agents.

The efficient regioselective bromination and iodination of the nonsteroidal anti-inflammatory drug (NSAID) carprofen were achieved by using bromine and iodine monochloride in glacial acetic acid. The novel halogenated carprofen derivatives were functionalized at the carboxylic group by esterification. The regioselectivity of the halogenation reaction was evidenced by NMR spectroscopy and confirmed by X-ray analysis. The compounds were screened for their in vitro antibacterial activity against planktonic cells and also for their anti-biofilm effect, using Gram-positive bacteria ( Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and Gram-negative bacteria ( Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853). The cytotoxic activity of the novel compounds was tested against HeLa cells. The pharmacokinetic and pharmacodynamic profiles of carprofen derivatives, as well as their toxicity, were established by in silico analyses.

(1) Background: The research aims to find new treatments for neurodegenerative diseases, in particular, Alzheimer's disease. (2) Methods: This article presents a bioinformatics and pathology study of new Schiff bases, ( EZ )-N'-benzylidene-(2 RS )-2-(6-chloro-9 H -carbazol-2-yl)propanehydrazide derivatives, and aims to evaluate the drug-like, pharmacokinetic, pharmacodynamic and pharmacogenomic properties, as well as to predict the binding to therapeutic targets by applying bioinformatics, cheminformatics and computational pharmacological methods. (3) Results: We obtained these Schiff bases by condensing (2 RS )-2-(6-chloro-9 H -carbazol-2-yl)propanehydrazide with aromatic aldehydes, using the advantages of microwave irradiation. The newly synthesized compounds were characterized spectrally, using FT-IR and NMR spectroscopy, which confirmed their structure. Using bioinformatics tools, we noticed that all new compounds are drug-likeness features and may be proposed as potentially neuropsychiatric drugs (4) Conclusions: Using bioinformatics tools, we determined that the new compound 1e had a high potential to be used as a good candidate in neurodegenerative disorders treatment.

Antimicrobial resistance is one of the major public health threats at the global level, urging the search for new antimicrobial molecules. The fluorene nucleus is a component of different bioactive compounds, exhibiting diverse pharmacological actions. The present work describes the synthesis, chemical structure elucidation, and bioactivity of new O-aryl-carbamoyl-oxymino-fluorene derivatives and the contribution of iron oxide nanoparticles to enhance the desired biological activity. The antimicrobial activity assessed against three bacterial and fungal strains, in suspension and biofilm growth state, using a quantitative assay, revealed that the nature of substituents on the aryl moiety are determinant for both the spectrum and intensity of the inhibitory effect. The electron-withdrawing inductive effect of chlorine atoms enhanced the activity against planktonic and adhered Staphylococcus aureus , while the +I effect of the methyl group enhanced the anti-fungal activity against Candida albicans strain. The magnetite nanoparticles have substantially improved the antimicrobial activity of the new compounds against planktonic microorganisms. The obtained compounds, as well as the magnetic core@shell nanostructures loaded with these compounds have a promising potential for the development of novel antimicrobial strategies.

Since the discovery of penicillin by Alexander Fleming in 1929 as a therapeutic agent against staphylococci, β-lactam antibiotics (BLAs) remained the most successful antibiotic classes against the majority of bacterial strains, reaching a percentage of 65% of all medical prescriptions. Unfortunately, the emergence and diversification of β-lactamases pose indefinite health issues, limiting the clinical effectiveness of all current BLAs. One solution is to develop β-lactamase inhibitors (BLIs) capable of restoring the activity of β-lactam drugs. In this review, we will briefly present the older and new BLAs classes, their mechanisms of action, and an update of the BLIs capable of restoring the activity of β-lactam drugs against ESKAPE ( Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa , and Enterobacter spp.) pathogens. Subsequently, we will discuss several promising alternative approaches such as bacteriophages, antimicrobial peptides, nanoparticles, CRISPR (clustered regularly interspaced short palindromic repeats) cas technology, or vaccination developed to limit antimicrobial resistance in this endless fight against Gram-negative pathogens.

Starting from isoniazid and carboxylic acids as precursors, thirteen new hydrazides and 1,3,4-oxadiazoles of 2-(4-substituted-phenoxymethyl)-benzoic acids were synthesized and characterized by appropriate means. Their biological properties were evaluated in terms of apoptosis, cell cycle blocking, and drug metabolism gene expression on HCT-8 and HT-29 cell lines. In vitro antimicrobial tests were performed by the microplate Alamar Blue assay for the anti-mycobacterial activities and an adapted agar disk diffusion technique for other non-tubercular bacterial strains. The best antibacterial activity (anti- Mycobacterium tuberculosis effects) was proved by 9 . Compounds 7 , 8 , and 9 determined blocking of G1 phase. Compound 7 proved to be toxic, inducing apoptosis in 54% of cells after 72 h, an effect that can be predicted by the increased expression of mRNA caspases 3 and 7 after 24 h. The influence of compounds on gene expression of enzymes implicated in drug metabolism indicates that synthesized compounds could be metabolized via other pathways than NAT2, spanning adverse effects of isoniazid. Compound 9 had the best antibacterial activity, being used as a disinfectant agent. Compounds 7 , 8 , and 9 , seemed to have antitumor potential. Further studies on the action mechanism of these compounds on the cell cycle may bring new information regarding their biological activity.

The increasing threat of antimicrobial resistance to all currently available therapeutic agents has urged the development of novel antimicrobials. In this context, a series of new benzoylthiourea derivatives substituted with one or more fluorine atoms and with the trifluoromethyl group have been tested, synthesized, and characterized by IR, NMR, CHNS and crystal X-ray diffraction. The molecular docking has provided information regarding the binding affinity and the orientation of the new compounds to Escherichia coli DNA gyrase B. The docking score predicted the antimicrobial activity of the studied compounds, especially against E. coli, which was further demonstrated experimentally against planktonic and biofilm embedded bacterial and fungal cells. The compounds bearing one fluorine atom on the phenyl ring have shown the best antibacterial effect, while those with three fluorine atoms exhibited the most intensive antifungal activity. All tested compounds exhibited antibiofilm activity, correlated with the trifluoromethyl substituent, most favorable in para position.

In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[ b , e ]oxepin-11(6 H )one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a - j ) were confirmed by 1 H-NMR, 13 C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a - j , characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus , B. subtilis , Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues.

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-9 H -carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl ( RS )-2-(6-chloro-9 H -carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to ( RS )-2-(6-chloro-9 H -carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N -[(2 RS )-2-(6-chloro-9 H -carbazol-2-yl)propanoil]- N '- R -substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the ( RS )-1-(6-chloro-9 H -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-9 H -carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, 1 H-NMR and 13 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 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.

Background: Alzheimer's disease (AD) is considered a severe, irreversible and progressive neurodegenerative disorder. Currently, the pharmacological management of AD is based on a few clinically approved acethylcholinesterase (AChE) and N-methyl-D-aspartate (NMDA) receptor ligands, with unclear molecular mechanisms and severe side effects., Methods: Here, we reviewed the most recent bioinformatics, cheminformatics (SAR, drug design, molecular docking, friendly databases, ADME-Tox) and experimental data on relevant structurebiological activity relationships and molecular mechanisms of some natural and synthetic compounds with possible anti-AD effects (inhibitors of AChE, NMDA receptors, beta-secretase, amyloid beta (Aβ), redox metals) or acting on multiple AD targets at once. We considered: (i) in silico supported by experimental studies regarding the pharmacological potential of natural compounds as resveratrol, natural alkaloids, flavonoids isolated from various plants and donepezil, galantamine, rivastagmine and memantine derivatives, (ii) the most important pharmacokinetic descriptors of natural compounds in comparison with donepezil, memantine and galantamine., Results: In silico and experimental methods applied to synthetic compounds led to the identification of new AChE inhibitors, NMDA antagonists, multipotent hybrids targeting different AD processes and metal-organic compounds acting as Aβ inhibitors. Natural compounds appear as multipotent agents, acting on several AD pathways: cholinesterases, NMDA receptors, secretases or Aβ, but their efficiency in vivo and their correct dosage should be determined., Conclusion: Bioinformatics, cheminformatics and ADME-Tox methods can be very helpful in the quest for an effective anti-AD treatment, allowing the identification of novel drugs, enhancing the druggability of molecular targets and providing a deeper understanding of AD pathological mechanisms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

(1) Background: Graphene oxide is a new carbon-based material that contains functional groups (carboxyl, hydroxyl, carbonyl, epoxy) and therefore can be easily functionalized with organic compounds of interest, yielding hybrid materials with important properties and applications. (2) Methods: Graphene oxide has been obtained by a modified Hummers method and activated by thionyl chloride in order to be covalently functionalized with amines. Thus obtained hybrid materials were characterized by infrared and Raman spectroscopy, elemental analysis and scanning electron microscopy and then tested for their antimicrobial and anti-biofilm activity. (3) Results: Eight amines of interest were used to functionalize grapheme oxide and the materials thus obtained were tested against Gram-negative ( Escherichia coli , Pseudomonas aeruginosa ) and Gram-positive ( Staphylococcus aureus ) bacterial strainsin plankonic and biofilm growth state. Both amines, as well as the functionalized materials, exhibited anti-microbial features. Three to five functionalized graphene oxide materials exhibited improved inhibitory activity against planktonic strains as compared with the respective amines. In exchange, the amines alone proved generally more efficient against biofilm-embedded cells. (4) Conclusions: Such hybrid materials may have a wide range of potential use in biomedical applications.

In order to identify compounds with potential toxicity problems, particular attention is paid to structural alerts, which are high chemical reactivity molecular fragments or fragments that can be transformed via bioactivation by human enzymes into fragments with high chemical reactivity. The concept has been introduced in order to reduce the likelihood that future candidate substances as pharmaceuticals will have undesirable toxic effects. A significant proportion (∼78-86%) of drugs characterized by residual toxicity contain structural alerts; there is also evidence indicating the formation of active metabolites as a causal factor for the toxicity of 62-69% of these molecules. On the other hand, the pharmacological action of certain drugs depends on the formation of reactive metabolites. Detailed assessment of the potential for the formation of active metabolites is recommended to characterize a biologically active compound. Although many prescribed drugs frequently contain structural alerts and form reactive metabolites, the vast majority of these drugs are administered in low daily doses. Avoiding structural alerts has become almost a norm in new drug design. An in-depth review of the biochemical reactivity of these structural alerts for new drug candidates is critical from a safety point of view and is currently being monitored in the discovery of drugs. The chemical strategies applied to structural alerts in molecules to limit the toxicity are: •partial replacement or full replacement of the structural alert;•reduction of electronic density;•introduction of a structural element of metabolic interest (metabolic switching);•multiple approaches. Therefore, chemical intervention strategies to eliminate bioactivation are often interactive processes; their success depends largely on a close working relationship between drug chemists, pharmacologists and researchers in metabolic science.

The continuously increasing global impact of fungal infections is requiring the rapid development of novel antifungal agents. Due to their multiple pharmacological activities, thiourea derivatives represent privileged candidates for shaping new drugs. We report here the preparation, physico-chemical characterization and bioevaluation of hybrid nanosystems based on new 2-((4-chlorophenoxy)methyl)- N -(substituted phenylcarbamo-thioyl)benzamides and Fe₃O₄@C 18 core@shell nanoparticles. The new benzamides were prepared by an efficient method, then their structure was confirmed by spectral studies and elemental analysis and they were further loaded on Fe₃O₄@C 18 nanostructures. Both the obtained benzamides and the resulting hybrid nanosystems were tested for their efficiency against planktonic and adherent fungal cells, as well as for their in vitro biocompatibility, using mesenchymal cells. The antibiofilm activity of the obtained benzamides was dependent on the position and nature of substituents, demonstrating that structure modulation could be a very useful approach to enhance their antimicrobial properties. The hybrid nanosystems have shown an increased efficiency in preventing the development of Candida albicans ( C. albicans ) biofilms and moreover, they exhibited a good biocompatibility, suggesting that Fe₃O₄@C 18 core@shell nanoparticles could represent promising nanocarriers for antifungal substances, paving the way to the development of novel effective strategies with prophylactic and therapeutic value for fighting biofilm associated C. albicans infections., Competing Interests: The authors declare no conflict of interest.

Novel derivatives were prepared by reaction of aromatic amines with 2-(4-ethylphenoxymethyl)benzoyl isothiocyanate, affording the N-[2-(4-ethylphenoxymethyl) benzoyl]-Nꞌ-(substituted phenyl)thiourea. Structural elucidation of these compounds was performed by IR, NMR spectroscopy and elemental analysis. The new compounds were used in combination with Fe3O4 and polyvinylpyrrolidone (PVP) for the coating of medical surfaces. In our experiments, catheter pieces were coated by Matrix Assisted Pulsed Laser Evaporation (MAPLE) technique. The microbial adherence ability was investigated in 6 multi-well plates by using culture based methods. The obtained surfaces were also assessed for their cytotoxicity with respect to osteoblast cells, by using fluorescence microscopy and MTT assay. The prepared surfaces by advanced laser processing inhibited the adherence and biofilm development ability of Staphylococcus aureus and Pseudomonas aeruginosa tested strains while cytotoxic effects on the 3T3-E1 preosteoblasts embedded in layer shaped alginate hydrogels were not observed. These results suggest that the obtained medical surfaces, based on the novel thiourea derivatives and magnetic nanoparticles with a polymeric shell could represent a promising alternative for the development of new and effective anti-infective strategies.

The purpose of this study was to design a new nanosystem for catheter surface functionalization with an improved resistance to Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 colonization and subsequent biofilm development. New 2-((4 ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl)-benzamides were synthesized and used for coating a core/shell nanostructure. Their chemical structures were elucidated by NMR, IR and elemental analysis, being in agreement with the proposed ones. Fe(3)O(4)/C(12 )of up to 5 nm size had been synthesized with lauric acid as a coating agent and characterized by XRD, FT-IR, TGA, TEM and biological assays. The catheter pieces were coated with the fabricated nanofluid in magnetic field. The microbial adherence ability was investigated in 6 multiwell plates by using culture based methods and Scanning Electron Microscopy (SEM). The nanoparticles coated with the obtained compounds 1a-c inhibited the adherence and biofilm development ability of the S. aureus and P. aeruginosa tested strains on the catheter functionalized surface, as shown by the reduction of viable cell counts and SEM examination of the biofilm architecture. Using the novel core/shell/adsorption-shell to inhibit the microbial adherence could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with improved anti-biofilm properties.

In this paper, we report the design of a new nanofluid for anti-pathogenic surface coating. For this purpose, new 2-((4-ethylphenoxy)methyl)-N-(substituted-phenylcarbamothioyl)-benzamides were synthesized and used as an adsorption shell for Fe3O4/C12 core/shell nanosized material. The functionalized specimens were tested by in vitro assays for their anti-biofilm properties and biocompatibility. The optimized catheter sections showed an improved resistance to Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 in vitro biofilm development, as demonstrated by the viable cell counts of biofilm-embedded bacterial cells and by scanning electron microscopy examination of the colonized surfaces. The nanofluid proved to be not cytotoxic and did not influence the eukaryotic cell cycle. These results could be of a great interest for the biomedical field, opening new directions for the design of film-coated surfaces with improved anti-biofilm properties.

A series of dibenzo[b,e]ox(thi)epin-11(6H)-one O-benzoyloximes has been synthesized and structurally elucidated by means of IR, (1)H-NMR, (13)C-NMR, MS, and elemental analysis. The newly developed compounds were screened at concentrations of 200-25 μg/mL for their antibacterial activity against Gram+ve organisms such as Methicillin-Resistant Staphylococcus Aureus (MRSA), Gram-ve organisms such as Escherichia coli (E. coli), and at the same concentration range for their antifungal activity against fungal strain Aspergillus niger (A. niger) by the cup plate method. Ofloxacin and ketoconazole (10 μg/mL) were used as reference standards for antibacterial and antifungal activity, respectively. The dibenzo[b,e]oxepines 6a-c and 6e-h showed low antimicrobial activity (MIC 125-200 μg/mL) compared to the reference substances, whereas a major improvement (MIC 50-75 μg/mL) was achieved with the synthesis of the corresponding bromomethyl derivative 6d. Moreover, replacement of oxygen by its bioisosteric sulfur led to isomeric dibenzo[b,e]thi-epine derivatives 6g,h which significantly exhibited higher antimicrobial activity (MIC 25-50 μg/mL) against all tested culture strains used in the present study, demonstrating that a change of chemical class from dibenzo[b,e]oxepine to dibenzo[b,e]thiepine significantly improves the antimicrobial activity. Further variation, such as the oxidation of the thiepine sulfur to the corresponding isomeric dibenzo[b,e]thiepine 5,5-dioxide derivative 9, comparatively failed to exhibit high activity (MIC 200 μg/mL) against S. aureus, E. coli or A. niger.

A number of acylthioureas, 2-((4-methylphenoxy)methyl)-N-(aryl-carbamothioyl)benzamides (aryl = 3,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichloro-phenyl, 2,4,5-trichlorophenyl, 3,4,5-trichlorophenyl, 2-bromophenyl, 2,4-dibromophenyl, 2,5-dibromophenyl, 2-iodophenyl, 3-fluorophenyl, 2,3,4-trifluorophenyl, 2,4,5-trifluoro-phenyl, 2,4,6-trifluorophenyl) have been synthesized, characterized by elemental analysis, IR and NMR spectroscopy and tested for their interaction with bacterial cells in free and adherent state. The anti-pathogenic activity was correlated with the presence of one iodine, bromide or fluorine, and two or three chloride atoms on the N-phenyl substituent of the thiourea moiety, being significant especially on Pseudomonas aeruginosa and Staphylococcus aureus strains, known for their ability to grow in biofilms. Our results demonstrate the potential of these derivatives for further development of novel anti-microbial agents with antibiofilm properties.

In this paper we present the antimicrobial activity of some newly synthesized dibenz[b,e]oxepin derivatives bearing the oximino moiety, and fluorine (F) and trifluoromethyl (CF(3)) group substituents. The chemical structure and purity of the new compounds were assessed by using elemental analysis, NMR and FTIR spectroscopy. The new compounds were screened for their antibacterial activity towards Gram-positive and Gram-negative strains, by qualitative and quantitative assays. Our results demonstrated that the CF(3) and F disubstituted compounds could be considered for the further development of novel antimicrobial drugs.

The aim of the present study was to evaluate the antimicrobial activity of new 2-(4-ethyl-phenoxymethyl) benzoic acid thioureides. The synthesis of the new compounds was done in three steps starting with the synthesis of 2-(4-ethyl-phenoxymethyl) benzoic acid. In the second stage, the 2-(4-ethyl-phenoxymethyl)-benzoyl chloride was prepared and the new thioureides were synthesized in the third step by the reaction of 2-(4-ethyl-phenoxymethyl) benzoyl isothiocyanate with various primary aromatic amines. The original compounds were screened for their in vitro antimicrobial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) as well as to fungal strains (Candida albicans, Aspergillus niger), using both reference and clinical, multidrug resistant strains. The qualitative screening of the susceptibility spectra of various microbial strains versus these compounds was performed by three adaptated diffusion methods: (1) impregnation of the filter paper disks with the respective substance solutions, (2) distribution of the tested solutions into agar wells and (3) spotting of the respective solutions on the solid medium previously inoculated with the microbial suspensions. The quantitative assay of the antimicrobial activity was performed by broth microdilution method in 96-well microplates in order to establish the minimal inhibitory concentration (MIC). The tested compounds exhibited specific antimicrobial activity with MICs ranging from 3.9 microg/mL to 250 microg/mL.

Fifty members of a novel class of antimicrobial compounds, 2-(4-R-phenoxymethyl)benzoic acid thioureides, were synthesized and characterized with respect to their activities against three parasites of human relevance, namely the protozoa Giardia lamblia and Toxoplasma gondii, and the larval (metacestode) stage of the tapeworm Echinococcus multilocularis. To determine the selective toxicity of these compounds, the human colon cancer cell line Caco2 and primary cultures of human foreskin fibroblasts (HFF) were also investigated. The new thioureides were obtained in a three-step-reaction process and subsequently characterized by their physical constants (melting point, solubility). The chemical structures were elucidated by (1)H NMR, (13)C NMR, IR spectral methods and elemental analysis. The analyses confirmed the final and intermediate compound structures and the synthesis. The compounds were then tested on the parasites in vitro. All thioureides, except two compounds with a nitro group, were totally ineffective against Giardia lamblia. 23 compounds inhibited the proliferation of T. gondii, three of them with an IC(50) of approximately 1 microM. The structural integrity of E. multilocularis metacestodes was affected by 22 compounds. In contrast, HFF were not susceptible to any of these thioureides, while Caco2 cells were affected by 17 compounds, two of them inhibiting proliferation with an IC(50) in the micromolar range. Thioureides may thus present a promising class of anti-infective agents.

The purpose of this study was to evaluate in vitro, by means of qualitative and quantative methods, the antimicrobial activity of some new synthesized chemical compounds previously solubilized in DMF (Dimethyl formamide). The qualitative screening of the susceptibility spectra of different microbial strains versus these compounds was performed by three adaptated diffusion methods: paper filter disk impregnation with the tested substances solutions, the disposal of tested solutions in agar wells and the spotting of tested solutions on solid medium previously inoculated with microbial suspension. The quantitative assay of the antimicrobial activity was performed by broth microdilution method in 96-well microplates in order to establish the minimal inhibitory concentration (MIC).The antimicrobial activity was tested against Gram-positive strains (Staphylococcus) aureus sp., Bacillus subtilis sp.), Gram-negative (Escherichia coli sp, Pseudomonas aeruginosa sp., Klebsiella pneumonia sp.) and fungal strains (Candida albicans sp, Aspergillus nige rsp.). All tests were performed by comparison with the reference strains: K. pneumoniae IC 13420, E. coli IC 13529, S. aureus IC 13204, P. aeruginosa IC 13202, B. subtilis IC 12488, C. albicans IC 249, A. niger IC 13534. Our results indicated that the tested compounds exhibited specific antimicrobial activity, the highest activity being noticed against planktonic fungal cells (MIC ranging from 62.5 microg to 15.6 microg), followed by P. aeruginosa (MICs from 250 microg to 31.5 microg). Only few compounds exhibited antimicrobial activity against E. coli and K. pneumoniae. Antimicrobial activity against Gram positive bacteria was noticed for the most of the tested compounds, five of them exhibiting very low MIC values (MICs from 1000 microg to 62.5 microg).

We report here the characterisation of eight newly synthesized thioureides of 2-(4-chlorophenoxymethyl)-benzoic acid and the evaluation of the in vitro antimicrobial activity of the new compounds against Gram-positive [Listeria monocytogenes,Staphylococcus aureus, Bacillus subtilis], Gram-negative [Psedomonas aeruginosa,Escherichia coli, Salmonella enteritidis], as well as Candida spp., using both reference and clinical multidrug resistant strains to establish the minimal inhibitory concentration (MIC)values. Our results showed that the tested compounds exhibited specific antimicrobial activities, both concerning the spectrum of antimicrobial activity and the corresponding MIC values, which ranged widely between 1024 and 32 mug/mL, depending on the nature and position of the substituents on the benzene ring. The most active compounds were N-[2-(4-chlorophenoxymethyl)-benzoyl]-N'-(2,6-dichlorophenyl)-thiourea (5 g) and N-[2-(4-chlorophenoxymethyl)-benzoyl]-N'-(4-bromophenyl)-thiourea (5h), which showed a broad spectrum of antimicrobial activity against enterobacterial strains (E. coli and S. enteritidis),P. aeruginosa, S. aureus and Candida spp. All the tested compounds except 5f were highly active against S. aureus (MIC=32 mug/mL), suggesting their possible use in the treatment of MRSA infections. Four of compounds also exhibited antifungal activity (MIC =256-32 microg/mL) against C. albicans, but L. monocytogenes as well as B. subtilis were resistant to all tested compounds. Our studies thus demonstrated that among other biological activities,the thioureides of 2-(4-chlorophenoxymethyl)-benzoic acid also exhibit selective and effective antimicrobial properties that could lead to the selection and use of these compounds as efficient antimicrobial agents, especially for the treatment of multidrug resistant infections.