The antifungal activity evaluation of new 2-((4-chlorophenoxy) methyl )-N- (arylcarbamothioyl) benzamides

Disciplina de Chimie farmaceutică, Facultatea de Farmacie , Universitatea de Medicină și Farmacie “Carol Davila”, București, România, Departamentul de Microbiologie, Facultatea de Biologie, Universitatea din București, București, RomâniaObiectivul studiului: Au fost proiectaţi, obţinuţi şi caracterizaţi noi derivați ai tioureei, în scopul evaluării activităţii antifungice. Materiale şi metode: Acidul 2-(4-clorofenoximetil)benzoic a fost refluxat cu clorură de tionil, obţinându-se clorura de 2-(4-clorofenoximetil)benzoil, care a reacționat cu tiocianatul de amoniu. Izotiocianatul de 2-(4-clorofenoximetil) benzoil rezultat, a fost tratat cu amine primare pentru a obţine noi derivaţi ai N-[2-(4-clorofenoximetil) benzoil]-tioureei N’-fenil substituite. Pentru evaluarea acţiunii antifungice s-au utilizat 6 tulpini de levuri izolate din surse industriale, 9 tulpini de levuri izolate din mediul clinic şi 11 tulpini de fungi filamentoşi izolaţi în urma procesului de control microbiologic al unor produse alimentare. Activitatea antifungică s-a testat calitativ, printr-o metodă difuzimetrică adaptată. Analiza cantitativă s-a realizat prin metoda microdiluţiilor seriale binare în mediu lichid. Studiul efectului sinergic al unor antifungice cu benzamidele nou sintetizate s-a realizat prin metoda E-Test. Rezultate: În urma screening-ului calitativ al activităţii antifungice a noilor bezamide testate pe levuri, s-a observat că eficienţa acestora a variat în funcţie de specia testată şi de compus. Dintre tulpinile industriale, cea mai sensibilă specie levurică s-a dovebit a fi Debariomyces hansenii. Sensibile au fost şi majoritatea tulpinilor clinice de Candida albicans. În metoda calitativă de determinare a activităţii noilor compuşi asupra tulpinilor de fungi filamentoşi, s-au observat modificări ale caracterelor de cultură, în sensul apariţiei unor colonii de dimensiuni mai reduse, ca urmare a afectării gradului de dezvoltare şi de maturare a hifelor miceliene. În determinarea cantitativă a activităţii antifungice prin stabilirea concentraţiei minime inhibitorii (CMI), în cazul levurilor, rezultate moderat vizibile s-au observat la unele specii de Candida albicans, compuşii cei mai activi fiind selectaţi pentru testarea efectului sinergic cu antifungice standard, prin metoda E-Test. În cazul testării pe tulpinile fungice de Aspergillus niger, pentru determinarea valorii CMI, s-a observat faptul că, în prezenţa unora dintre compuşi, la concentraţii mai mari, are loc persistenţa miceliului primar şi întârzierea fenomenului de maturare a miceliului secundar şi de sporulare, precum şi apariţia de corpi micelieni modificaţi. În cazul metodei E- Test, combinarea flucitozinei cu unii dintre compuși, a crescut gradul de sensibilitate al celulelor de Candida albicans la acţiunea antimicoticului. Concluzii: Au fost sintetizaţi și caracterizaţi prin spectrometrie IR, RMN și prin analiză elementală noi derivați ai benzamidei. Rezultatele testării acţiunii antifungice sugerează că acești compuși ar putea fi folosiţi în terapeutică. Studiile au fost finanţate prin contractul 13/23.12.2013 din competiţia „N. Testemiţanu”

Synthesis and Pharmacological Research Regarding New Compounds with Quinazolin-4-One Structure

The quinazoline scaffold is found in the chemical structure of many marketed drugs used in CNS disorders as antidepressants, anxiolytics, or hypnotics. Also, the carbamate ester derivatives have different certain therapeutic actions, such as hypnotic or parasympathomimetic ones. We have obtained new 4(3H)-quinazolinones by bringing together in the same structure the quinazoline nucleus and carbamate ester group. The compounds named Q1–Q5 were characterized by measuring the melting points, by determining the infrared and NMR spectra, and by elemental analysis. The pharmacological tests evidenced that the compounds have a very low acute toxicity, lethal doses being >2000 mg/kg bw. The compounds had different actions observed in forced swimming test (FST), tail suspension test (TST), or elevated plus maze (EPM), probably influenced by the presence of different radicals on the nucleus. Thus, Q1 with a nitro group in structure manifested the highest antidepressant effect, showing a reduction of immobilization time in FST and TST. On the other hand, Q3 and Q5, with two groups methoxy, respective ethoxy, had a slight anxiolytic effect, highlighted by an increase of the time spent in open arms and a decrease of the time spent in closed arms of EPM

Antimicrobial Activity of Some New Thioureides Derived from 2-(4-Chlorophenoxymethyl)benzoic Acid

We report here the characterisation of eight newly synthesized thioureides of 2-(4-chlorophenoxymethyl)-benzoic acid and the evaluation of the in vitro antimicrobialactivity 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 andclinical multidrug resistant strains to establish the minimal inhibitory concentration (MIC)values. Our results showed that the tested compounds exhibited specific antimicrobialactivities, both concerning the spectrum of antimicrobial activity and the correspondingMIC values, which ranged widely between 1024 and 32 μg/mL, depending on the natureand position of the substituents on the benzene ring. The most active compounds were N-[2-(4-chlorophenoxymethyl)-benzoyl]-N\u27-(2,6-dichlorophenyl)-thiourea (5g) and N-[2-(4-chlorophenoxymethyl)-benzoyl]-N\u27-(4-bromophenyl)-thiourea (5h), which showed a broadspectrum 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 μg/mL), suggesting their possible use in the treatment ofMRSA infections. Four of compounds also exhibited antifungal activity (MIC =256-32μg/mL) against C. albicans, but L. monocytogenes as well as B. subtilis were resistant toall tested compounds. Our studies thus demonstrated that among other biological activities,the thioureides of 2-(4-chlorophenoxymethyl)-benzoic acid also exhibit selective andeffective antimicrobial properties that could lead to the selection and use of thesecompounds as efficient antimicrobial agents, especially for the treatment of multidrugresistant infections

Novel Hybrid Formulations Based on Thiourea Derivatives and Core@Shell Fe3O4@C18 Nanostructures for the Development of Antifungal Strategies

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@C18 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@C18 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@C18core@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

Bioevaluation of Novel Anti-Biofilm Coatings Based on PVP/Fe3O4 Nanostructures and 2-((4-Ethylphenoxy)methyl)-N- (arylcarbamothioyl)benzamides

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

Bioevaluation of Novel Anti-Biofilm Coatings Based on PVP/Fe3O4 Nanostructures and 2-((4-Ethylphenoxy)methyl)-N- (arylcarbamothioyl)benzamides

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

In Silico and In Vitro Experimental Studies of New Dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)-oximes Designed as Potential Antimicrobial Agents

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(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a–j) were confirmed by 1H-NMR, 13C-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