Antibacterial Activity of New Dibenzoxepinone Oximes with Fluorine and Trifluoromethyl Group Substituents

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 (CF3) 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 CF3 and F disubstituted compounds could be considered for the further development of novel antimicrobial drugs

Experimental pharmacological research regarding the antidepressant effect of associating doxepin and selegiline in normal mice

The severity and complexity of depression can vary widely among individuals, thus making single drug therapy ineffective in some cases. Taking this fact into account and using a mouse model, we set on investigating the possibility of obtaining a synergism of action between a classical tricyclic antidepressant that inhibits noradrenalin and serotonin reuptake (doxepin), and a modern antidepressant that inhibits type-B monoamine oxidase (selegiline). We measured the antidepressant effect using the forced swimming test and the tail suspension test. We determined motor activity using the Activity Cage test. Our results have shown that the antidepressant effect intensifies significantly in the animals treated with both antidepressants simultaneously compared to those treated only with doxepin. Furthermore, we observed that selegiline decreases the sedative effect of doxepin in the Activity Cage test

Experimental pharmacological research regarding some new quinazolin-4-ones derivatives

A series of new compounds with quinazolin-4-one structure, synthesized by the Pharmaceutical Chemistry Department of the Faculty of Pharmacy of the University of Medicine and Pharmacy “Carol Davila” Bucharest, was studied. Five of them were selected, conventionally named S1, S2, S3, S4, S5, and investigated in terms of their potential influence on the central nervous system (CNS). For this purpose, the antidepressant effect was determined using the forced swimming test; the anxiolytic/ anxiogenic effect was determined using the suspended plus-shaped maze (Ugo Basile); the effect on the motor activity was determined using the Ugo Basile activity cage; and the potential analgesic effect was investigated using the hot plate test (Ugo Basile). Compounds S3 and S5 lowered the motor activity and showed an anxiolytic effect, while S1 and S2 proved to have antidepressant and analgesic effects. A good correlation between antidepressant and analgesic effects was observed, consistent with the fact that analgesic drugs, by increasing norepinephrine and serotonin levels in the pain inhibiting descendent pathways, can be used as co-analgesics in therapy

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”

New -(2-dial kylaminoethyl)-benzanilides with potential antipsychotic action

Universitatea de Medicină şi Farmacie „Carol Davila” Facultatea de Farmacie, Bucureşti, România, Centrul Știintific în Domeniul Medicamentului, IP USMF „Nicolae Testemiţanu”, Republica MoldovaObiectivul studiului: Scopul acestui studiu a fost sinteza, caracterizarea fizico-chimică, determinarea toxicităţii şi cercetarea efectului antipsihotic al unor noi compuşi din clasa N-(2-dialchilaminoetil)benzanilidelor, ştiind că benzamidele reprezintă o clasă importantă de agenţi antipsihotici atipici cu mare afinitate pentru receptorii dopaminergici D2. Material şi metode: Compuşii au rezultat în urma unei sinteze în 3 etape, care constă într-o reacţie de alchilare a unor amine aromatice cu clorhidrat de N-(2-cloretil)-N,N-dialchilamină, folosind ca mediu de reacţie toluenul anhidru şi captator de hidracid, carbonatul de sodiu, urmată de reacția anilinelor intermediare cu diferite cloruri ale acizilor aromatici printr-o reacţie de condensare Scotten- Baumann, desfşurată în toluen anhidru, în prezenţa trietilaminei. Amidele rezultate se transformă în clorhidrați prin tratarea lor cu soluție eterică de HCI la rece. Compuşii finali, obţinuţi sub formă de clorhidraţi, au fost caracterizaţi prin proprietăţile lor fizice şi spectrale (IR, RMN). Pentru determinarea toxicităţii acute a fost folosită metoda “up and down” care permite o estimare a intervalului în care se găsește DL50, iar pentru cercetarea acțiunii antipsihotice a benzanilidelor nou-sintetizate, am utilizat testului actometriei şi testului platformei la animale cu sindrom hiperdopaminergic indus prin administrare de selegilină. Rezultate: Au fost sintetizate şi analizate patru noi N-(2- dialchilaminoetil)-benzanilide (clorhidraţi), care au fost caracterizate fzico-chimic şi spectral, punându-se în evidenţă identitatea şi puritatea acestor compuşi: N-(2-dietilaminoetil)-N-(3-clorofenil)-4-metilbenzamida (clorhidrat) (C1) N-(2-dimetilaminoetil)-N-(3-clorofenil)-2-clorobenzamida (clorhidrat) (C2) N-(2-dimetilaminoetil)-N-(3-trifluorometilfenil)- benzamida (clorhidrat) (C3) N-(2-dietilaminoetil)-N-(2,6-dimetilfenil)-3-fluoro- 5-trifluorometilbenzamida (clorhidrat) (C4) Valorile DL50 înregistrate au variat între 130,29 mg/kg şi 274 mg/kg. Dintre compușii investigați, se constată că C2, C3 şi C4 protejează animalele față de stimularea prin selegilină. La doza administrată, hiperactivitatea motorie indusă de selegilină este antagonizată semnificativ de către compusul C3. Efectul selegilinei asupra curiozității și capacității de explorare este antagonizat de către toți cei trei compuși. Concluzii: Compuşii sintetizaţi şi testaţi dovedesc că au un profil molecular favorabil apariţiei efectului antipsihotic, dovedindu-se benefică substituţia cu grupe CF3 la o distanţă de trei atomi de faţă de grupa amidică, asemănător antipsihoticelor clasice din clasa fenotiazinelor, trifluperazina şi triflupromazina. În plus se confirmă şi prin testele efectuate că grupa trifluorometil potenţează în general acţiunea farmacologică a substanţelor medicamentoase din clasa antipsihoticelor. 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

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

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

Synthesis, Spectroscopic Properties and Antipathogenic Activity of New Thiourea Derivatives

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Synthesis and Antimicrobial Evaluation of Dibenzo[b,e]oxepin-11(6H)-one O-Benzoyloxime Derivatives

A series of dibenzo[b,e]ox(thi)epin-11(6H)-one O-benzoyloximes has been synthesized and structurally elucidated by means of IR, 1H-NMR, 13C-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