Barbara Rajtar

Synthesis and in vitro activity of 1,2,4-triazole-ciprofloxacin hybrids against drug-susceptible and drug-resistant bacteria

A series of novel 1,2,4-triazole-ciprofloxacin hybrids was designed, synthesised and evaluated in vitro against drug-susceptible and drug-resistant bacteria. A significant part of the compounds obtained showed antibacterial activity higher than the activity of ciprofloxacin, both towards Gram-positive and Gram-negative species. Despite relatively small number of synthesised derivatives, it was possible to observe important dependences between their structure and activity.

Search for factors affecting antibacterial activity and toxicity of 1,2,4-triazole-ciprofloxacin hybrids.

A series of 1,2,4-triazole-based compounds was designed as potential antibacterial agents using molecular hybridization approach. The target compounds (23-44) were synthesized by Mannich reaction of 1,2,4-triazole-3-thione derivatives with ciprofloxacin (CPX) and formaldehyde. Their potent antibacterial effect on Gram-positive bacteria was accompanied by similarly strong activity against Gram-negative strains. The toxicity of the CPX-triazole hybrids for bacterial cells was even up to 18930 times higher than the toxicity for human cells. The results of enzymatic studies showed that the antibacterial activity of the CPX-triazole hybrids is not dependent solely on the degree of their affinity to DNA gyrase and topoisomerase IV.

Determination of the Primary Molecular Target of 1,2,4-Triazole-Ciprofloxacin Hybrids

We have synthesized and examined the antibacterial activity, toxicity and affinity towards bacterial type II topoisomerases of a series of 1,2,4-triazole-ciprofloxacin hybrids. A number of these compounds displayed enhanced activity against Gram-positive and Gram-negative bacteria when compared to ciprofloxacin. The toxic concentrations of the obtained derivatives, evaluated on HEK-293 cells using MTT assay, were much higher than concentrations required to produce antibacterial effect. Finally, the results of enzymatic studies showed that the analyzed compounds demonstrated other preferences as regards primary and secondary molecular targets than ciprofloxacin.

Synthesis and Antibacterial Activity of Novel Fused 1,3‐Thiazoles and 1,3‐Thiazines Incorporating a 2,4‐Dihydroxyphenyl Residue

In an attempt to find a new class of antimicrobial agents, a series of benzothiazoles, 1,3‐thiazolo[5,4‐b]pyridines, 4H‐3,1‐benzothiazines, naphtho[2,3‐d][1,3]thiazole‐4,9‐diones and other related compounds containing a 2,4‐dihydroxyphenyl moiety were prepared. They were obtained via the reaction of aryl‐modified sulfinyl[bis(2,4‐dihydroxyphenylmethanethione)]s with appropriate commercial chemical reagents in the endocyclization processes. The MIC values of the compounds towards eight reference bacterial strains were assessed by the two‐fold serial micro‐dilution broth method. They exhibited inhibitory effects against the Gram‐positive strains tested opposite to Gram‐negative ones. Some compounds were more effective than the reference drug. 4‐(6‐Chloro‐4H‐3,1‐benzothiazin‐2‐yl)‐6‐methylbenzene‐1,3‐diol (5b) due to its very good activity (MIC from 1.56 to 3.13 µg/mL) and low cytotoxicity (IC50 > 50 µg/mL) may be regarded as a promising precursor for the development of novel antibacterial agents.

Synthesis and antiviral activity of 1-(1,3-disubstitutedimidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives

Abstract Novel 1-(1,3-disubstituted-imidazolidyn-2-ylidene)-3-ethoxycarbonylmethylurea derivatives (3a–3j) were obtained from appropriate 1-aryl-3-arylsulfonyl-1H-imidazolidine-2-imines (1a–1j) and ethyl isocyanatoacetate (2), which were subjected to condensation. Seven compounds were tested for their antiviral activity against HSV-1 and CVB3 viruses. Among the tested compounds, 3c was found to be active against HSV-1, proving that 4-methoxy substituent as R and 4-methyl substituent as R1 are most beneficial for activity against this virus. Furthermore, 3e and 3g were active against CVB3, which demonstrated that both 4-methyl and 4-chloro substitution is tolerated as R1, whereas 4-chloro and 2-methoxy substituents are best as R. It was also shown that the active compounds are characterized by relatively big surface area, small ovality, and greatest HOMO and LUMO energies in comparison to the rest of the compounds.

The influence of extracts from Peucedanum salinum on the replication of adenovirus type 5

Introduction The aim of the study was to examine the cytotoxicity and evaluate the antiviral and virucidal activity of methanol and methanol/H2O extracts from the herb of Peucedanum salinum. Plants belonging to the genus Peucedanum (Apiaceae family) have been used in traditional medicine for a long time. Material and methods The examination of the cytotoxicity of the extracts in the concentrations of 0.1, 0.2, 0.5, 1, 2, 4 mg/ml was carried out on the cell culture line HEK-293. Cytotoxicity of the examined extracts was measured by the colorimetric MTT (tetrazolium) method. After determination of the highest non-toxic concentration of examined extracts, antiviral and virucidal activity against adenovirus type 5 (Adenoviridae) was established. Results The non-toxic doses were as follows: 1 mg/ml of methanol extract and 2 mg/ml of methanol/H2O extract (1 : 1 v/v). Antiviral activity was observed for the methanol extract of Peucedanum salinum in concentrations of 0.5 and 1 mg/ml. The extract caused the decrease of titre of the virus by 2 log and 1.33 log, respectively. The methanol/H2O extract (1 : 1 v/v) decreased the titre of the virus by 1.33 log and 1.5 log in concentrations of 1 and 2 mg/ml, respectively. The examined extracts had no virucidal activity against adenovirus type 5. Conclusions The examined extract is a new, potentially active source of active substances possessing antiviral activity and further studies are needed.

Design, synthesis, structure elucidation and in vitro antiviral and antimicrobial evaluation

In this study, we described the synthesis of the derivatives of thiosemicarbazide, dicarboximide, 1,2,4-triazole-5-thione and 4-oxo-1,3-thiazolidine. Two different dicarboxylic acid anhydrides reacted with 4-substituted-3-thiosemicarbazide, and derivatives of thiosemicarbazide and dicarboximide were obtained. Next, cyclization reaction of dicarboximide derivatives in alkaline media was used to prepare 1,2,4-triazole-5-thione. The 4-oxo-1,3-thiazolidine was synthesized by the reaction of dicarboximide with ethyl bromoacetate. All obtained derivatives were analysed by 1H and 13C NMR spectra, and for one compound, the X-ray crystallography was done. Antimicrobial, antiviral and in vitro evaluations of cytotoxicity were examined. According to the preliminary antiviral screening, compounds 3 and 4 presented the antiviral activity against HSV-1 and CVB3. Additionally, compound 3 shows selective in vitro toxic effect against human epithelial cells FaDu, without affecting normal animal cell line (Vero). The same derivatives 3 and 4 also displayed a wide spectrum of antimicrobial activity against reference microorganisms and indicated both antibacterial and antifungal potential activities.

Dual Antibacterial and Anticancer Activity of 4-Benzoyl-1-dichlorobenzoylthiosemicarbazide Derivatives

OBJECTIVE/METHOD A group of 4-benzoyl-1-dichlorobenzoylthiosemicarbazides endowed with antibacterial activity was evaluated for its cytotoxic properties against breast cancer cells (MCF-7, MDA-MB-231) and head and neck squamous cell carcinomas (FaDu, SCC-25). Cytotoxicity of the investigated compounds was measured using MTT and [3H]-thymidine incorporation bioassays. RESULT 1-(2,3-Dichlorobenzoyl)-4-(2-methylbenzoyl)thiosemicarbazide (TA-4), 1-(2,4-dichlorobenzoyl)- 4-(2-methylbenzoyl)thiosemicarbazide (TA-18), and 1-(2,4-dichlorobenzoyl)-4-(4-nitrolbenzoyl)- thiosemicarbazide (TA-20) were found to possess anticancer activity equipotent or even stronger than that of reference drug - etoposide. In order to clarify the molecular mode of action of the mentioned compounds, the relaxation assay kit for human DNA topoisomerase II was used. It turned out that reduction of viability of cancer cells was a result of inhibition of human DNA topoII. Molecular docking studies proved that 4-benzoyl-1-dichlorobenzoylthiosemicarbazides strongly interact with DNAdependent subunit of that enzyme.

Antiviral activity of ciprofloxacin on BK virus in an in vitro culture – pilot study

Introduction. Reactivation of BKV infection caused by decrease of immunity associated with organ transplantation can lead to nephropathy and organ loss. Antiviral drugs such as ganciclovir or foscarnet did not display any activity against BK virus. A source of hope can be found in chemotherapeutics usually used in bacterial infections that inhibit the replication of viral genetic material in cells. One of the aforementioned chemotherapeutics is ciprofloxacin. The aim of the study is to evaluate the antiviral activity of ciprofloxacin against BK virus in vitro culture. Materials and method. Initially, the effects of ciprofloxacin on Vero cell viability were assessed with MTT. After determining the 3 largest non-cytotoxic concentrations of antibiotics, their effect on viral replication in cells was determined. 24-h cells culture in DMEM medium supplemented with 10% serum after 2h incubation with a 6.3 x 105 copies/ml infection virus were used to evaluate the effects of different concentrations of ciprofloxacin on the number of BKV copies. Quantification of BKV replication in the culture was performed by real-time PCR. Results. By means of the MTT test, the 3 largest non-cytotoxic ciprofloxacin concentrations were determined as follows: 31.25; 62.5; 125 μg/ml. Cells treated with ciprofloxacin at a concentration of 125 μg/ml display the greatest decrease in BKV replication that equaly 1.8 – 3 log/5.8 – 9.2 Ct, compared to the control of the virus without drugs. A decline in the number of copies of the virus was observed during the lower concentration of the antibiotic (62.5, 31.25 μg/ml) by 1.3 – 2 log/4 – 6.4 Ct and 0 – 0.8 log/0 – 2, 4 Ct, respectively. Conclusions. Ciprofloxacin exhibits antiviral activity against the BK virus by inhibiting its replication in the in vitro culture

Chemical profile, antioxidant activity and cytotoxic effect of extract from leaves of Erythrochiton brasiliensis Nees & Mart. from different regions of Europe

Abstract The total phenolic content (TPC), total tannin content (TTC) and total flavonoid content (TFC) as well as the antioxidant activity and the cytotoxic effect of the extract from leaves of Erythrochiton brasiliensis Nees & Mart. (Rutaceae) were evaluated. Raw material was collected in different European botanical gardens. Statistical analysis revealed a clear grouping of populations according to their climatic zone. The average TPC, TTC and TFC in tested samples were 35.92 (± 7.11) mg GAE·g–1 DW, 14.98 (± 4.08) mg PyE·g–1 DW and 2.92 (± 0.76) mg QuE·g–1 DW, respectively. The scavenged DPPH and Trolox equivalents determined by EPR spectroscopy were 1.23–4.14 and 0.50–1.44 mmol·g–1 of dry extract, respectively. Thirteen compounds (derivatives of bezoic acid acid and trans-cinnammic acid) were identified in the samples. The flavonoid vitexin was also present as the major component in three investigated samples. The in vitro cytotoxicity test of the extract on Vero cells provided IC50 and IC10 values of 175.6 and 72.5 μg·mL–1, respectively. Incubation of samples with HHV-1 infected Vero cells had no effect on the occurrence of cytopathic effect.