Vol. 16 No. 3(63) (2018)
The information related to the methods of the synthesis of 4- and 6-trifluoromethyl-3,4-dihydropyrimidine- 2-ones and their condensed analogs as potent molecular platforms for the synthesis of bioactive compounds has been analyzed and systematized. The role of inter- and intramolecular cyclocondensations of CF3-containing substrates, as well as nucleophilic addition to C=N bond as key steps for construction of 4-trifluorinated derivatives has been emphasized. The major part of this article is devoted to the construction of trifluoromethyldihydropirimidones of a high optical purity and their thioanalogs based on the condensation of the chiral ureas and thioureas. A special attention is paid to asymmetric reactions, which are used for the synthesis of chiral analogs of the anti-HIV drug Efavirenz. It has been noted that Biginelly reaction of the corresponding fluorinated ketoesters is the common way for obtaining 6-trifluoromethylpyrimidones. The method allows obtaining the target products in one stage although it has limitations due to the need to isolate intermediate cyclic products, which in the future should be subjected to dehydration. The effect of the catalyst nature on the course of Biginelly reaction of trifluoromethylated substrates has been analyzed. It has been shown that nucleophilic 3,6-addition to 4-CF3- dihydropyrimidones is effective method for the synthesis of dihydroorotic acid derivatives.
Aim. To compare sulfonylcalixarene derivatives containing ionizable or non-ionizable substituents at the upper rim of the macrocycle as inhibitors of protein tyrosine phosphatase 1B (PTP1B) and other PTPs.
Results and discussion. The properties of sulfonylcalixarene with four phosphonic acid groups introduced at the upper rim were compared with those of the macrocycles containing four non-ionizable tert-butyl or trifluoroacetamide functions. The sulfonylcalixarene tetrakis-methylphosphonic acid was found to inhibit PTP1B with IC50 value in the low-micromolar range without selectivity over other PTPs, such as TC-PTP, MEG1, MEG2, SHP2, and PTPβ. At the same time, modification of sulfonylcalixarene with trifluoroacetamide substituents led to inhibition of PTP1B with IC50 of 1.4 μM and 4- to 28 fold selectivity over the other PTPs. In order to understand the ability of inhibiting PTP1B by sulfonylcalixarene with introduced trifluoroacetamide groups the molecular docking and molecular dynamic simulations were performed. The inhibition mechanism was discussed.
Experimental part. The activities of the test compounds in vitro were examined spectrophotometrically measuring the rate of hydrolysis of p-nitrophenyl phosphate as a substrate of PTPs. The molecular docking was performed by AutoDock Vina.
Conclusions. This study can start an approach to develop new inhibitors of PTPs by variations in the nonionogenic substituents on the upper rim of sulfonylcalixarene scaffold.
Secnidazole is one of antiprotozoal medicines from the group of 5-nitroimidazoles, the method of HPLC with different types of detection is widely used for secnidazole determination.
Aim. To develop the HPLC/UV-procedure of secnidazole quantification with application of the system of a “MiLiChrome® A-02” HPLC-analyzer and carry out the step-by-step validation of the procedure developed. Results and discussion. The specificity of the chromatographic conditions proposed was confirmed in relation to other medicines of the group of 5-nitroimidazoles (metronidazole, tinidazole, ornidazole and nimorazole). The retention time for secnidazole was 8.16 min. 0.01 M solution of hydrochloric acid was proposed for preparation of the reference and model solutions in developing the HPLC/UV-procedure of secnidazole quantification. To prove the possibility of application of the procedure proposed in further analysis its validation was carried out in the variants of the method of the calibration curve and the method of standard. Such validation parameters as in-process stability, linearity/calibration model, accuracy and precision (repeatability) were estimated using model solutions. Experimental part. The HPLC/UV analyses were performed using a MiLiChrome® A-02 high pressure liquid chromatograph (EcoNova, Russia). Eluent A (0.2 M LiClO4 – 0.005 M HClO4) and Eluent B (acetonitrile) were used as the mobile phase components. The HPLC microcolumn with the size of Ø2 × 75 mm and the ProntoSIL 120-5-C18 AQ reversed phase, 5 μm (BISCHOFF Analysentechnik und -geräte GmbH, Germany) was used as an analytical column. The analysis was performed at 40 °С and the flow rate of 100 μl/min. The mobile phase was run in the gradient elution mode, namely from 5 % to 100 % of Eluent B for 40 min, then 100 % of Eluent B for 3 min. Detection was performed at 277 nm. Conclusions. A new procedure of the secnidazole quantitative determination by the method of HPLC/UV has been developed. Its validation has been carried out, and acceptability for its application has been shown.
5-Sulfurofunctionalized (1,3-thiazolidin-2-ylidene)pyrimidine-2,4,6-triones and their antibacterial activity
Aim. Studying of the antimicrobial and antifungal activity of 5-sulfurofunctionalized derivatives (1,3-thiazolidine-2-ylidene)pyrimidine-2,4,6(1H,3H,5H)-triones, obtained by the interaction of [5-(iodomethyl)thiazolidine-2-ylidene]pyrimidine-2,4,6(1H,3H,5H)-triones with a number of S-nucleophilic reagents.
Results and discussion. A series of new derivatives containing 5-thiocyanato(acetylthio, butylxanthonato)methyl groups has been synthesized by functionalization of [5-(iodomethyl)thiazolidine-2-ylidene]pyrimidine-2,4,6(1H,3H,5H)-triones with sulfur-containing reagents. Among the synthesized compounds substances with moderate antibacterial and antifungal activity were found.
Experimental part. Novel 5-thiofunctionalized derivatives were obtained by reaction of [5-(iodomethyl)thiazolidine-2-ylidene]pyrimidine-2,4,6(1H,3H,5H)-triones with potassium thiocyanate, potassium thioacetate in dimethylformamide or potassium buthylxanthate in ethanol with 72-99% yields. The structure of new compounds was confirmed by complex spectral methods. Screening of the antifungal and antimicrobial effects of the synthesized compounds was carried out using a micro-method of double serial dilutions in a liquid nutrient medium.
Conclusions. 5-Sulfurofunctionalized (1,3-thiazolidine-2-ylidene)pyrimidine-2,4,6-triones, obtained by the reaction of corresponding 5-iodomethyl derivatives with a number of S-nucleophilic reagents, have shown moderate antimicrobial and antifungal activity and are promising for further in-depth research.
Aim. To create a convenient preparative method for the synthesis of new 4-aminopirazolo[1,5-a] pyrazines derivatives and perform the screening of their antibacterial and antifungal properties.
Results and discussion. It was determined that 4-chloropyrazolo[1,5-a]pyrazines selectively reacted with various alkylamines producing the corresponding 4-aminopyrazolo[1,5-a]pyrazines with high yields. The biological screening of the derivatives synthesized allowed us to identify compounds with the antibacterial and antifungal activity in the concentrations of 31.25-250 μg/ml.
Experimental part. The new 4-aminopyrazolo[1,5-a]pyrazines derivatives were produced by the reaction of 4-chloropyrazolo[1,5-a]pyrazines with the primary and secondary alkylamines at room temperature or by refluxing in ethanol. The structures of the compounds synthesized were confirmed with 1H, 13C NMR-spectra and mass spectra. The results of the microbiological screening using a micromethod of double serial dilutions in a liquid nutrient medium showed that the compounds synthesized exhibited a moderate bactericidal activity.
Conclusions. It has been found that the reaction of 4-chloropyrazolo[1,5-a]pyrazines with the primary and secondary alkylamines is a convenient method for the synthesis of aminopirazolo[1,5-a]pyrazines that exhibit a moderate antimicrobial activity against S. aureus 209, B. subtilis ATCC 6633, M. luteus ATCC 4698 (bacteria) and the antifungal activity against C. ablicans 669/1080 and C. krusei ATCC 6258 (fungi).
The effect of 5,11,17,23-tetrakis(diisopropoxyphosphonyl)- 25,26,27,28-terapropoxycalixarene on the chromatographic separation of ecologically hazardous aromatic compounds
Aim. To study the effect of 5,11,17,23 tetrakis(diisopropoxyphosphonyl)-25,26,27,28-tetrapropoxycalix
arene additive to the MeCN/H2O mobile phase on selectivity of the HPLC separation of aromatic compounds using a Zorbax ODS support.
Results and discussion. Calixarene improves the separation due to formation of the Host-Guest inclusion complexes. The linear dependence of 1/k’ on the calixarene concentration allows calculating the stability constants KA of the complexes. The correlation of the separation selectivity induced by the calixarene additives with the ratio of the stability constants of the Host-Guest inclusion complexes of the aromatic analytes was found. The complexation is influenced by logP and pKa parameters of the analytes. Short contacts between the calixarene Host and the aromatic Guest indicate that the inclusion complexes are stabilized by various hydrogen bonds, nonvalence van der Waals, π-π and hydrophobic interactions.
Experimental part. The energy minimized structures of the calixarene complexes with p-fluorophenol, guaiacol, toluene and trichloromethylbezene were calculated using Hyper Chem 8, PM3, vacuum.
Conclusions. The data obtained can be used in design of new phases for HPLC.
Synthesis and the study of the antimicrobial activity of N-aryliden-2-oxo-3,3-diphenil-2,3- dihydro-1H-thieno[3,4-b]pyrrol-6-carbohydrazides
Aim. To perform the synthesis of 2-oxo-3,3-diphenyl-2,3-dihydro-1H-thieno[3,4-b]pyrrol-6-carbohydrazide, its N-arylidene derivatives and study the antimicrobial activity of the compounds synthesized.
Results and discussion. 2-Oxo-3,3-diphenyl-2,3-dihydro-1H-thieno[3,4-b]pyrrol-6-carbohydrazide 2 was synthesized by the interaction of the starting ester 1 with hydrazine hydrate. The interaction of the former with arenecarbaldehydes (3.1-3.8) led to the corresponding N-arylidenes. The structure of the compounds obtained was proven by instrumental methods. The data of the antimicrobial activity screening confirmed the high activity of the compounds synthesized against Staphylococcus aureus and Candida albicans.
Experimental part. The synthesis of the starting and target compounds was performed under common conditions. The instrumental methods of analysis of organic compounds, and well agar diffusion method were used.
Conclusions. 2-Oxo-3,3-diphenyl-2,3-dihydro-1H-thieno[3,4-b]pyrrol-6-carbohydrazide and series of its N-arylidene derivatives have been synthesized, and their structure has been unambiguously proven. The antimicrobial activity of 2-oxo-3,3-diphenyl-2,3-dihydro-1H-thieno[3,4-b]pyrrol-6-carboxylic acid derivatives (1, 2) and N-aryliden-2-oxo-3,3-diphenyl-2,3-dihydro-1H-thieno[3,4-b]pyrrol-6-carbohydrazides (4.1-4.8) has been studied. Compounds possessing a high level of the antimicrobial activity against gram-positive bacteria – Staphylococcus aureus, Bacillus subtilis, as well as fungal species of Candida albicans have been found. The moderate activity of the compounds synthesized against gram-negative bacteria – Proteus vulgaris, Escherichia coli, Pseudomonas aeruginosa has been also proven.