Studies on the Thermal Decomposition Course of Nitrogen-Rich Heterocyclic Esters as Potential Drug Candidates and Evaluation of Their Thermal Stability and Properties.

Drug candidates must undergo thermal evaluation as early as possible in the preclinical phase of drug development because undesirable changes in their structure and physicochemical properties may result in decreased pharmacological activity or enhanced toxicity. Hence, the detailed evaluation of nitrogen-rich heterocyclic esters as potential drug candidates, i.e., imidazolidinoannelated triazinylformic acid ethyl esters 1-3 (where R1 = 4-CH3 or 4-OCH3 or 4-Cl, and R2 = -COOC2H5) and imidazolidinoannelated triazinylacetic acid methyl esters 4-6 (where R1 = 4-CH3 or 4-OCH3 or 4-Cl, and R2 = -CH2COOCH3)-in terms of their melting points, melting enthalpy values, thermal stabilities, pyrolysis, and oxidative decomposition course-has been carried out, using the simultaneous thermal analysis methods (TG/DTG/DSC) coupled with spectroscopic techniques (FTIR and QMS). It was found that the melting process (documented as one sharp peak related to the solid-liquid phase transition) of the investigated esters proceeded without their thermal decomposition. It was confirmed that the melting points of the tested compounds increased in relation to R1 and R2 as follows: 2 (R1 = 4-OCH3; R2 = -COOC2H5) < 6 (R1 = 4-Cl; R2 = -CH2COOCH3) < 5 (R1 = 4-OCH3; R2 = -CH2COOCH3) < 3 (R1 = 4-Cl; R2 = -COOC2H5) < 1 (R1 = 4-CH3; R2 = -COOC2H5) < 4 (R1 = 4-CH3; R2 = -CH2COOCH3). All polynitrogenated heterocyclic esters proved to be thermally stable up to 250 °C in inert and oxidising conditions, although 1-3 were characterised by higher thermal stability compared to 4-6. The results confirmed that both the pyrolysis and the oxidative decomposition of heterocyclic ethyl formates/methyl acetates with para-substitutions at the phenyl moiety proceed according to the radical mechanism. In inert conditions, the pyrolysis process of the studied molecules occurred with the homolytic breaking of the C-C, C-N, and C-O bonds. This led to the emission of alcohol (ethanol in the case of 1-3 or methanol in the case of 4-6), NH3, HCN, HNCO, aldehydes, CO2, CH4, HCl, aromatics, and H2O. In turn, in the presence of air, cleavage of the C-C, C-N, and C-O bonds connected with some oxidation and combustion processes took place. This led to the emission of the corresponding alcohol depending on the analysed class of heterocyclic esters, NH3, HCN, HNCO, aldehydes, N2, NO/NO2, CO, CO2, HCl, aromatics, and H2O. Additionally, after some biological tests, it was proven that all nitrogen-rich heterocyclic esters-as potential drug candidates-are safe for erythrocytes, and some of them are able to protect red blood cells from oxidative stress-induced damage.

Application of Simultaneous and Coupled Thermal Analysis Techniques in Studies on the Melting Process, Course of Pyrolysis and Oxidative Decomposition of Fused Triazinylacetohydrazides.

The effect of the structure of promising antioxidant agents with prospective medical use, i.e., unsubstituted and para-substituted annelated triazinylacetic acid hydrazides, on their melting points, thermal stabilities, pyrolysis and oxidative decomposition stages and the type of volatiles emitted under heating with the use of DSC and TG/DTG/FTIR/QMS methods was evaluated and discussed. The melting point of the investigated compounds increased with an enhanced number of electrons (directly correlated with their molecular weight). Melting enthalpy values were determined and presented for all the studied compounds. The pyrolysis and oxidative decomposition processes of the analysed molecules consisted of several poorly separated stages, which indicated a multi-step course of the decomposition reactions. It was found that the thermal stability of the tested compounds depended on the type of substituent at the para position of the phenyl moiety or its absence. In both atmospheres used (air and helium), the thermal stability increased in relation to R as follows: -CH3 ≤ -OCH3 < -H < -OC2H5. In an inert atmosphere, it was higher by approx. 8-18 °C than in an oxidative atmosphere. The pyrolysis was connected with the emission of NH3, HCN, HNCO, HCONH2, HCHO, CO2, CO and H2O in the case of all the tested compounds, regardless of the substituent attached. In the case of the derivative containing the para-CH3 group, para-toluidine was an additional emitted aromatic product. In turn, emissions of aniline and alcohol (methanol or ethanol) for compounds with the para-OCH3 and para-OC2H5 groups, respectively, were confirmed. In oxidative conditions, the release of NH3, NO, HCN, HNCO, HCONH2, CO2, H2O and cyanogen (for all the compounds) and para-toluidine (for the para-CH3 derivative), aniline (for para-OCH3, para-OC2H5 and unsubstituted derivatives) and acetaldehyde (for the para-OC2H5 derivative) were clearly observed. No alcohol emissions were recorded for either compound containing the para-OCH3- or para-OC2H5-substitututed phenyl ring. These results confirmed that the pyrolysis and oxidative decomposition of the investigated annelated triazinylacetohydrazides occurred according to the radical mechanism. Moreover, in the presence of oxygen, the reactions of volatiles and residues with oxygen (oxidation) and the combustion process additionally proceeded.

Thermal Decomposition Path-Studied by the Simultaneous Thermogravimetry Coupled with Fourier Transform Infrared Spectroscopy and Quadrupole Mass Spectrometry-Of Imidazoline/Dimethyl Succinate Hybrids and Their Biological Characterization.

The thermal decomposition path of synthetically and pharmacologically useful hybrid materials was analyzed in inert and oxidizing conditions for the first time and presented in this article. All the imidazoline/dimethyl succinate hybrids (1-5) were studied using the simultaneous thermogravimetry (TG) coupled with Fourier transform infrared spectroscopy (FTIR) and quadrupole mass spectrometry (QMS). It was found that the tested compounds were thermally stable up to 200-208 °C (inert conditions) and up to 191-197 °C (oxidizing conditions). In both furnace atmospheres, their decomposition paths were multi-step processes. At least two major stages (inert conditions) and three major stages (oxidizing conditions) of their decomposition were observed. The first decomposition stage occurred between T5% and 230-237 °C. It was connected with the breaking of one ester bond. This led to the emission of one methanol molecule and the formation of radicals capable of further radical reactions in both used atmospheres. At the second decomposition stage (Tmax2) between 230-237 °C and 370 °C (inert conditions), or at about 360 °C (oxidizing conditions), the cleavage of the second ester bond and N-N and C-C bonds led to the emission of CH3OH, HCN, N2, and CO2 and other radical fragments that reacted with each other to form clusters and large clusters. Heating the tested compounds to a temperature of about 490 °C resulted in the emission of NH3, HCN, HNCO, aromatic amines, carbonyl fragments, and the residue (Tmax2a) in both atmospheres. In oxidizing conditions, the oxidation of the formed residues (Tmax3) was related to the production of CO2, CO, and H2O. These studies confirmed the same radical decomposition mechanism of the tested compounds both in inert and oxidizing conditions. The antitumor activities and toxicities to normal cells of the imidazoline/dimethyl succinate hybrids were also evaluated. As a result, the two hybrid materials (3 and 5) proved to be the most selective in biological studies, and therefore, they should be utilized in further, more extended in vivo investigations.

Experimental Studies on the Thermal Properties and Decomposition Course of a Novel Class of Heterocyclic Anticancer Drug Candidates.

The experimental studies on the thermal properties and decomposition course of a novel class of potential anticancer drugs (1-5) containing in their heterobicyclic structures the asymmetrical triazine template were performed with the use of differential scanning calorimetry (DSC) and simultaneous thermogravimetry/differential scanning calorimetry (TG/DTG/DSC) coupled online with Fourier transform infrared spectroscopy (FTIR) and quadrupole mass spectrometry (QMS) in inert and oxidizing conditions. All the compounds were thermally characterized in detail for the first time in this article. The DSC studies proved that the melting points of the tested compounds depended on the position and type of the substituent at the phenyl moiety, whereas they did not depend on the furnace atmosphere. All the tested polynitrogenated heterocycles proved to be molecules with high thermal stability in both atmospheres, and most of them (1, 3-5) were more stable in oxidizing conditions, which indicated the formation of a more thermally stable form of the compounds when interacting with oxygen. The simultaneous TG/FTIR/QMS analyses confirmed that their pyrolysis process occurred in one main stage resulting in the emission of volatiles such as NH3, HNCO, HCN, CO, CO2, H2O, NO2, aromatic amine derivatives, alkenes (for compounds 1-5), and HCl (for the compound 5). On the other hand, the oxidative decomposition process was more complicated and proceeded in two main stages leading to the emission of NH3, CO2, CO, HCN, HNCO, H2O, some aromatics (for compounds 1-5), HCl (for compounds 3-5) as well as the additional volatiles such as N2, NO2, NH2OH, and (CN)2. The type of the formed volatiles indicated that the decomposition process of the studied heterocycles under the influence of heating was initiated by the radical mechanism. Their decomposition was related to the symmetric cleavage of C-N and C-C bonds (inert conditions) and additional reaction of the volatiles and residues with oxygen (oxidizing conditions).

UV Polymerization of Methacrylates-Preparation and Properties of Novel Copolymers.

More environmentally friendly polymeric materials for use in corrosive conditions were obtained in the process of UV polymerization of terpene methacrylate monomers: geranyl methacrylate and citronellyl methacrylate and the commercially available monomer methyl methacrylate. Selected properties (solvent resistance, chemical resistance, glass transition temperature, thermal stability, and decomposition course during heating) were evaluated. It was found that the properties of the materials directly depended on the monomer percentage and the conditioning temperatures used. An increase in the geranyl or citronellyl methacrylate monomer content in the copolymers reduced the solubility and chemical resistance of the materials post-cured at 50 °C. The samples post-cured at 120 °C were characterized by high resistance to polar and non-polar solvents and the chemical environment, regardless of the percentage composition. The glass transition temperatures for samples conditioned at 120 °C increased with increasing content of methyl methacrylate in the copolymers. The thermal stability of copolymers depended on the conditioning temperatures used. It was greater than 200 °C for most copolymers post-cured at 120 °C. The process of pyrolysis of copolymers led to the emission of geranyl methacrylate, citronellyl methacrylate, and methyl methacrylate monomers as the main pyrolysis volatiles.

The effect of the grafting percent on some of the physico-chemical and thermal properties and the decomposition course of novel starch-g-poly(cinnamyl acrylate) copolymers.

This paper focuses on the chemical modification of potato starch by the cinnamyl acrylate monomer during the graft copolymerization. The maximum of the grafting percent (G) was found to be 49.2% ±â€¯0.3 at the temperature of 65 °C for 120 min in the presence of 1.0 wt% of potassium persulfate at the starch and monomer ratio 1:2.5. The copolymers exhibited excellent resistance to polar solvents and moisture which was independent of their G values. It was due to the presence of poly(cinnamyl acrylate) chains in their structure and their very compact, non-porous structure. The chemical stability of the copolymers was dependent on the G values. The copolymers showed the highest chemical resistance to neutral and acidic environments rather than to the alkaline one. Their thermal stability was ca. 210 °C under the inert and oxidative conditions. The decomposition mechanism of the copolymers was complex and included a lot of multiple simultaneous processes combined with the emission of various volatiles. The interesting fact was that the pyrolysis of starch from the copolymers occurred before that of the grafted polymer. However, the oxidative decomposition of the grafted polymer began at lower temperatures than that of starch from the copolymers.

Rubber elastomeric nanocomposites with antimicrobial properties.

In this paper we show an elastomeric nanocomposite that exhibits antibacterial and antifungal activity. It comprises a rubber blend matrix and a nanofiller, which is a modified bentonite clay (Nanobent® ZR2). We have developed innovative technology for the nanofiller incorporation into the rubber matrix. This new approach was successfully implemented in pilot production at the Polish chemical manufacturer Spoiwo (Spoldzielnia Pracy Chemiczno-Wytworczej 'Spoiwo', Radom, Poland). Here we reveal that addition of the functionalised bentonite affects the mechanical and thermal behaviour of elastomers. For example, by adding 1-3% of bentonite nanoparticles we strongly enhanced elongation and tensile stress at break, whereas stiffness remained unchanged. We observed improvement of the thermal properties of the nanocomposites yielded and extension of the temperature usage range (from -29 to 311°C). As a proof of concept we present the antimicrobial effect of elastomeric nanocomposites verified on a wide range of both pathogenic and opportunistic reference bacteria strains, as well as reference strains of yeasts. The proposed method of hydrophilic nanofiller introduction into the rubber elastomer is economically viable and enables fabrication of elastomeric elements with high added value. Their significant antibacterial and antifungal activity makes them desirable in medicine, biomedical engineering, and the food industry.

Effect of some parameters on the synthesis and the physico-chemical properties of new amphiphilic starch-g-copolymers.

The detailed studies on the graft copolymerization of phenyl methacrylate onto gelatinized potato starch in water using potassium persulfate as radical initiator were presented. The different reaction parameters such as effect of initiator concentration, starch to monomer ratio, reaction temperature and reaction time were studied in terms of grafting efficiency, grafting percent and percent homopolymer formation. It was found that grafting process of aromatic methacrylate monomer onto potato starch backbone allowed obtaining new amphiphilic copolymers with different physicochemical properties as compared to non-modified starch. The influence of the copolymer structure on the swelling behavior in polar and non-polar solvents, moisture absorbance, gelatinization properties, acid and base resistance, surface morphology and thermal properties was discussed.

Microwave-Assisted Synthesis of Cinnamyl Long Chain Aroma Esters.

Cinnamyl long chain aroma esters were prepared by using the conventional and microwave-assisted methods. The esterification reaction of naturally occurring 3-phenyl-prop-2-en-1-ol and different chain lengths acidic and diol reagents was carried out at the temperature of 140 °C under solvent free conditions. As acidic reagents, oxolane-2,5-dione, oxane-2,6-dione, hexanedioic acid and decanedioic acid were applied. Ethane-1,2-diol and 2,2'-[oxybis(2,1-ethandiyloxy)]diethanol were used as diol reagents. The synthesis of high molecular mass cinnamyl esters under conventional method conditions requires a long time to obtain high yields. The studies confirm that by using microwave irradiation, it is possible to reduce the reaction times to only 10-20 min. The structures of prepared esters were confirmed on the basis of FTIR, 1H-NMR and 13C-NMR. In addition, the newly obtained cinnamyl long chain esters were tested for their thermal properties. The TG studies proved the high thermal resistance of the obtained esters under inert and oxidative conditions.

3-Hydroxy-3-methylbutyrate administration diminishes fundectomy-induced osteopenia of the lumbar spine in pigs.

OBJECTIVE: The aim of the study was to test the hypothesis that oral administration with 3-hydroxy-3-methylbutyrate (HMB) positively influences bone metabolism and diminishes fundectomy-induced osteopenia of the axial skeleton in pigs. The pig model was chosen because of its recognized physiologic and anatomic similarities of the gastrointestinal tract and skeletal system to those of humans. METHODS: Eighteen male pigs were divided into three weight-matched groups at 40 d of life. Animals from the first and second groups were subjected to experimental fundectomy and the third group was sham operated. Starting the day after the fundectomy, the first and second groups received placebo and HMB, respectively. Animals were sacrificed at the age of 8 mo to obtain L(5) and L(6) vertebrae for analysis. The effects of HMB administration on plasma amino acids concentrations, bone mineral density, morphology, and mechanical properties of the lumbar vertebrae were determined. RESULTS: The HMB treatment increased the weight of the vertebrae, bone mineral density, bone mineral content, total bone volume, trabecular bone mineral density, mean volumetric bone mineral density, calcium hydroxyapatite density in the trabecular and cortical bones, and plasma amino acid concentrations in the fundectomized pigs (P < 0.05). Mechanical strength of the spine, expressed by the values of ultimate force, Young's modulus, ultimate stress, stiffness, and work to the ultimate force point was increased in HMB-treated pigs (P < 0.05). CONCLUSION: HMB administration to fundectomized pigs improved plasma amino acids concentrations and diminished development of fundectomy-induced osteopenia of the axial skeleton.