Arkadiusz Matwijczuk

On polymorphism of 2-(4-fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole (FABT) DMSO solvates

Structural and computational studies of two polymorphic (triclinic P and monoclinic P21/n) DMSO solvates of the biologically active molecule 2-(4-fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole (FABT) show that their structures are stabilized mainly by hydrogen bonds between the FABT and DMSO molecules. The geometry of both polymorphic molecules is very similar with a few significant differences in the corresponding valence angles. The only exceptions are the valence angles associated with the terminal para-hydroxyl group in both polymorphs. This group is differently H-bonded to the neighbouring solvent molecules. Additionally, the molecule in the second polymorph is slightly bent compared to the molecule in the first one. Both polymorphs also have very similar packing with layers of FABT molecules separated by DMSO moieties. The Hirshfeld surface analysis shows the most significant differences in the relative contributions of intermolecular interactions to the total Hirshfeld surface area for the FABT polymorphs. They are found for the C⋯H, C⋯C and H⋯H interactions. The triclinic polymorph crystallises as the first one and is thermodynamically less stable, while the monoclinic one is thermodynamically more stable but occurs in the crystallization mixture after a much longer time. According to the computational results, the monoclinic polymorph is ca. −9.93 kJ mol−1 more stable than the triclinic one, and dispersive interactions are dominant in these polymorphic crystals. It appears that the FABT⋯FABT interactions in the crystal lattice are stronger (ca. −75 kJ mol−1) for both polymorphs than the interactions of the central FABT moiety with the neighbouring DMSO molecules (ca. −52 kJ mol−1). Interlayer interaction energies calculated for the most characteristic slabs defined in the crystal lattices of the both polymorphs can be related to the stability of crystals.

Effect of 2-(4-fluorophenylamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole on the molecular organisation and structural properties of the DPPC lipid multibilayers

Interactions and complex formation between lipids and biologically active compounds are crucial for better understanding of molecular mechanisms occurring in living cells. In this paper a molecular organisation and complex formation of 2-(4-fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole (FABT) in DPPC multibilayers are reported. The simplified pseudo binary phase diagram of this system was created based on the X-ray diffraction study and fourier transform infrared spectroscopic data. The detailed analysis of the refraction effect indicates a much higher concentration of FABT in the polar zones during phase transition. Both the lipid and the complex ripple after cooling. It was found that FABT occupied not only the hydrophilic zones of the lipid membranes but also partly occupied the central part of the non polar zone. The infrared spectroscopy study reveals that FABT strongly interact with hydrophilic (especially PO(2)(-)) and hydrophobic (especially kink vibrations of CH(2) group). The interactions of FABT molecules with these groups are responsible for changes of lipid multibilayers observed in X-ray diffraction study.

Spectroscopic Studies of Intramolecular Proton Transfer in 2-(4-Fluorophenylamino)-5-(2,4-Dihydroxybenzeno)-1,3,4-Thiadiazole

Spectroscopic studies of the biologically active compound 2-(4-fluorophenylamino)-5-(2,4-dihydroxybenzeno)-1,3,4-thiadiazole (FABT), have been performed. Absorption studies in the UV-Vis region for FABT in polar solvents, like water or ethanol, exhibit the domination of the enol form over its keto counterpart, with a broad absorption band centered around 340xa0nm. In non-polar solvents such as n-heptane or heavier alkanes the 340xa0nm absorption band disappears and an increase of the band related to the keto form (approximately 270xa0nm) is observed. Fluorescence spectra (with 270xa0nm and 340xa0nm excitation energies used) show a similar dependence: for FABT in 2-propanol a peak at about 400xa0nm dominates over that at 330xa0nm while in n-heptane this relation is reversed. The solvent dependent equilibrium between the keto and enol forms is further confirmed by FTIR and Raman spectroscopies. As can be expected, this equilibrium also shows some temperature dependences. We note that the changes between the two tautomeric forms of FABT are not related to the permanent dipole moment of the solvent but rather to its dipole polarizability.

Spectroscopic Studies of Fluorescence Effects in Bioactive 4-(5-Heptyl-1,3,4-Thiadiazol-2-yl)Benzene-1,3-Diol and 4-(5-Methyl-1,3,4-Thiadiazol-2-yl)Benzene-1,3-Diol Molecules Induced by pH Changes in Aqueous Solutions

AbstractThis paper presents the results of stationary fluorescence spectroscopy and time-resolved spectroscopy analyses of two 1,3,4-thiadiazole analogues, i.e. 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (C1) and 4-(5-heptyl-1,3,4-thiadiazol-2-yl)benzene-1,3-diol (C7) in an aqueous medium containing different concentrations of hydrogen ions. An interesting dual florescence effect was observed when both compounds were dissolved in aqueous solutions at pH below 7 for C1 and 7.5 for C7. In turn, for C1 and C7 dissolved in water at pH higher than the physiological value (mentioned above), single fluorescence was only noted. Based on previous results of investigations of the selected 1,3,4-thiadiazole compounds, it was noted that the presented effects were associated with both conformational changes in the analysed molecules and charge transfer (CT) effects, which were influenced by the aggregation factor. However, in the case of C1 and C7, the dual fluorescence effects were visible in a higher energetic region (different than that observed in the 1,3,4-thiadiazoles studied previously). Measurements of the fluorescence lifetimes in a medium characterised by different concentrations of hydrogen ions revealed clear lengthening of the excited-state lifetime in a pH range at which dual fluorescence effects can be observed. An important finding of the investigations presented in this article is the fact that the spectroscopic effects observed not only are interesting from the cognitive point of view but also can help in development of an appropriate theoretical model of molecular interactions responsible for the dual fluorescence effects in the analysed 1,3,4-thiadiazoles. Furthermore, the study will clarify a broad range of biological and pharmaceutical applications of these compounds, which are more frequently used in clinical therapies.n Graphical AbstractUpper left corner – C7 molecule at high pH, right upper corner - fluorescence emission spectrum for C7 dissolved in H2O at high pH (7–12) - single fluorescence. Bottom left corner – C7 molecule at low pH (1–7), lower right corner - fluorescence emission spectrum for C7 dissolved in water at low pH – two fluorescence emissions. The circles indicate the group related to dissociation of molecules at low and high pH and the additional long circles indicate C1 or a molecule with a shorter acyl chain.

Synthesis and biological activity of novel benzoazoles, benzoazines and other analogs functionalized by 2,4-dihydroxyphenyl moiety

Novel benzoazoles, benzoazines, benzothiazoles, benzothiazines and other related compounds possessing a 2,4-dihydroxyphenyl moiety were prepared. The compounds were obtained by the reaction of sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s with the appropriate heterocyclic amines or hydrazines. The structures of the compounds were proved by IR, 1H NMR, and mass spectral data. Human cancer lines, Candida species and phytopathogenic fungi were used for the evaluation of biological potency of compounds. Additionally, drug-like properties were estimated in silico.

Spectroscopic and Theoretical Studies of Fluorescence Effects in 2-Methylamino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole Induced by Molecular Aggregation

The article presents the results of fluorescence analyses of 2-methylamino-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (MDFT) in an aqueous environment. MDFT dissolved in aqueous solutions with a pH value in the range from 1 to 4.5 yielded an interesting effect of two clearly separated fluorescence emissions. In turn, a single fluorescence was observed in MDFT dissolved in water solutions with a pH value from 4.5 to 12. As it was suggested in the previous investigations of other 1,3,4-thiadiazole compounds, these effects may be associated with conformational changes in the structure of the analysed molecule accompanied by aggregation effects. Crystallographic data showed that the effect of the two separated fluorescence emissions occurred in a conformation with the –OH group in the resorcyl ring bound on the side of the sulphur atom from the 1,3,4-thiadiazole ring. The hypothesis of aggregation as the mechanism involved in the change in the spectral properties at low pH is supported by the results of (Time-Dependent) Density Functional Theory calculations. The possibility of rapid analysis of conformational changes with the fluorescence spectroscopy technique may be rather important outcome obtained from the spectroscopic studies presented in this article. Additionally, the presented results seem to be highly important as they can be easily observed in solutions and biologically important samples.

Effect of polyols on the DMPC lipid monolayers and bilayers

In this study, the effect of polyols, erythritol, xylitol, mannitol, on a model membrane systems composed of DMPC was investigated using differential scanning calorimetry and Fourier transform infrared spectroscopy. Generally, it is considered that polyols possess strong hydrophilic properties, and either does not interact with the hydrophobic environment at all, or these interactions are very weak. To better understand the mutual interactions between polyols and the lipid system, the Langmuir technique was used to examine the molecular organization of monolayers and to calculate their thickness in the presence of polyols at the subphase. The detailed description of the interactions between polyols and DMPC molecules was complemented by the analysis of the morphology of monolayers with the application of Brewster angle microscopy. From ATR FTIR, the significant spectral shift is observed only for the PO2- stretching band, which correlates strongly with the polyol chain-length. The longer the polyol chain, the weaker the observed interactions with lipid molecules. The most important findings, obtained from thickness measurements, reveal that short-chain polyols may prevent the formation of bilayers by the DMPC molecules under high surface pressure. The changes in the organization of DMPC monolayers on the surface, as visualized by Brewster angle microscopy, showed that the domains observed for phospholipid film spread on pure water differ substantially from those containing polyols in the subphase.