Nadya Hristova-Avakumova

The effect of the chlorine atom in the sixth position and methyl group in the third position of the uracil ring on the structural parameters, NBO charge distribution, and molecular properties of the 6-chloro-3-methyluracil (M6CU) biomolecule was analyzed in the isolated state, solid-state arrangement and within a double-stranded RNA microhelix. This effect, which was also compared to those with uracil and several uracil derivatives, leads to higher reactivity and the special properties of this pharmaceutical compound. Several correlations were established using MP2 and several DFT methods. The structural characterization of M6CU and a detailed analysis of the experimental FT-IR and FT-Raman spectra in the solid state was another aim studied in detail. For an accurate assignment, a simple approximation to a crystalline unit cell was optimized using a trimer form and the wavenumbers were subsequently corrected using several scaling procedures. The modified nucleobase M6CU forms base pairs with the complementary adenine and, therefore, it could replace uracil in the helix; based on our calculations, it leads to a noticeable helix deformation. This computational finding suggests its possible potential effect by binding to cancer-related or viral RNA helices. Molecular docking also revealed that M6CU could act as an active ligand within the 1JPW active site of the target β-catenin/Tcf4 protein complex.

High-frequency immersed plasma discharge represents an efficient method for the generation of reactive oxygen and nitrogen species (RONS) in liquid media, leading to complex redox and oxidative processes in biologically relevant systems. Although plasma-generated reactive species in liquids have been widely investigated, it remains insufficiently understood how working-gas-dependent plasma chemistry translates into oxidative outcomes in iron-containing model systems, where plasma-derived species may interact with transition-metal redox cycling. The novelty of this study lies in the combined assessment of gas-dependent RONS accumulation, deoxyribose oxidative degradation, and plasma-induced changes in Fe(II) availability using a high-frequency immersed plasma discharge. Herein, we examined whether treatment with high-frequency immersed discharge influences the redox state of iron in a working gas-dependent manner, thereby affecting oxidative degradation in the deoxyribose model. Plasma treatment was performed under air and argon working gas conditions, and oxidative degradation was evaluated using the thiobarbituric acid reactive substances (TBA-RS) assay. In parallel, the concentrations of long-lived reactive species, including hydrogen peroxide, nitrites, and nitrates, were determined spectrophotometrically. The results demonstrated a treatment-time-dependent increase in oxidative degradation and reactive species accumulation, with more pronounced oxidative effects observed under argon plasma conditions. In the presence of ferrous ions, plasma treatment resulted in a gas-dependent effect, characterized by a synergistic enhancement of oxidative degradation under argon and a biphasic effect under air. Most notably, in Fe(II)-containing samples, 10 min of argon plasma treatment increased TBA-RS formation to approximately 2.7-fold of the Fe(II) control, whereas air plasma produced a biphasic response, with an initial decrease followed by an approximately 40% increase at the longest exposure time. Additional experiments suggest that plasma may influence the redox state and availability of ferrous ions, thereby affecting their participation in Fenton-type reactions and radical-mediated processes. The findings suggest that the overall oxidative outcome in plasma-treated systems is governed not only by the concentration of plasma-generated reactive species but also by plasma-induced modifications of transition metal redox chemistry. These preliminary results on the combined roles of plasma-generated reactive species and transition-metal chemistry contribute to understanding plasma–liquid interactions in such systems.

Unpredictable, dose-limiting toxicity remains a challenge in cancer treatment. We evaluated dihydropyrimidine dehydrogenase (DPD) and UDP-glucuronosyltransferase 1A1 (UGT1A1) plasma levels in the context of chemotherapy-induced toxicity and disease progression. Seventy gastrointestinal cancer patients (30 FOLFOX; 40 FOLFIRI) were enrolled. DPD and UGT1A1 plasma levels were determined using ELISA. Univariable and bivariable analyses and a general linear model (GLM) framework were used. Post-infusional reductions in white blood cell and granulocyte counts were observed. For FOLFOX, the granulocyte counts decreased by 17% (r = 0.54; p = 0.0030), while FOLFIRI caused a 41% reduction (r = 0.43; p = 0.0063). DPD levels were lower in FOLFOX than in FOLFIRI (2.543 vs. 3.579; p = 0.0363; Cohen’s d = 0.52). The multiple linear regression models associated DPD levels with cancer progression (b* = 0.258, p = 0.034). The bivariate analysis and multiple linear regression indicated some trends of association between UGT1A1 levels and reduction in white blood cell (b* = 0.359, p = 0.042) and granulocyte counts (b* = 0.383, p = 0.030) among FOLFIRI-treated patients. These preliminary observations suggest that DPD and UGT1A1 might contribute to evaluating response assessment.

The effect of La, Ce, Pr and Nd ions on four Ln(ligand)₃ complexes and at three DFT levels of calculation was analyzed. Four ligands were chosen, three of which were based on the 1,2,3-triazole ring. The DFT methods used were B3LYP, CAM-B3LYP and M06-2X. The relationships established were between the geometric parameters, atomic charges, HOMO-LUMO energies and other molecular properties. These comparisons and trends will facilitate the synthesis of new complexes by selecting the ligand and lanthanide ion best suited to the desired property of the complex. The experimental IR and Raman spectra of Ln(2b′)₃ complexes where Ln = La, Ce, Pr, Nd, Sm, Gd, Dy, Ho and Er ions have been recorded and compared to know the effect of the lanthanide ion on the complex. The hydration in these complexes was also analyzed. Additionally, the effect of the type of coordination center on the ability of an Ln(ligand)₃ complex to participate in electron exchange and hydrogen transfer was investigated using two in vitro model systems—DPPH and ABTS.

Given the importance of molecular structure in pharmacological activity and interaction with biological receptors, we conducted a study on the 3,4-dihydroxybenzaldehyde hydrazone derivative of 5-methoxy-indole carboxylic acid (5MICA) and a newly synthesised analogue bearing a 2-methoxy-4-hydroxyphenyl ring using single-crystal X-ray diffraction. We studied the ability of the two compounds to scavenge hypochlorite ions using luminol-enhanced chemiluminescence and their potential to modulate oxidative damage induced by iron on the biologically significant molecules lecithin and deoxyribose in order to evaluate possible antioxidant and prooxidant effects. The X-ray study revealed highly conserved geometry and limited rotation and deformation freedom of the respective indole and phenyl fragments. Interestingly, a conformational difference between the two independent molecules in the asymmetric unit of 3b was found. The X-ray study revealed a combination of hydrogen bonding interactions, short contacts, and π–π stacking stabilizing the specific three-dimensional packing of the molecules of 3a and 3b in the crystal structures. The three-dimensional packing of the molecules of 3b produced a zigzag layering projected along the c-axis. Both compounds effectively decreased luminol-dependent chemiluminescence in model systems with KO₂-produced superoxide. They displayed opposite effects when applied in a xanthine/xanthine oxidase system. The hydrazones of 5MICA do not trigger a prooxidant effect or subsequent toxicity under conditions of iron-induced oxidative stress. The 3,4-dihydroxy-substituted derivative demonstrated excellent radical scavenging properties in all model systems, making it the lead compound for the development of compounds with combined neuroprotective and antioxidant properties.

(1) Background: In this work, a series of benzimidazole derivatives containing colchicine-like and cathechol-like moieties with methyl group substitution in the benzimidazole ring were evaluated for their in vitro antiproliferative, pro-apoptotic and antioxidative activity against highly invasive breast cancer cell line MDA-MB-231 and related impairment of tubulin dynamics; (2) Methods: MTT assay was used to evaluate the antiproliferative activity. In vitro tubulin polymerization assay as well as docking analysis was applied to prove the alterations in tubulin polymerization. Immunofluorescent and DAPI staining reveal the pro-apoptotic potential of benzimidazole derivatives and the effect on tubulin’s dynamics in living cells. The antioxidant activity was evaluated by scavenging of H2O2 and hypochlorite ion and ortho-phenanthroline tests; (3) Results: The compounds containing colchicine-like moiety displayed significant growth inhibitory effect against cancer cell line as was highlighted the role of methyl functional group on the tubulin aggregation and blockage of mitosis. All compounds showed an ability to scavenge H2O2, while the compounds with cathecol-like moiety were more effective against hypochlorite ion and chelation of iron; (4) Conclusions: The benzimidazole derivative containing colchicine-like moiety and methyl group substitution in benzimidazole ring is a potential antiproliferative and microtubule destabilizing agent.

Four models of Ce(III) complexes with four ligands based on a 1,2,3-triazole derivatives were studied at four DFT levels. The effect of different ligands on the atomic charge value on the cerium ion was analyzed. Several relationships were clearly established between this atomic charge and that of the surrounding atoms, as well as with several geometric parameters of the ligand and with the molecular properties of the Ce(III) complex. The experimental IR and Raman spectra of the newly obtained Ce(III) complex with the (pyrrolidin-1-yl)-2H-1,2,3-triazole-4-carboxylate ligand were interpreted based on their comparison to the theoretical scaled ones using the scaling equations determined by two procedures and four DFT levels. Therefore, the structure predicted for the synthesized Ce(III) complex was clearly characterized and confirmed. The potential antioxidant action of Ce(III) complex was elucidated and compared with other Ln(III) complexes in order to find out the differences in their biological activity profiles.

In light of the known neuroprotective properties of indole compounds and the promising potential of hydrazone derivatives, two series of aldehyde-heterocyclic hybrids combining those pharmacophores were synthesized as new multifunctional neuroprotectors. The obtained derivatives of indole-3-propionic acid (IPA) and 5-methoxy-indole carboxylic acid (5MICA) had good safety profiles: Hemolytic effects < 5% (200 μM) and IC₅₀ > 150 µM were found in the majority of the SH-SY5Y and bEnd3 cell lines. The 2,3-dihydroxy, 2-hydroxy-4-methoxy, and syringaldehyde derivatives of 5MICA exhibited the strongest neuroprotection against H₂O₂-induced oxidative stress in SH-SY5Y cells and 6-OHDA-induced neurotoxicity in rat-brain synaptosomes. All the compounds suppressed the iron-induced lipid peroxidation. The hydroxyl derivatives were also the most active in terms of deoxyribose-degradation inhibition, whereas the 3,4-dihydroxy derivatives were able to decrease the superoxide-anion generation. Both series of compounds showed an increased inhibition of hMAO-B, with greater expression detected in the 5MICA hybrids. The in vitro BBB model with the bEnd3 cell line showed that some compounds increased the permeability of the endothelial monolayer while maintaining the tight junctions. The combined results demonstrated that the derivatives of IPA and 5MICA showed strong neuroprotective, antioxidant, MAO-B inhibitory activity and could be considered as prospective multifunctional compounds for the treatment of neurodegenerative disorders.

Parasitic infections, caused mainly by the species Trichinella spiralis (T. spiralis), are widespread around the world and lead to morbidity and mortality in the population. Meanwhile, some studies have showed that these parasites induce oxidative stress in the infected host. With the aim of developing a class of compounds combining anthelmintic with antioxidant properties, a series of new benzimidazolyl-2-hydrazones 5a-l, bearing hydroxyl- and methoxy-groups, were synthesized. The anthelmintic activity on encapsulated T. spiralis was studied in vitro thus indicating that all hydrazones were more active than the clinically used anthelmintic drugs albendazole and ivermectin. 5b and 5d killed the total parasitic larvae (100% effectiveness) after 24 hours incubation period at 37 °C in both concentrations (50 and 100 μg ml⁻¹). The antioxidant activity of the target compounds was elucidated in vitro against stable free radicals DPPH and ABTS as well as iron induced oxidative damage in model systems containing biologically relevant molecules lecithin and deoxyribose. The two 2,3- and 3,4-dihydroxy hydrazones 5b and 5d were the most effective radical scavengers in all studied systems. DFT calculations were applied to calculate the reaction enthalpies in polar and nonpolar medium and estimate the preferred mechanism of antioxidant activity. The relative radical scavenging ability of compounds 5a-l showed a good correlation to the experimentally observed trends. It was found that the studied compounds are capable to react with various free radicals – ˙OCH₃, ˙OOH and ˙OOCH₃, through several possible reaction pathways – HAT in nonpolar medium, SPLET in polar medium and RAF in both media.