Gabriel Marc

Thiocarbohydrazone derivatives are of interest due to their extended conjugated systems and versatile structural features. In this study, a new symmetric thiocarbohydrazone derivative of β-ionone was synthesized and characterized. The obtained compound was investigated by FTIR and UV–Vis spectroscopy, mass spectrometry, and ¹H and ¹³C NMR spectroscopy. The ¹H NMR spectrum confirmed the expected symmetry of the molecule and showed two olefinic doublets with a ³J_H,H coupling constant of 16.5 Hz, consistent with a trans (E) configuration of the conjugated C=C bonds. The ¹³C NMR spectrum showed the characteristic thiocarbonyl and imine carbon signals at δ 174.48 ppm and δ 141.88 ppm, respectively, together with the expected olefinic and aliphatic carbon resonances. Mass spectrometric analysis revealed a prominent ion at m/z 455.3158, assigned to the protonated molecular ion [M + H] ⁺, in agreement with the proposed molecular mass. The FTIR spectrum further supported the formation of the title compound. Overall, the combined spectroscopic and mass spectrometric data support the proposed structure of the synthesized compound.

Background/Objectives: Combining heterocyclic fragments provides a strategy for developing compounds for exploratory anticancer evaluation. This study aimed to synthesize and characterize five thiazolyl-methylthio-1,3,4-thiadiazolyl-quinazolin-4(3H)-one compounds (5a–e), assess their properties in silico, and investigate the selected ones for cytotoxicity and their effects on irradiation-associated DNA lesions. Methods: Structures were characterized by IR, HRMS, and ¹H- and ¹³C-NMR spectroscopy. Computational studies included physicochemical and ADMETox predictions, multi-platform target prediction, and molecular docking to A2A, Erβ, and CDK5. Compounds 5a and 5b were evaluated for cytotoxicity and cell-death profiles on one colorectal cancer (CRC) cell line (HT-29), two breast cancer (BC) cell lines (MCF-7 and MDA-MB-231), and one healthy fibroblast cell line (BJ), using cisplatin (Cis) as a reference. DNA lesions were assessed by the Comet assay in both breast cancer models before, immediately after, and 24 h after 4 Gy irradiation. Results: Compounds 5a–e were obtained in yields of 45.17–83.27%. Compounds 5a and 5b had lower 24-h IC₅₀ values than cisplatin in MCF-7 cells, but higher values in the other tested cell lines. Compound 5b showed higher selectivity indexes than both 5a and cisplatin across the cancer models, although its values of 1.14–1.34 indicated modest selectivity. Cell-death profiles differed between treatments, with larger necrotic fractions following 5a or 5b treatment in MCF-7 cells. Both compounds were associated with higher post-irradiation lesion scores than untreated irradiated controls. Scores increased further at 24 h in MCF-7 cells but decreased in MDA-MB-231 (triple-negative) cells. Pre-irradiation scores were also elevated in treated MCF-7 cells. Computational profiling identified comparatively more favorable predicted solubility for 5a and 5b. Cross-platform ADMET comparison consistently indicated low Caco-2 permeability, CYP3A4 inhibition, potential liver-injury risk, and high plasma–protein binding, while several absorption, transporter, and safety endpoints remained discordant. Target predictions showed weak cross-platform convergence. Docking provided the strongest, although moderate, structural support for A2A binding by 5a–d. Conclusions: The findings support further investigation of 5a and 5b, particularly their effects on irradiation-associated DNA lesions. Priorities include improving potency and selectivity, validating in silico predictions, and evaluating radiosensitizing potential through clonogenic survival studies.

Background: Walnut (Juglans regia L.) processing generates polyphenol-rich by-products, including the septum (WS) and pellicle (WP). This study comparatively characterized the phytochemical composition of WS and WP from Romania and investigated their antioxidant and preliminary immunomodulatory properties using chemical, computational, and cell-based approaches. Methods: Extracts were characterized by targeted LC–QTOF–MS/MS, and antioxidant capacity was evaluated using ABTS, DPPH, and FRAP assays. Major phenolic compounds were docked against Kelch-like ECH-associated protein 1 (KEAP1), followed by 100 ns molecular dynamics simulations. Cytocompatibility was evaluated in Caco-2, Jurkat, and THP-1 cells, and cellular antioxidant activity was assessed in H₂O₂-stimulated Caco-2 cells using the DCFH-DA assay. Immunomodulatory potential was investigated following lipopolysaccharide (LPS) stimulation of the same cell lines. Results: WSLE contained 25 quantified compounds, with ellagic acid, catechin, procyanidins, and quercitrin among the major quantified constituents, whereas WP contained 13, with higher ellagic acid, gallic acid, and castalagin levels. WPE showed greater cell-free antioxidant capacity, while both extracts attenuated the H₂O₂-induced increase in intracellular DCF fluorescence in Caco-2 cells. Simulations suggested favorable KEAP1 interactions, with quercitrin and catechin predicted to form the most stable complexes. LPS induced an insufficient cytokine response in Caco-2 and Jurkat cells. In THP-1 cells, IL-8 was the only responsive marker, and both extracts reduced its LPS-induced secretion. Conclusions: The extracts showed distinct polyphenolic profiles and redox-related cellular activity. Their effects on IL-8 secretion in THP-1 cells and predicted KEAP1 binding are preliminary and hypothesis-generating; Nrf2 activation was not measured, and validation in physiologically relevant in vivo and clinical models is required to establish the biological relevance and potential applications of these extracts.

Novel thiazolyl–polyphenolic derivatives were designed and synthesized to investigate the influence of aromatic substituents on antioxidant activity, molecular properties, and cytotoxicity. Eight derivatives (E1–E8) were synthesized by a Hantzsch reaction and their structures were confirmed by MS, FT-IR, and ¹H/¹³C NMR spectroscopy. Antioxidant activity was evaluated using DPPH, ABTS, TAC, RP, FRAP, and CUPRAC assays. The experimental results were supported by DFT calculations and SwissADME prediction, while cytotoxicity was evaluated against A549 lung adenocarcinoma cells and normal BJ fibroblasts. The antioxidant activity depended on the nature of the aromatic substituent. Compound E5 showed a superior antioxidant profile, presenting the highest DPPH radical scavenging activity and the strongest reducing power in the RP assay. The theoretical calculations supported these findings, showing favorable HOMO energy and low O–H bond dissociation energy values. Compound E6 showed the highest activity in the CUPRAC assay and exhibited the strongest cytotoxic activity against A549 cells together with the highest selectivity index. All synthesized compounds complied with Lipinski’s rule of five. Overall, the results show that the electronic properties of the aromatic substituent strongly influence both the antioxidant and cytotoxic activities of this series. These compounds may represent useful scaffolds for further development of antioxidant and anticancer agents.

Introduction: In the context of rapid rise of resistant pathogen strains, antimicrobial peptides (AMPs) represent promising scaffolds that complement conventional antibiotics, especially given the specific toxicities that limit classic drugs like fluoroquinolones and nitroimidazoles. AMP monotherapy faces major drawbacks, primarily due to inherent host-cell toxicity and a short half-life. Methods: To overcome these limitations, this study details the design and synthesis of dual-mechanism prodrugs by conjugating the membrane-active AMPs scaffolds of urechistachykinin I and decoralin to norfloxacin and metronidazole via a pathogen-cleavable ester linker. To minimize off-target toxicity, both AMP sequences were synthesized with a C-terminal carboxyl group, as these variants exhibit negligible hemolytic and neurotoxic activity compared to their amidated analogues. The designed antibiotic-peptide conjugates were synthesized on solid support starting from the C-terminus, followed by N-terminal chain elongation to attach the antibiotics. Specific derivatization methods ensured the covalent ester linkage of norfloxacin and metronidazole to the N-termini of urechistachykinin I (resulting in conjugates 1a and 1b ) and decoralin (resulting in conjugates 2a and 2b ). Structural behavior was assessed by 200 ns molecular dynamics simulations in water. Antimicrobial activity was evaluated by broth microdilution against Gram-negative, Gram-positive bacteria and fungi, and compared to parent peptides and reference antibiotics as positive controls. Results: All conjugates exhibited increased flexibility and solvent exposure relative to their parent peptides, as evidenced by increased RMSD, radius of gyration, H-bonding with water and higher solvent accessible surface area. In vitro screening identified 1a , 2a and 2b as the most active conjugates. Norfloxacin conjugate 1a exhibited potent activity against Escherichia coli ATCC 8739 (MIC 0.56 μM) and Candida parapsilosis (MIC 2.26 μM). Norfloxacin conjugate 2a showed broad-spectrum inhibition, including Escherichia coli ATCC 8739 (MIC 8.64 μM), Salmonella enterica ATCC BAA-2162 (MIC 8.64 μM) and Listeria monocytogenes DSMZ 115292 (MIC 4.32 μM), with improved activity over unmodified decoralin. Metronidazole conjugate 2b was active against Listeria monocytogenes DSMZ 115292 (MIC 11.86 μM) and Enterococcus faecalis ATCC 29212 (MIC 23.12 μM). Discussion: These in vitro assays demonstrate retained peptide membrane-disrupting properties and synergistic effects with the antibiotics. The dual-mechanism design represents a promising strategy to reduce toxicity and overcome antimicrobial resistance.

Valproic acid is a clinically important therapeutic agent whose biological properties have stimulated the development of structurally modified derivatives with improved pharmacological profiles. In the present study, nine amino–valproic acid hybrids were synthesized by a rapid mechanochemical approach using a planetary ball mill under solvent-minimized conditions. The synthesized compounds were formulated in a newly developed deep eutectic solvent composed of urea and propylene glycol (1:4 molar ratio), which was characterized by solvatochromic and Kamlet–Taft analyses. The biological activities of the derivatives were evaluated by hydrogen peroxide scavenging activity (HPSA), hydroxyl radical-scavenging activity (HRSA), and inhibition of albumin denaturation (IAD) assays. Among the investigated compounds, derivative 3h exhibited the highest biological activity, showing IC₅₀ values of 291 µM and 163 µM in the HPSA and HRSA assays, respectively, and the strongest anti-inflammatory activity in the IAD assay. All synthesized derivatives demonstrated lower IC₅₀ values than ibuprofen in the albumin denaturation model. Dose–response relationships were analyzed using four- and five-parameter logistic models, with the 5PL model providing a statistically superior fit to the experimental data. Lipophilicity measurements and in silico studies further supported the favorable physicochemical profile of the synthesized compounds. These results identify compound 3h as the most promising derivative and demonstrate the potential of mechanochemical synthesis for the preparation of biologically active valproic acid hybrids.

The purpose of this study was the chemical design, synthesis, and evaluation of the anticonvulsant potential of 15 novel thiazolyl-methylthio-quinazolin-4(3H)-one hybrid compounds (4a-o). The compounds were designed based on a scaffold that reunited thiazole and quinazolin-4(3H)-one heterocycles of two well-known anticonvulsants, clomethiazole and methaqualone, through a condensation reaction. The compounds were evaluated in vivo for anticonvulsant activity using the pentylenetetrazole-induced seizure animal model. A Rotarod test was employed to evaluate the neuromotor coordination after the administration of the tested compounds, and a flumazenil antagonism assay was subsequently performed to investigate if the observed anticonvulsant effects were mediated through the compounds’ interaction with the GABA_A receptor. The in silico assessment consisted of molecular docking, evaluation of the druggability, and ADMETox prediction. All compounds presented anticonvulsant activity to varying degrees. The most notable activity was observed in compounds 4k (ED₅₀ = 84.313 mg/kg) and 4c (ED₅₀ = 178.165 mg/kg). The in vivo results positively correlated with the observations drawn in the molecular docking study on the human α₁β₂γ₂ GABA_A receptor and on the NR1 ligand-binding core of the NMDA receptor. The potential of anticonvulsant activity was also supported by the druggability and ADMETox predictions that highlighted an increased possibility of brain–blood barrier permeation, supported by the computed parameters TPSA, logD, and logBB. The results of the flumazenil antagonism assay additionally highlighted the possible mechanism of action of compounds 4c and 4k as positive allosteric modulators of the GABA_A receptor. Preliminary evaluation confirmed the anticonvulsant potential of the tested compounds, with further testing being necessary for a better understanding and confirmation of the activity.

Background/Objectives: The purpose of this study was the chemical design, synthesis, and evaluation of the antimicrobial and antibiofilm potentials of 20 novel thiazolyl-methylthio-thiadiazole hybrid compounds (6a–j and 8a–j). Methods: The compounds were designed as structural analogues of halicin with two points of variation and were synthesized through a process with multiple condensation steps. The compounds were evaluated in vitro through MIC determinations for the antimicrobial activity and percentage of biofilm inhibition, and in silico, respectively, through molecular docking, druggability, and ADMETox prediction. A 2D-QSAR study was conducted for antimicrobial activity using the Free-Wilson model. Results: In terms of antibacterial activity, all compounds displayed important activity on the tested strains (MICs = 15.62–250 μg/mL), except against Staphylococcus aureus. Regarding the antifungal activity, the effect against Candida albicans was similar to fluconazole in most cases (MIC = 15.62 μg/mL). With respect to the antibiofilm activity, the most effective activity was registered against the Pseudomonas aeruginosa biofilm. The in vitro results for the antibacterial activity against Escherichia coli were correlated with the observations drawn in the molecular docking study on the ATPase domain of the GyrB subunit of E. coli. The in silico predictions of the molecular properties concluded that all compounds have good druggability properties, while the ADMETox predictions concluded that the compounds could have low gastrointestinal absorption and blood–brain barrier permeation capacity, but raised safety flags (e.g., hepatotoxicity and high acute oral toxicity). The 2D-QSAR study concluded that the thiazolyl-methylthio-thiadiazole scaffold had the highest contribution to antimicrobial activity in almost all cases. Conclusions: The two series of compounds highlight the impact of structural modulations of the scaffold and its substituents on the investigated biological activities.

The microwave-assisted improved synthesis of ethyl 2-(2-((6-methyl-4-oxo-4H-chromen-3-yl)methylene)hydrazinyl)thiazole-4-carboxylate is described. The antioxidant potential of the target compound was evaluated using spectrophotometric methods, including the DPPH• and ABTS•⁺ radical scavenging assays, as well as three additional electron-transfer assays employing metal-based oxidizing agents. The title compound exhibited good antioxidant activity compared to reference antioxidants. For the title compound theoretical quantum chemical (DFT) calculations were performed.

Herein, we report the mechanochemical synthesis of a novel hybrid molecule, N-(4-methoxyphenethyl)-2-propylpentanamide. This solvent-minimized synthesis aligns with the principles of Green Chemistry and exemplifies the emerging paradigm of medicinal mechanochemistry, offering an efficient, sustainable route to pharmaceutically relevant amides. The newly synthesized compound was fully characterized by melting point determination, ¹H and ¹³C NMR spectroscopy, infrared (IR) spectroscopy, and mass spectrometry.