Search Results (54)

Background/Objectives: Fluorothiazinone (FT), a small molecule of the 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-one class, is known to inhibit the type III secretion system (T3SS) in Gram-negative bacteria and has shown therapeutic potential in animal models and clinical trials. Given the evolutionary relationship between the T3SS and the bacterial flagellar apparatus, this study aimed to investigate the effects of FT on bacterial motility and flagellum assembly. Methods: Motility was assessed in Pseudomonas aeruginosa, Proteus mirabilis, pathogenic Escherichia coli, and Listeria monocytogenes using a semisolid agar assay and a microfluidic motility system. The mechanism of FT’s action was further examined through time-course analysis, Western blotting of surface flagella proteins, and transmission electron microscopy (TEM). Results: FT inhibited motility of P. aeruginosa, P. mirabilis, and E. coli in a dose-dependent manner, while L. monocytogenes motility remained unaffected. The inhibitory effect was not immediate but delayed 2–3 h post FT addition. Western blotting revealed the absence of surface flagella in EHEC grown with FT, and TEM confirmed structural disruption of flagella in P. mirabilis. Conclusions: FT selectively inhibits flagellum-based motility in Gram-negative bacteria. Obtained data suggested FT interference with flagellum biosynthesis rather than disruption of rotation. Motility inhibition can contribute to FT therapeutic effects on Gram-negative bacterial infections. Full article

In this study, a series of novel β-phenylalanine derivatives were synthesised and evaluated for their anticancer activity. The 3-(4-methylbenzene-1-sulfonamido)-3-phenylpropanoic acid (2) was prepared using β-phenylalanine as a core scaffold. The β-amino acid derivative 2 was converted to the corresponding hydrazide 4, which enabled the development of structurally diverse heterocyclic derivatives including pyrrole 5, pyrazole 6, thiadiazole 8, oxadiazole 11, triazoles 9 and 12 with Schiff base analogues 13 and series1,2,4-triazolo [3,4-b][1,3,4]thiadiazines 14. These modifications were designed to enhance chemical stability, solubility, and biological activity. All compounds were initially screened for cytotoxicity against the A549 human lung adenocarcinoma cell line, identifying N-[3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxo-1-phenylpropyl]-4-methylbenzenesulfonamide (5) and (E)-N-{2-[4-[(4-chlorobenzylidene)amino]-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]-1-phenylethyl}-4-methylbenzenesulfonamide (13b) as the most active. The two lead candidates were further evaluated in H69 and H69AR small cell lung cancer lines to assess activity in drug-sensitive and multidrug-resistant models. Schiff base 13b containing a 4-chlorophenyl moiety, retained potent antiproliferative activity in both H69 and H69AR cells, comparable to cisplatin, while compound 5 lost efficacy in the resistant phenotype. These findings suggest Schiff base derivative 13b may overcome drug resistance mechanisms, a limitation commonly encountered with standard chemotherapeutics such as doxorubicin. These results demonstrate the potential role of β-phenylalanine derivatives, azole-containing sulphonamides, as promising scaffolds for the development of novel anticancer agents, particularly in the context of lung cancer and drug-resistant tumours. Full article

The reaction of 2-(3-chloro-5-phenyl-4H-1,2,6-thiadiazin-4-ylidene)malononitrile with ammonia in anhydrous THF, at ca. 20 °C, for 24 h, gave 6-amino-4-phenylpyrrolo[2,3-c][1,2,6]thiadiazine-5-carbonitrile in 95% yield. The product was characterized by ¹H and ¹³C NMR, SC-XRD, MALDI-TOF mass spectrometry, FTIR, and UV-vis spectroscopy. Intermolecular hydrogen bonding interactions were observed in the solid state between the C≡N and N-H groups of adjacent molecules. Full article

Dazomet (tetrahydro-3,5-dimethyl-2H-1,3,5-thiadiazine-2-thione) is a solid fumigant that breaks down into gaseous methylisothiocyanate (MITC) in the presence of water, a process that can be enhanced by the addition of accelerant chemicals. Experiments to discover the ideal conditions for dazomet decomposition were largely performed at the lab scale or on field-scale full utility poles or sections thereof. A rapid assessment method in wood commodities would improve the ability to assess a wider range of treatments to improve performance. Here, we present a method to test dazomet performance at the mesocosm scale in 102 × 152 mm (4 × 6-inch nominal) lumber. The protocol was trialed using two EPA-registered dazomet formulations to produce MITC under varying moisture conditions using different copper-containing accelerants. The test allowed the assessment of MITC levels at different locations and the full visual inspection of the treatment hole after splitting the block. MITC levels tended to be higher in the wood interior, closer to the treatment holes in test blocks. Below-ground portions also tended to have higher MITC levels at higher-moisture conditions. The method developed reduces the time required to test dazomet formulations and application methods in whole wood and will help improve the development of new dazomet formulations and application methods. Full article

Background: Substances with antibacterial properties have become crucial in light of the continuous increase in infections caused by multidrug-resistant bacteria. In this context, thiadiazines have emerged as heterocyclic compounds already known for their pharmacological activities. However, their potential as antibacterial agents and inhibitors of the efflux system found in resistant bacteria remains poorly understood. From this perspective, the present study highlights the synthesis of thiadiazine-derived compounds and evaluates their antibacterial activity and efflux pump inhibition against the Staphylococcus aureus 1199B strain. Methods: To this end, Minimum Inhibitory Concentration (MIC) tests were conducted, along with the analysis of antibacterial activity through the inhibition of the NorA efflux system using 96-well microdilution assays. Additionally, to assess efflux system inhibition, ethidium bromide (EtBr) fluorescence emission tests were performed, alongside in silico molecular docking studies. Results: Based on the results obtained, it was observed that compound IJ28 exhibited direct activity against the tested SA 1199B strains, with an MIC of 512 µg/mL. It also demonstrated antibacterial activity through efflux pump inhibition, resulting in increased fluorescence rates emitted by EtBr. Compound IJ28 showed a more significant reduction in the Minimum Inhibitory Concentration (MIC) of ethidium bromide, decreasing from 26.6 µg/mL to 0.5 µg/mL, compared to the other compounds. Conclusions: Therefore, it is essential to conduct further studies to investigate the mechanism of action and clarify the feasibility and effects of compound IJ28 as a potential antibacterial agent. Full article

Background/Objectives: Thiadiazine thione (THTT) has gained significant interest owing to its pharmacological potentials, particularly its antiparasitic and anti-inflammatory properties. Leishmaniasis is a clinical syndrome caused by infection with Leishmania species and is associated with an inflammatory response and nociception. The available treatments against leishmaniasis are inadequate, as they are associated with high cost, toxicity, and increased resistance. Methods: In the current study, the antileishmanial potential of five Thiadiazine thione derivatives (C1–C5) was evaluated in vivo against Leishmania tropica. Experiments were performed on BALB/c mice infected with promastigotes and treated with THTT derivatives for 15 days. Additionally, the derivatives were evaluated for their anti-inflammatory, antinociceptive, antipyretic, and antisedative properties using standardized models, including carrageenan-induced paw edema, acetic acid-induced abdominal writhes, yeast-induced fever, and white wood apparatus, respectively. Results: Of the tested derivatives, C5 exhibited the most promising results, with a 61.78% reduction in lesion size and significant decrease in parasite load. Among the derivatives, C1 showed the highest anti-inflammatory activity, with 63.66% inhibition in the paw edema test at the 5th hour post treatment. In the antipyretic assay, C1 and C5 were able to reduce body temperature to a normal level within 1 h of treatment. Furthermore, compounds C4, C2, and C1 showed high nociceptive activity, while C1 and C5 demonstrated the most notable antisedative effects (94 ± 2 and 92 ± 1, respectively), outperforming the standard drug diazepam (13 ± 1). Conclusion: These in vivo findings suggest that THTT derivatives have the potential to serve as a template for developing leishmanicidal drugs, with added anti-inflammatory and analgesic properties. Full article

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, marked by cognitive impairment. Currently, the available treatment provides only symptomatic relief and there is a great need to design and formulate new drugs to stabilize AD. In the search for a new anti-Alzheimer’s drug, 3,5-bis(2-hydroxyethyl)-1,3,5-thiadiazinane-2-thione (THTT), a tetrahydro-2H-1,3,5-thiadiazine-2-thione derivative, was investigated against a scopolamine-induced Alzheimer’s model. The selected test compound was administered intraperitoneally in three doses (15 mg/kg, 30 mg/kg, and 45 mg/kg). The test compound exhibited an IC50 value of 69.41 µg/mL, indicating its ability to inhibit the acetylcholinesterase enzyme. An antioxidant DPPH assay revealed that the IC50 value of the test compound was 97.75 µg/mL, which shows that the test compound possesses antioxidant activity. The results of behavior tests including the Y-maze and elevated plus maze (EPM) show that the test compound improved short-term memory and spatial memory, respectively. Furthermore, in the Morris water maze (MWM) and light/dark model, the test compound shows improvements in learning and memory. Moreover, the results of histological studies show that the test compound can protect the brain against the harmful effects of scopolamine. Overall, the findings of our investigation suggest that our chosen test compound has disease-modifying and neuroprotective activities against the scopolamine-induced Alzheimer’s model. The test compound may be beneficial, subject to further elaborate investigation for anti-amyloid disease-modifying properties in AD. Full article

This review article examines the synthetic pathways for triazolothiadiazine derivatives, such as triazolo[3,4-b]thiadiazines, triazolo[5,1-b]thiadiazines, and triazolo[4,3-c]thiadiazines, originating from triazole derivatives, thiadiazine derivatives, or thiocarbohydrazide. The triazolothiadiazine derivatives exhibit several biological actions, including antibacterial, anticancer, antiviral, antiproliferative, analgesic, anti-inflammatory, and antioxidant properties. The review article aims to assist researchers in creating new biologically active compounds for designing target-oriented triazolothiadiazine-based medicines to treat multifunctional disorders. Full article

2H-Benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxide (BTD) based carbonic anhydrase (CA) inhibitors are here explored as new anti-mycobacterial agents. The chemical features of BTD derivatives meet the criteria for a potent inhibition of β-class CA isozymes. BTD derivatives show chemical features meeting the criteria for a potent inhibition of β-class CA isozymes. Specifically, three β-CAs (MtCA1, MtCA2, and MtCA3) were identified in Mycobacterium tuberculosis and their inhibition was shown to exert an antitubercular action. BTDs derivatives 2a-q effectively inhibited the mycobacterial CAs, especially MtCA2 and MtCA3, with K_i values up to a low nanomolar range (MtCA3, K_i = 15.1–2250 nM; MtCA2, K_i = 38.1–4480 nM) and with a significant selectivity ratio over the off-target human CAs I and II. A computational study was conducted to elucidate the compound structure-activity relationship. Importantly, the most potent MtCA inhibitors demonstrated efficacy in inhibiting the growth of M. tuberculosis strains resistant to both rifampicin and isoniazid—standard reference drugs for Tuberculosis treatment. Full article

Heterocyclic derivatives of hormones have attracted great interest as a privileged scaffold for drug discovery due to their outstanding biological activity. A number of them are potent anticancer agents which are used in the chemotherapy of breast and prostate cancers. Here, the data obtained by the authors in the field of studying functionalized thiohydrazides as simple “versatile agents” for the installation of heterocyclic moiety to the steroid core are summarized. Namely, a flexible synthetic approach to unknown pyrazolines, 1,3,4-thiadiazole, thiadiazine, and pyridazine derivatives of steroids with selective control of heterocyclization patterns are discussed. Steroidal 1,3,4-thiadiazoles were obtained via the oxidative heterocyclization of oxamic acid thiohydrazides with 16-hydroxymethylidene-∆^1,3,5(10)-estratrieno-17-one. An extension of this reaction to steroidal α,β-unsaturated ketones resulted in androst-5-ene-[17,16d]-pyrazolines. Spiro-androstene-17,6′[1′,3′,4′]thiadiazines were exclusively synthesized employing 16β,17β-epoxypregnenolone. Using 21-bromopregna-5,16-dien-20-one as a substrate, 17-[1′,3′,4′]thiadiazine-substituted androstenes were prepared. 18-Nor-5α-androsta-2,13-diene[3,2-d]pyridazines, androsta-2-ene[3,2-d]pyridazines and ∆^1,3,5(10)-estratrieno[16,17-d]pyridazines were synthesized via two steps involving the Vilsmeier–Haack reaction of enolizable steroidal ketones, giving chlorovinyl aldehydes, followed by the imination of the former with oxamic acid thiohydrazides. The antiproliferative activity of the synthesized compounds against breast and prostate cancer cell lines, along with lead compounds’ in-depth characterization, are included. The lead compounds were found to have potent selectivity and, in some cases, a significant effect on the signaling pathways in parental and 4-hydroxytamoxifen-resistant cells. Full article

Malaria is a parasitic infection caused by a protozoon of the genus Plasmodium, transmitted to humans by female biting mosquitoes of the genus Anopheles. Chloroquine and its derivates have caused the parasite to develop drug resistance in endemic areas. For this reason, new anti-malarial drugs as treatments are crucial. This work aimed to evaluate the humoral response. with hyper-immune sera, of mice immunized with six derivatives of tetrahydro-(2H)-1,3,5-thiadiazine-2-thione (bis-THTT) by indirect ELISA test. The cross-reactivity between the compounds as antigens and their microbial activity on Gram-positive and Gram-negative bacteria was evaluated. The results of the humoral evaluation by indirect ELISA show that three bis-THTTs react with almost all of the above. Besides, three compounds used as antigens stimulate the BALB/c mice’s immune system. The best combination of two antigens as a combined therapy displays similar absorbances between the antigens in the mixture, showing similar recognition by antibodies and their compounds. In addition, our results showed that different bis-THTT presented antimicrobial activity on Gram-positive bacteria, mainly on Staphylococcus aureus strains, and no inhibitory activity was observed on the Gram-negative bacteria tested. Full article

This study of the interaction system of binucleophilic 3-substituted 4-amino-4H-1,2,4-triazole-5-thiols and 3-phenyl-2-propynal made it possible to develop a new approach to synthesis of such isomeric classes as 7-benzylidene-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine and 8-phenyl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazepine. Among the 20 compounds studied in vitro against influenza A/Puerto Rico/8/34 (H1N1) virus, half of them demonstrated selectivity index (SI) of 10 or higher and one of them (4-((3-phenylprop-2-yn-1-yl)amino)-4H-1,2,4-triazole-3-thiol) possessed the highest (SI > 300). Docking results and values showed that the preferred interactant for our ligands was M2 proton channel of the influenza A virus. Protein-ligand interactions modeling showed that the aliphatic moiety of ligands could negatively regulate target activity level. Full article