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Buprofezin (BUP) is an insect growth regulator widely used in agriculture to control hemipteran pests, particularly the melon aphid, Aphis gossypii, due to its efficiency and low toxicity. Although approved by the Chinese government, its maximum residue limit (MRL) in food is strictly regulated, and conventional techniques for detecting BUP have several limitations. Our study reports successful BUP detection using a supramolecular fluorescent probe DP@ALB, constructed with chalcone-based fluorescent dye DP and albumin as the host. The probe offers advantages such as low cost, visual signal output with high fluorescence color variation, rapid response, and high sensitivity. Additionally, portable test strips enable convenient on-site BUP detection and simplifying field monitoring of spiked real samples. The study achieves precise qualitative and quantitative BUP analysis in grape fruit, groundwater, and soil with satisfactory recoveries. Further, the biological applicability of sensor for the in vitro detection of BUP in L929 living cells was demonstrated. This research breakthrough overcomes the limitations of traditional analytical methods, offering an efficient and reliable approach for food and environmental monitoring and pesticide residue detection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

During last decades, 3,5-disubstituted-tetrahydro- 2H -thiadiazine-2-thione scaffold remains the center of interest due to their ease of preparation, diverse range substituents at N-3 and N-5 positions, and profound biological activities. In the current study, a series of 3,5-disubstituted-tetrahydro- 2H -thiadiazine-2-thiones were synthesized in good to excellent yield, and the structure of the compounds were confirmed by various spectroscopic techniques such as FTIR, 1 H-NMR, 13 C-NMR and Mass spectrometry, and finally evaluated against Leishmania major . Whereas, all the evaluated compounds (1-33), demonstrate potential leishmanicidal activities with IC 50 values in the range of (1.30- 149.98 uM). Among the evaluated compounds such as 3, 4, 6, and 10 exhibited excellent leishmanicidal activities with IC 50 values of (2.17 μM), (2.39 μM), (2.00 μM), and (1.39 μM), respectively even better than the standard amphotericin B (IC 50 = 0.50) and pentamidine (IC 50 = 7.52). In order to investigate binding interaction of the most active compounds, molecular docking study was conducted with Leishmania major . Further molecular dynamic simulation study was also carried out to assess the stability and correct binding of the most active compound 10, within active site of the Leishamania major . Likewise, the physiochemical properties, drug likeness, and ADMET of the most active compounds were investigated, it was found that none of the compounds violate Lipiniski's rule of five, which show that this class of compounds had enough potential to be used as drug candidate in near future.Communicated by Ramaswamy H. Sarma.

Antimicrobials fight microorganisms, preventing and treating infectious diseases. However, antimicrobial resistance (AMR) is a growing concern due to the inappropriate and excessive use of these drugs. Several mechanisms can lead to resistance, including efflux pumps such as the NorA pump in Staphylococcus aureus, which reduces the effectiveness of fluoroquinolones. Thiadiazines are heterocyclic compounds whose chemical structure resembles that of cephalosporins. Therefore, these compounds and their derivatives have been studied for their potential in combating increased bacterial resistance. To analyze this hypothesis, direct activity assays, antibiotic action-modifying activity, fluorescence assays to evaluate the retention of ethidium bromide inside bacteria, and molecular docking were carried out. These experiments involved serial dilutions in microplates against Staphylococcus aureus strain 1199B under the influence of six thiadiazine derivatives (IJ10, IJ11, IJ21, IJ22, IJ23, and IJ25). The tests revealed that, despite not showing effective direct activity, some thiadiazine derivatives (IJ11, IJ21, and IJ22) inhibited the function of the bromide pump both in microdilution tests and in fluorescence and docking assays. Particularly, the IJ11 compound stood out for its activity similar to efflux inhibitors, as well as its inhibition of the norfloxacin pump of this bacterium. Among the results of this study, it deserves to be highlighted for anchoring future experiments, as it represents the first investigation of this group of thiadiazine derivatives against the NorA pump., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl- N -(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC 50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11 ) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11 )) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score ( S , kcal/mol) ranged between -8.23 (for compound 5 ), -8.12 (for compound 3 ) and -8.03 (for compound 9 ) to -6.01 (for compound 8 ). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds ( 5 , 3 , and 9 ) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (Δ E ) of compounds 5 , 3 , and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.

Compound L-36, a new derivative of 6H-1,3,4-thiadiazine, was studied in in vitro and in vivo experiments. This compound exhibits high antiplatelet and antithrombogenic activity. In in vitro experiments, compound L-36 by its antiplatelet activity (by IC 50 ) was superior to acetylsalicylic acid by 9.4 times. In in vivo experiments, compound L-36 by its ED 50 value was close to the comparison drug. On the model of pulmonary artery thrombosis, compound L-36 ensured better survival of experimental animals than acetylsalicylic acid. Morphological studies showed that compound L-36 effectively attenuated the thrombosis processes in the pulmonary tissue induced by intravenous injection of a thrombogenic mixture (epinephrine and collagen)., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic., Objectives: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines., Methods: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets., Results: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action., Conclusions: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out., (© 2023 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pirotte Bernard reports financial support was provided by Servier Laboratories Suresnes. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC 50 values of 0.75, 0.94, 2.90, and 4.15 μM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC 50  > 100 μM). The mechanism study revealed that 7j caused the G 2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells., (© 2023 Wiley Periodicals LLC.)

Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4H-1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pirotte Bernard reports financial support was provided by Laboratoires Servier. Pirotte Bernard reports a relationship with Laboratoires Servier that includes: funding grants., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

A series of alkyl/aryl/aralkylamines or amino acids appended tetrahydro-2H-1,3,5-thiadiazine-2-thiones (4a-i, 5a-g, 6 and 7) were synthesized via one pot domino synthesis. The synthesis involved reacting alkyl/aryl/aralkylamines or amino acids with carbon disulfide employing basic aqueous medium and further cyclization with formaldehyde and alkyl/aryl/aralkylamines or amino acids. In addition, the carboxy-functionalized 1,3,5-thiadiazine-2-thione 6 was further subjected to esterification. All the structures were confirmed through spectral techniques i.e IR, 1 H NMR, 13 C NMR, and MS analysis. Furthermore, the newly synthesized compounds were biologically assessed via in vitro COX-2 and 5-LOX assays, in vivo anti-nociceptive and anti-inflammatory activities. Among the screened compounds, 6, 5f, and 7 exhibited highest inhibitory potency against COX-2 with IC 50 values of 11.96, 13.54, and 13.93 μM, respectively. Moreover, compounds 6 and 7 exhibited excellent inhibitory potential against 5-LOX with IC 50 values of 14.01 and 14.13 μM. The in-vivo anti-inflammatory bioassay studies showed that compounds 6, 7 and 5f dramatically reduced the paw edema size at 1 h and 3 h time intervals. In the anti-nociceptive activity, compound 6 showed pain protection comparative to Tramadol in all tested time intervals. In addition, studies of molecular docking revealed the compounds binding modes in the allosteric site of COX-2 and active site of 5-LOX, where these compounds exhibited higher binding scores and good binding interactions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A new series of ( ±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

We report the promising urease inhibitory activity of four sets of tetrahydro thiadiazine thiones (THTT) namely 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine thiones: THTT 5-8 (set A) having alkyl/aryl substituents at N-3 and N-5 positions; THTT 9-12 (set B) and THTT 13-14 (set C) with 3-carboxylic acid derivatives and tetrahydro-2H-1,3,5-thiadiazine-6-thione esters 15-16 (set D). Gratifyingly, all four sets of THTT were recognized as promising inhibitors of urease enzyme. Among 12 tested compounds; THTT 6, 8, 10, 14 and 15 from each set respectively, demonstrated significant urease inhibitory activity with IC 50 values between 11.2-29.8μM which is mostly found higher than that for thiourea, a standard urease inhibitor with IC 50 value of 22.4μM. Furthermore, compound 7 showed almost the same level of inhibition (IC 50 = 22.5μM) as of standard. In addition, molecular docking study supported the phenomenon that thiadiazinane ring itself is an active pharmacophore that binds through CH 2 groups and S atom via carbon-hydrogen/π-sulfur interactions respectively to the active site of the urease enzyme. The optimistic results from this study suggest the use of thiadiazinane skeleton as a guided template for the advancement of new urease inhibitors in drug discovery.

Seven derivatives of 1-phenyl ethyl group containing 3,5-disubstituted tetrahydro-2H-1,3,5-thiadiazine-thiones (THTT) were prepared and examined for their antibacterial and antifungal properties by using Microplate Alamar Blue Assay (MABA) and agar tube dilution protocol respectively. In vitro antifungal potential was investigated against five human pathogens and compared with the standard drugs amphotericin B and miconazole. In vitro antibacterial activity was investigated against four pathogens and compared with the ofloxacin. All compounds exhibited very promising antifungal activities against all tested pathogens. Structure activity relationship showed the importance of the presence of 1-phenyl ethyl substituent at N-3 of THTT nucleus for antifungal effects. However, these compounds showed significant antibacterial activity only against S. aureus. The compound 6c of the series was found most active compound that displayed promising antifungal potential against all tested pathogens [Growth Inhibition (GI) = 100%], and also showed promising antibacterial potential against S. aureus (GI% = 83.49) which is very much closer to the standard ofloxacin (GI% = 88.05). The study may be useful in the development of improved antimicrobial agents.

The N-methyl-d-aspartate receptor antagonist, ketamine, exhibits rapid and sustained antidepressant activity in patients with treatment-resistant depression (TRD), but its use is associated with psychotomimetic side effects. Evidence has suggested that the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors followed by activation of the mechanistic target of rapamycin (mTOR) signaling pathway and production of brain derived neurotrophic factor (BDNF) protein may underlie the antidepressant efficacy of ketamine. In this study, we characterized the antidepressant-like effects of TAK-653, a novel AMPA receptor potentiator with virtually no agonistic activity. In rat primary cortical neurons, TAK-653 significantly increased phosphorylated and activated forms of mTOR and p70S6 kinase and their upstream regulators Akt and extracellular signal-regulated kinase (ERK). TAK-653 also significantly increased BDNF protein levels in rat primary cortical neurons. Ketamine at 30 mg/kg, i.p. produced antidepressant-like effects in the reduction of submissive behavior model (RSBM) in rats. Ketamine's antidepressant-like effect was blocked by pretreatment with the AMPA receptor antagonist NBQX at 10 mg/kg, i.p., indicating the essential role of AMPA receptor activation in the antidepressant-like effect of ketamine. Consistent with this finding, a sub-chronic administration of TAK-653 for 6 days produced significant antidepressant-like effect in the rat RSBM. Unlike ketamine, however, TAK-653 did not induce a hyperlocomotor response in rats, which is a behavioral index associated with psychotomimetic side effects in humans. TAK-653 may be a promising drug for the treatment of major depressive disorders including TRD with the potential for an improved safety profile compared with ketamine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

A focused series of substituted 4 H -1,2,6-thiadiazin-4-ones was designed and synthesized to probe the anti-cancer properties of this scaffold. Insights from previous kinase inhibitor programs were used to carefully select several different substitution patterns. Compounds were tested on bladder, prostate, pancreatic, breast, chordoma, and lung cancer cell lines with an additional skin fibroblast cell line as a toxicity control. This resulted in the identification of several low single digit micro molar compounds with promising therapeutic windows, particularly for bladder and prostate cancer. A number of key structural features of the 4 H -1,2,6-thiadiazin-4-one scaffold are discussed that show promising scope for future improvement.

Efficient and safe nanopesticides play an important role in pest control due to enhancing target efficiency and reducing undesirable side effects, which has become a hot spot in pesticide formulation research. However, the preparation methods of nanopesticides are facing critical challenges including low productivity, uneven particle size and batch differences. Here, we successfully developed a novel, versatile and tunable strategy for preparing buprofezin nanoparticles with tunable size via anodic aluminum oxide (AAO) template-assisted method, which exhibited better reproducibility and homogeneity comparing with the traditional method. The storage stability of nanoparticles at different temperatures was evaluated, and the release properties were also determined to evaluate the performance of nanoparticles. Moreover, the present method is further demonstrated to be easily applicable for insoluble drugs and be extended for the study of the physicochemical properties of drug particles with different sizes.

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-β and VchCA-γ) and Burkholderia pseudomallei (BpsCA-β and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (K I values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; K I VchCA-α/K I hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (K I s of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Cumulative evidence suggests that β-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized. Biological evaluation showed that 13f exhibited good BACE-1 inhibitory activity (IC 50  = 1.06 μΜ) and potent GPx-like activity (ν 0  = 183.0 μM min -1 ). Aβ production experiment indicated that 13f could reduce the secretion of Aβ1-40 in HEK APPswe 293T cells. Moreover, 13f exerted a cytoprotective effect against the H 2 O 2 or 6-OHDA caused cell damage via alleviation of intracellular ROS, mitochondrial dysfunction, Ca 2+ overload and cell apoptosis. The mechanism studies indicated that 13f exhibited cytoprotective effect by activating the Keap1-Nrf2-ARE pathway and stimulating downstream anti-oxidant protein including HO-1, NQO1, TrxR1, GCLC, and GCLM. In addition, 13f significantly reduced the production of NO and IL-6 induced by LPS in BV2 cells, which confirmed its anti-inflammatory activity as a Nrf2 activator. The BBB permeation assay predicted that 13f was able to cross the BBB. In summary, 13f might be a promising multi-target-directed ligand for the treatment of AD., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

The spread of Plasmodium falciparum parasites resistant to most first-line antimalarials creates an imperative to enrich the drug discovery pipeline, preferably with curative compounds that can also act prophylactically. We report a phenotypic quantitative high-throughput screen (qHTS), based on concentration-response curves, which was designed to identify compounds active against Plasmodium liver and asexual blood stage parasites. Our qHTS screened over 450,000 compounds, tested across a range of 5 to 11 concentrations, for activity against Plasmodium falciparum asexual blood stages. Active compounds were then filtered for unique structures and drug-like properties and subsequently screened in a P. berghei liver stage assay to identify novel dual-active antiplasmodial chemotypes. Hits from thiadiazine and pyrimidine azepine chemotypes were subsequently prioritized for resistance selection studies, yielding distinct mutations in P. falciparum cytochrome b, a validated antimalarial drug target. The thiadiazine chemotype was subjected to an initial medicinal chemistry campaign, yielding a metabolically stable analog with sub-micromolar potency. Our qHTS methodology and resulting dataset provides a large-scale resource to investigate Plasmodium liver and asexual blood stage parasite biology and inform further research to develop novel chemotypes as causal prophylactic antimalarials.

The crystal structures of four new chiral [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines are described, namely, ethyl 5'-benzoyl-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C 19 H 22 N 4 O 3 S, ethyl 5'-(4-methoxybenzoyl)-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C 20 H 24 N 4 O 4 S, ethyl 6,6-dimethyl-5-(4-methylbenzoyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C 17 H 20 N 4 O 3 S, and ethyl 5-benzoyl-6-(4-methoxyphenyl)-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C 21 H 20 N 4 O 4 S. The crystallographic data and cell activities of these four compounds and of the structures of three previously reported similar compounds, namely, ethyl 5'-(4-methylbenzoyl)-5'H,7'H-spiro[cyclopentane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C 19 H 22 N 4 O 3 S, ethyl 5'-(4-methoxybenzoyl)-5'H,7'H-spiro[cyclopentane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate, C 19 H 22 N 4 O 4 S, and ethyl 6-methyl-5-(4-methylbenzoyl)-6-phenyl-6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine-3-carboxylate, C 22 H 22 N 4 O 3 S, are contrasted and compared. For both crystallization and an MTT assay, racemic mixtures of the corresponding [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines were used. The main manner of molecular packing in these compounds is the organization of either enantiomeric pairs or dimers. In both cases, the formation of two three-centre hydrogen bonds can be detected resulting from intramolecular N-H...O and intermolecular N-H...O or N-H...N interactions. Molecules of different enantiomeric forms can also form chains through N-H...O hydrogen bonds or form layers between which only weak hydrophobic contacts exist. Unlike other [1,2,3]triazolo[5,1-b][1,3,4]thiadiazines, ethyl 5'-benzoyl-5'H,7'H-spiro[cyclohexane-1,6'-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazine]-3'-carboxylate contains molecules of only the (R)-enantiomer; moreover, the N-H group does not participate in any significant intermolecular interactions. Molecular mechanics methods (force field OPLS3e) and the DFT B3LYP/6-31G+(d,p) method show that the compound forming enantiomeric pairs via weak N-H...N hydrogen bonds is subject to greater distortion of the geometry under the influence of the intermolecular interactions in the crystal. For intramolecular N-H...O and S...O interactions, an analysis of the noncovalent interactions (NCIs) was carried out. The cellular activities of the compounds were tested by evaluating their antiproliferative effect against two normal human cell lines and two cancer cell lines in terms of half-maximum inhibitory concentration (IC 50 ). Some derivatives have been found to be very effective in inhibiting the growth of Hela cells at nanomolar and submicromolar concentrations with minimal cytotoxicity in relation to normal cells.

A series of thiadiazino[5,6-b]quinoxaline and thiazolo[4,5-b]quinoxaline derivatives was designed and synthetized from the reaction of 2,3-dichloro-6-(morpholinosulfonyl)quinoxaline (2) with thiosemicarbazide or thiocarbohydrazide and thiourea derivatives to give nineteen quinoxaline derivatives 3-16. All the synthesized compounds were evaluated for in vitro antimicrobial potential against various bacteria and fungi strains that showed considerable antimicrobial activity against tested microorganisms. The most potent compounds 2, 7, 9, 10, 12 and 13c were exhibited bactericidal activity, in addition to fungistatic activity by dead live assay. Moreover, these compounds showed a significant result against all multi-drug resistance (MDRB) used especially compound 13c that displayed the best results with MICs of MDRB (1.95, 3.9, 2.6, 3.9 µg/mL) for stains used in this study, compared with Norfloxacin (1.25, 0.78, 1.57, 3.13 µg/mL). Also, cytotoxicity on normal cell (Vero cells ATCC CCL-81) by MTT assay was performed with lower toxicity results. Additionally, morphological studies, immunostimulatory potency and DNA gyrase inhibition assay of most active compounds was done. A molecular docking study has also been carried out to support the effective binding of the most promising compounds at the active site of the target enzyme S. aureus DNA gyrase (2XCT)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The soil phosphorus (P) cycle and P transformation are largely driven by the soil bacterial microbial community. However, little is known about the effects of dazomet (DZ) soil fumigation on soil P and soil microbial communities associated with P transformation. This research investigated P released from three farm soils as a result of DZ fumigation and changes in enzyme activity, gene abundance, and the encoding alkaline phosphatase PhoD microbial community. After DZ fumigation, we observed a briefly significant increase in the available P and the active P fractionation. The soil ALP activity, 16 s rRNA abundance, and the phoD gene decreased significantly after DZ fumigation. The abundance and diversity of phoD -harboring microbes also decreased shortly after fumigation, increased significantly 14-28 days later, and then decreased again toward the end of the experimental period of 86 days. The shared OTUs between treatments became fewer with increasing time after fumigation. The changes in available P and the active P fractionation after DZ fumigation were significantly correlated with the abundance of the dominant phoD -harboring microbes. DZ fumigation promoted P mineralization in these farm soils and changed the composition of phoD -harboring microbial communities, which will benefit crops able to absorb and use P.

Aromatase is involved in the biosynthesis of estrogen and thus is a critical target for breast cancer. In this study, to identify new aromatase enzyme inhibitors, seven 3-[4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenyl]-6-(substituted phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives were synthesized. First, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the inhibitory activity of the synthesized compounds on the MCF-7 cell line. The aromatase inhibitory activity was determined for the active compounds 5b, 5c, 5e, and 5g on the MCF-7 cell line. Compound 5g showed significant aromatase inhibitory activity (IC 50  = 0.037 ± 0.001 µM). Interestingly, this compound, which bears a difluoro substituent at positions 2 and 4 of the phenyl ring, displayed the most potent aromatase inhibitory activity without significant cytotoxicity to a normal healthy cell line (NIH3T3). Furthermore, the interactions between the best active compounds and the active site of the enzyme were analyzed through a docking study. The results of this study determined that benzimidazole-triazolothiadiazine derivatives are promising compounds that should be further developed as a novel class of aromatase inhibitors., (© 2020 Deutsche Pharmazeutische Gesellschaft.)

Although fungicides could be the best solution in combating fungal infections in crops, however, the phytotoxic level of fungicides to the crops should be tested first to ensure that it is safe for the crops. Moreover, nanocarrier systems of fungicides could play a significant role in the advancement of crop protection. For this reason, chitosan was chosen in the present study as a nanocarrier for fungicides of hexaconazole and/or dazomet in the development of a new generation of agronanofungicides with a high antifungal potent agent and no phytotoxic effect. Hence, the encapsulation of fungicides into the non-toxic biopolymer, chitosan was aims to reduce the phytotoxic level of fungicides. In the present study, the in vivo phytotoxicity of chitosan-fungicides nanoparticles on the physiological and vegetative growth of oil palm seedlings was evaluated in comparison to its pure fungicides as well as the conventional fungicides. The results revealed the formation of chitosan-fungicides nanoparticles could reduce the phytotoxic effect on oil palm seedlings compared to their counterparts, pure fungicides. The chitosan-fungicides nanoparticles were seen to greatly reduce the phytotoxic effect compared to the conventional fungicides with the same active ingredient., Competing Interests: Malaysian Palm Oil Board (MPOB) provided support in the form of salaries for authors ASI and NHZH but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

The rise of environmental and health concerns due to the excessive use of the conventional fungicide urges the search for sustainable alternatives of agronanofungicides where the latter is aimed to enhance plant uptake and minimize the volatilization, leaching, and runoff of fungicides. With this in mind, fungicides of hexaconazole and/or dazomet were encapsulated into chitosan nanoparticles for the formulation of chitosan-based agronanofungicides. In the present study, chitosan nanoparticles (2 nm), chitosan-hexaconazole nanoparticles (18 and 168 nm), chitosan-dazomet nanoparticles (7 and 32 nm), and chitosan-hexaconazole-dazomet nanoparticles (5 and 58 nm) were synthesized and used as potent antifungal agents in combating the basal stem rot (BSR) disease caused by Ganoderma boninense in which they were evaluated via an artificial inoculation of oil palm seedlings with the rubber woodblock, which was fully colonized with the fungal Ganoderma boninense mycelium. The results revealed that chitosan nanoparticles could act as dual modes of action, which are themselves as a biocide or as a nanocarrier for the existing fungicides. In addition, the particle size of the chitosan-based agronanofungicides plays a crucial role in suppressing and controlling the disease. The synergistic effect of the double-fungicide system of 5 nm chitosan-hexaconazole-dazomet nanoparticles can be observed as the system showed the highest disease reduction with 74.5%, compared to the untreated infected seedlings.

Gastric cancer and cervical cancer are two major malignant tumors that threaten human health. The novel chemotherapeutic drugs are needed urgently to treat gastric cancer and cervical cancer with high anticancer activity and metabolic stability. Previously we have reported the synthesis, characterization and identification of a novel combretastatin A-4 analog, 3-(3-methoxyphenyl)-6-(3-amino-4- methoxyphenyl) -7H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine (XSD-7). In this study, we sought to investigate its anticancer mechanisms in a human gastric cancer cell line (SGC-7901 cells) and human cervical carcinoma cell line (HeLa cells). The 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay showed that XSD-7 induced cytotoxicity in SGC-7901 and HeLa cells with inhibitory concentration 50 values of 0.11 ± 0.03 and 0.12 ± 0.05 µM, respectively. Immunofluorescence studies proved that XSD-7 inhibited microtubule polymerization during cell division in SGC-7901 and HeLa cells. Then, these cells were arrested at G2/M cell cycle and subsequently progressed into apoptosis. In further study, mitochondrial membrane potential analysis and Western blot analysis demonstrated that XSD-7 treatment-induced SGC-7901 cell apoptosis via both the mitochondria-mediated pathway and the death receptor-mediated pathway. In contrast, XSD-7 induced apoptosis in HeLa cells mainly via the mitochondria-mediated pathway. Hence, our data indicate that XSD-7 exerted antiproliferative activity by disrupting microtubule dynamics, leading to cell cycle arrest, and eventually inducing cell apoptosis. XSD-7 with novel structure has the potential to be developed for therapeutic treatment of gastric cancer and cervical cancer., (© 2019 Wiley Periodicals, Inc.)

A novel synthetic approach was developed for the synthesis of 3-hydrazinotriazolothiadiazines in just one step from Purpald and phenacyl bromides. They were then selectively tethered to naphthoquinone fragments through hydrazine moiety generating novel Naphthoquinone-hydrazinotriazolothiadiazine analogues. In vitro cytotoxicity for the synthesized chemical entities was validated against HepG2 and MCF-7 cell lines and recorded IC 50 inhibitory profile range of 0.07-19.68 µM and 1.19-67.32 µM respectively. Among the synthesized series, compound 4c had maximal cytotoxicity against HepG2 and was therefore selected for further downstream biological investigations. Caspase 3 apoptotic marker was significantly upregulated in cells treated with compound 4c with induction of apoptosis at Pre-G1 phase and cell death at G2/M phase. Compounds 4a, 4c and 4d exhibited the most powerful inhibitory range (0.55-0.64 µM) against Topo IIB. Molecular docking study revealed potential interactions of those compounds within the ATP catalytic binding domain of Topo-IIB with high scores. In conclusion, the novel Naphthoquinone-hydrazinotriazolothiadiazine analogues could serve as promising anticancer agents through inhibition of Topoisomerase-IIB., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In the present study, an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) approach was designed to measure the rat plasma levels of verubecestat with diazepam as the internal standard. Acetonitrile-based protein precipitation was applied for sample preparation, then the analyte verubecestat was subjected to gradient elution chromatography with a mobile phase composed of acetonitrile (A) and 0.1% formic acid in water (B). Verubecestat was monitored by m/z 410.1 → 124.0 transition for quantification by multiple reaction monitoring (MRM) in positive ion electrospray ionization (ESI) source. When the concentration of verubecestat ranged from 1 to 2500 ng/mL, the method exhibited good linearity. For verubecestat, the intra- and inter-day precision were determined with the values of 2.9-9.0% and 0.4-6.5%, respectively; and the accuracy ranged from -2.2% to 10.4%. Matrix effect, extraction recovery, and stability data were in line with the standard FDA guidelines for validating a bioanalytical method. The validity of the developed method was confirmed through the pharmacokinetic study., (© 2019 John Wiley & Sons, Ltd.)

Dissolution experiments to support an active pharmaceutical ingredient (API) form change in Verubecestat immediate release tablets were performed following current regulatory guidance published by health authorities in Canada, Australia, Japan, the EU, and the USA. Verubecestat API meets the requirements of a Biopharmaceutics Classification System class 1 compound and tablets are very  rapidly dissolving in aqueous dissolution media. While the in vitro data were reviewed favorably by these agencies, the divergence in regulatory requirements led to unnecessary work and highlights several issues companies operating globally face to justify product changes that have very little impact on quality. The data presented in this manuscript provide a compelling case for adjustments to the current draft ICH M9 guidance which provides recommendations for biowaiver applications. Specifically, this manuscript contains recommendations with respect to API attributes, selection of dissolution media and apparatus, and methods to assess dissolution similarity if needed, which should be considered for inclusion in a science- and risk-based global guidance document to benefit patients, regulators, and the pharmaceutical industry.

A series of triazolo-thiadiazepines 4a - k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b . The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a - k and not the enamine-tautomer 6a - k . The structures of the newly synthesized triazolo-thiadiazepines 4a - k and triazolo-thiadiazines 8a - b were elucidated using NMR ( 1 H, and 13 C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC 50 between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the tested cancer cell lines respectively, compared to doxorubicin (IC 50 4.0 µg/mL). Docking studies revealed that the thiadiazepine scaffold presented a suitable anchor, allowing good interaction of the various binding groups with the enzyme binding regions and sub-pockets.

New 1,3,4-thiadiazine-thiourea derivatives have been synthesized. All the synthesized compounds were examined for in vitro cytotoxic activity against Non-Small Cell Lung Cancer (NSCLC) cell line A549, using MTT bioassay. Compounds 5d, 5i, 5j showed the highest cytotoxic activity with IC 50 values of 0.27 ± 0.01, 0.30 ± 0.02, and 0.32 ± 0.012 μM respectively with sorafenib as reference (IC 50 3.85 ± 0.27 μM). These compounds were chosen for further investigations against various biological targets known to play roles in NSCLC specifically: vascular endothelial growth factor receptor 2 (VEGFR2), B-RAF and matrix metalloproteinase 9 (MMP9). Encouraging results were exhibited by the three compounds against the selected targets. Compound 5j was specially promising as it exhibited inhibitory activity of VEGFR2 close to sorafenib (IC 50 0.11 ± 0.01 μM), most potent B-RAF activity inhibition (IC 50 0.178 ± 0.004 μM) and MMP9 inhibition (IC 50 0.08 ± 0.004 μM). Moreover, cell cycle analysis of A549 cells treated with 5j exhibited cell cycle arrest at G2-M phase and pro-apoptotic activity as indicated by Annexin V-FITC staining. Also, it reflected antinvasive and antimigration properties to A549 cells. Additionally, docking study of 5j on VEGFR2, B-RAF and MMP9 revealed that it binds to the target enzymes in a similar way as the co-crystallized ligand. The three compounds exhibited significantly high selectivity to A549 cancer cells against the normal human fetal lung fibroblast cell line WI-38 with higher selectivity index compared to sorafenib (5d IC 50 136.76 ± 2.38 μM, SI = 506.52; 5i IC 50 89.20 ± 2.11 μM, SI = 297.33; 5j IC 50 79.60 ± 3.8 μM, SI = 248.75; sorafenib IC 50 30.32 ± 2.41 μM, SI = 7.88). In conclusion, compounds 5d, 5i and 5j, specially 5j are promising anticancer agents targeting important pathways in NSCLC and warrant further preclinical and clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4- d ]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N -(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N -(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6 , the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1 H -pyrazolo[3,4- d ]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide derivatives 1 5a-J and 16a-d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues 15a and 15b with the IC 50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4 , these 2 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation., Competing Interests: The authors declare no conflict of interest.

A flexible approach to previously unknown spirofused and linked 1,3,4-thiadiazine derivatives of steroids with selective control of heterocyclization patterns is disclosed. (N-Arylcarbamoyl)spiroandrostene-17,6' [1,3,4]thiadiazines and (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes, novel types of heterosteroids, were prepared from 16β,17β-epoxypregnenolone and 21-bromopregna-5,16-dien-20-one in good to high yields by the treatment with oxamic acid thiohydrazides. The synthesized compounds were screened for antiproliferative activity against the human androgen receptor-positive prostate cancer cell line 22Rv1. Most of (N-arylcarbamoyl)17-[1',3',4']thiadiazine-substituted androstenes exhibit better antiproliferative potency (IC 50  = 2.1-6.6 µM) than the antiandrogen bicalutamide. Compounds 7d with IC 50  = 3.0 μM and 7j with IC 50  = 2.1 μM proved to be the most active in the series under study. Lead synthesized compound 7j downregulates AR expression and activity in 22Rv1 cells. NF-κB activity is also blocked in 7j-treated 22Rv1 cells. Apoptosis is considered as a possible mechanism of 7j-induced cell death., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The one-pot telescopic approach has been developed for the chemoselective synthesis of substituted benzo[ e ]pyrido/pyrazino/pyridazino[1,2- b ][1,2,4]thiadiazine dioxides using readily available 2-aminopyridines/pyrazines/pyridazine and 2-chloro benzene sulfonyl chloride. This one-pot procedure involves the chemoselective sulfonylation of 2-aminopyridines/pyrazines/pyridazine with 2-chloro benzene sulfonyl chloride followed by a Cu(I)-catalyzed Ullmann-type C-N coupling reaction to obtain benzo[ e ]pyrido/pyrazino/pyridazino[1,2- b ][1,2,4]thiadiazine dioxides with broad substrate scope and high functional group tolerance. The synthetic sequence merges well with the nucleophilic attack on the 2-amino group of pyridines/pyrazines/pyridazines on the 2-chloro benzene sulfonyl chloride, followed by Cu(I)-catalyzed ipso chloro displacement to C-N bond formation resulting in a more modular and straightforward approach. Moreover, the biological significance of the synthesized benzothiadiazine dioxides was evaluated by following their ability to bind to protein macromolecules and their anti-inflammatory activity.

Ketamine produces a rapid-onset antidepressant effect in patients with treatment-resistant depression (TRD), although it concurrently causes undesirable psychotomimetic side effects. Accumulating evidence suggests that ketamine produces antidepressant effects via activation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA-R), with consequent activation of the mammalian target of rapamycin (mTOR) pathway and up-regulation of brain-derived neurotrophic factor (BDNF). We previously reported that TAK-137, an AMPA-R potentiator with little agonistic effect, had potent procognitive effects with lower risks of bell-shaped dose-response and seizure induction. In this study, we characterized the potential of TAK-137 as a novel antidepressant in rats. In rat primary cortical neurons, TAK-137 increased the phosphorylated form of Akt, extracellular signal-regulated kinase, mTOR, and p70S6 kinase, and dose-dependently increased the expression level of BDNF protein. The antidepressant-like effects of ketamine and TAK-137 were assessed on the day after final administration using the novelty-suppressed feeding test in rats. A single intraperitoneal administration of ketamine shortened the latency to feed. Under these conditions, oral administration of TAK-137 for 3 days shortened the feeding latency. Ketamine induced hyperlocomotion and reduced prepulse inhibition, which may be associated with psychotomimetic effects, while TAK-137 did not. TAK-137 may be a safer and rapid-onset therapeutic drug for the treatment of major depressive disorder, including TRD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A series of novel 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N'-phenylacethydrazide derivatives were designed, synthesized and evaluated for their antifungal activities against Fusarium graminearum (Fg), Rhizoctonia solani (Rs), Botrytis cinerea (Bc) and Colletotrichum capsici (Cc). The bioassay results in vitro showed that most of the title compounds exhibited impressive antifungal activities against the above plant fungi. Particularly, the compounds 5c, 5f, 5g, 5i, 5m and 5p displayed desirable anti-Rs activities, with the corresponding EC 50 values of 0.37, 0.32, 0.49, 0.50, 0.46 and 0.45 µg/mL, respectively, which are superior to the positive control carbendazim (0.55 µg/mL). Further in vivo bioassay results showed that the anti-Rs activity of title compound 5f at 200 µg/mL reached 95.84% on detached rice leaves and 93.96% on rice plants. Featuring convenient synthesis, novel structures and desirable antifungal activity, these 2-(6-thioxo-1,3,5-thiadiazinan-3-yl)-N'-phenylacethydrazide derivatives could be further studied as the potential candidates of novel agricultural fungicides.

Alzheimer disease (AD) is a cruel neurodegenerative disorder caused by the deposition of amyloid β (Aβ) peptide inside the brain. The β-secretase (beta amyloid precursor protein (APP) cleaving enzyme 1, BACE1) is one of the enzymes involved in the cleavage of APP that leads to the Aβ formation and it is the primary target for the treatment of AD. Recent report outlines that verubecestat molecule strongly inhibits BACE1; however, its structure, binding mechanism and the stability in the active site of BACE1 are not yet known. The present study aims to determine the structure, binding affinity and the stability of verubecestat molecule in the active site of BACE1 from the molecular docking, quantum mechanics/molecular mechanics (QM/MM)-based charge density analysis and molecular dynamics simulation. Verubecestat molecule was docked at BACE1; it shows high binding affinity towards BACE1. Further, the conformational geometry and the intermolecular interactions of verubecestat in the active site of BACE1 were determined. The molecule forms strong interaction with the neighboring amino acids in the active site of BACE1. The onsite QM/MM-based charge density analysis reveals the nature of charge density distribution and the topological properties of intermolecular interactions of verubecestat molecule in the active site of BACE1. The calculated electrostatic potential (ESP) of verubecestat in the active site of BACE1 displays high negative and positive ESP regions of the molecule. This onsite QM/MM analysis is more relevant to the physiological situation. The molecular dynamics simulation has been performed, which confirms the high stability and compactness of verubecestat in the active site of BACE1. The MM-generalized Born surface area and MM-Poisson Boltzmann surface area free energy calculations of verubecestat-BACE1 also confirm the high binding affinity of verubecestat. Communicated by Ramaswamy H. Sarma.

The downregulation of the glutamate system may be involved in positive, negative, and cognitive symptoms of schizophrenia. Through enhanced glutamate signaling, the activation of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor, an ionotropic glutamate receptor, could be a new therapeutic strategy for schizophrenia. TAK-137 is a novel AMPA receptor potentiator with minimal agonistic activity; in this study, we used rodents and nonhuman primates to assess its potential as a drug for schizophrenia. At 10 mg kg -1 p.o., TAK-137 partially inhibited methamphetamine-induced hyperlocomotion in rats, and at 3, 10, and 30 mg kg -1 p.o., TAK-137 partially inhibited MK-801-induced hyperlocomotion in mice, suggesting weak effects on the positive symptoms of schizophrenia. At 0.1 and 0.3 mg kg -1 p.o., TAK-137 significantly ameliorated MK-801-induced deficits in the social interaction of rats, demonstrating potential improvement of impaired social functioning, which is a negative symptom of schizophrenia. The effects of TAK-137 were evaluated on multiple cognitive domains-attention, working memory, and cognitive flexibility. TAK-137 enhanced attention in the five-choice serial reaction time task in rats at 0.2 mg kg -1 p.o., and improved working memory both in rats and monkeys: 0.2 and 0.6 mg kg -1 p.o. ameliorated MK-801-induced deficits in the radial arm maze test in rats, and 0.1 mg kg -1 p.o. improved the performance of ketamine-treated monkeys in the delayed matching-to-sample task. At 0.1 and 1 mg kg -1 p.o., TAK-137 improved the cognitive flexibility of subchronic phencyclidine-treated rats in the reversal learning test. Thus, TAK-137-type AMPA receptor potentiators with low intrinsic activity may offer new therapies for schizophrenia.

The use of nanotechnology could play a significant role in the agriculture sector, especially in the preparation of new-generation agronanochemicals. Currently, the economically important plant of Malaysia, the oil palm, faces the threat of a devastating disease which is particularly caused by a pathogenic fungus, Ganoderma boninense. For the development of an effective antifungal agent, a series of chitosan nanoparticles loaded with a fumigant, dazomet, were prepared using various concentrations of sodium tripolyphosphate (TPP)-2.5, 5, 10, and 20 mg/mL, abbreviated as CDEN2.5, CDEN5, CDEN10, and CDEN20, respectively. The effect of TPP as a crosslinking agent on the resulting particle size of the synthesized nanoparticles was investigated using a particle size analyzer and high-resolution transmission electron microscopy (HRTEM). Both methods confirmed that increasing the TPP concentration resulted in smaller particles. In addition, in vitro fumigant release at pH 5.5 showed that the release of the fumigant from the nanoparticles was of a sustained manner, with a prolonged release time up to 24 h. Furthermore, the relationship between the chitosan-dazomet nanoparticles and the in vitro antifungal activity against G. boninense was also explored, where the nanoparticles of the smallest size, CDEN20, gave the highest antifungal efficacy with the lowest half maximum effective concentration (EC 50 ) value of 13.7 ± 1.76 ppb. This indicates that the smaller-sized agronanoparticles were more effective as an antifungal agent. The size can be altered, which plays a crucial role in combatting the Ganoderma disease. The agronanoparticles have controlled release properties and high antifungal efficacy on G. boninense , thus making them a promising candidate to be applied in the field for Ganoderma treatment.

Extensive application of pesticides has caused a lot of environmental pollution and health problems, prompting the development of highly efficient and lowly toxic pesticide formulations. Here, buprofezin (BPF)-loaded poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (P(HB-HH)) microspheres were prepared by O/W emulsion/solvent evaporation method. Under optimal conditions (P(HB-HH) 7.07% (w/v) and PVA 1.84% (w/v)), the spherical and monodispersed microspheres were obtained. The average particle size, pesticide loading (PL), and encapsulation efficiency (EE) of the optimized microspheres were 1.2 μm, 15.68%, and 78%, respectively. Release of 80% BPF from the microspheres in pH 5 (192 h) was faster than that in pH 7 (228 h) and 8 (204 h). Moreover, kinetic analysis indicated that BPF release behaved in a non-Fickian diffusion manner (0.43 < n < 0.85) and the release mechanism was the combined effects of pesticide diffusion and hydrolysis of polymer. The bioassay and toxicity results showed that encapsulation of BPF could exhibit high efficacy on the target organism and low toxicity to the non-target organism. Therefore, these results demonstrated that BPF-loaded P(HB-HH) microspheres with good stability were prepared successfully, and they could be further explored for constructing other highly efficient and lowly toxic pesticide formulations.

With the aim to reduce multidrug resistance several molecules were synthesized and tested for their ability to inhibit ATP-binding cassette (ABC) proteins, which are responsible for drugs transport out from cells. The compound 8-(4-chlorophenyl)-5-methyl-8-[(2Z)-pent-2-en-1-yloxy]-8H-[1,2,4]oxadiazolo[3,4-c][1,4]thiazin-3-one namely 2c, is structurally related to the myocardial-calcium-channel-modulator diltiazem and is considered one of the most efficient P-glycoprotein inhibitors, able to induce apoptosis at low concentrations of doxorubicin in multidrug resistant ovarian cells. In this study experiments were carried out to evaluate other biological activities of compound 2c. We verified the ability of 2c to inhibit ABC transporters do not involved in drug resistance and considering the inhibitory effect of diltiazem on recombinant human carboxylesterase, we observed its inhibitory effect on the esterase activity. Our findings demonstrated that 2c exhibits broad-spectrum activity as ABC transporters inhibitor being able to inhibit ABCC6, a protein belonging to the ABC family although poorly involved in drug resistance. 2c also inhibits cell esterase activity, acetylcholine esterase activity in vitro and cell histone H3 acetylation according to its structural homology with some known HAT inhibitors. The results obtained provide new knowledge on the biological activities of 2c and represent useful information when it is used as an inhibitor of drug resistance., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A (DYRK1A) is an enzyme that has been implicated as an important drug target in various therapeutic areas, including neurological disorders (Down syndrome, Alzheimer's disease), oncology, and diabetes (pancreatic β-cell expansion). Current small molecule DYRK1A inhibitors are ATP-competitive inhibitors that bind to the kinase in an active conformation. As a result, these inhibitors are promiscuous, resulting in pharmacological side effects that limit their therapeutic applications. None are in clinical trials at this time. In order to identify a new DYRK1A inhibitor scaffold, we constructed a homology model of DYRK1A in an inactive, DFG-out conformation. Virtual screening of 2.2 million lead-like compounds from the ZINC database, followed by in vitro testing of selected 68 compounds revealed 8 hits representing 5 different chemical classes. We chose to focus on one of the hits from the computational screen, thiadiazine 1 which was found to inhibit DYRK1A with IC 50 of 9.41 μM (K d  = 7.3 μM). Optimization of the hit compound 1, using structure-activity relationship (SAR) analysis and in vitro testing led to the identification of potent thiadiazine analogs with significantly improved binding as compared to the initial hit (K d  = 71-185 nM). Compound 3-5 induced human β-cell proliferation at 5 μM while showing selectivity for DYRK1A over DYRK1B and DYRK2 at 10 μM. This newly developed DYRK1A inhibitor scaffold with unique kinase selectivity profiles has potential to be further optimized as novel therapeutics for diabetes., (Copyright © 2018. Published by Elsevier Masson SAS.)

A novel series of pyrazolyl 1,3,4-thiadiazines 5a ⁻ c , 8a ⁻ c , 12 , 15a ⁻ c , 17a ⁻ c , and 20 was prepared from the reaction of pyrazole-1-carbothiohydrazide 1a , b with 2-oxo- N '-arylpropanehydrazonoyl chloride, 2-chloro-2-(2-arylhydrazono)acetate, and 3-bromoacetylcoumarin. Moreover, the regioselective reaction of 5-pyrazolone-1-carbothiohydrazide 1a with 4-substituted diazonium salts and 4-(dimethylamino)benzaldehyde gave the corresponding hydrazones 21a ⁻ c and 22 . The newly prepared compounds were characterized by spectroscopy and elemental analysis. Many new synthesized compounds showed considerable antimicrobial activity against tested microorganisms. Hydrazones 21a ⁻ c and 22 showed remarkable antibacterial and antifungal activities. 4-(2-( p -tolyl)hydrazineylidene)-pyrazole-1-carbothiohydrazide 21a displayed the highest antibacterial and antifungal activities with minimum inhibitory concentration (MIC) values lower than standard drugs chloramphenicol and clotrimazole, in the range of 62.5⁻125 and 2.9⁻7.8 µg/mL, respectively.

Alzheimer's disease (AD) is associated with multiple neuropathological events including β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibition and neuronal inflammation, ensuing degeneracy, and death to neuronal cells. Targeting such a complex disease via a single target directed treatment was found to be inefficacious. Hence, with an intention to incorporate multiple therapeutic effects within a single molecule, multitarget-directed ligands (MTDLs) have been evolved. Herein, for the first time, we report the discovery of novel thiazolyl-thiadiazines that can serve as MTDLs as evident from the in vitro and in vivo studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the in vivo studies demonstrated efficient anti-inflammatory activity with inherent gastrointestinal safety. Moreover, compound 6d unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment.

A novel fused system with three or four fused rings—pyridazino[3′,4′:5,6][1,2,4]triazino[4,3- b ][1,2,4,5]tetrazine and pyridazino[3′,4′:5,6][1,2,4]triazino[3,4- b ]pyrimido[4,5- e ][1,3,4]thiadiazine was obtained from the starting materials 4(6 H )-amino-3-hydrazino-7-(2-thienyl)pyridazino[3,4- e ][1,2,4]-triazine 2 and 9-amino-3-(2-thienyl)-2 H ,8 H -pyridazino[3′,4′:5,6][1,2,4]triazino[3,4- b ][1,3,4]thiadiazine-8-carbonitrile 12 . Each of the starting compounds was subjected to a number of cyclization reactions to obtain a series of new heterocyclic fused systems, 3 ⁻ 10 and 13 ⁻ 23 , via bifunctional reagents. Some of the synthesized compounds were screened against three cell lines including HepG2, HCT-116 and MCF-7 to discover their anticancer activity. The synthesized compounds were characterized depending on their elemental analyses and spectral data.

A novel series of 3,6-diaryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed, synthesized and biologically evaluated as vinylogous CA-4 analogues, which involved a rigid [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold to fix the configuration of (Z,E)-butadiene linker of A-ring and B-ring. Among these rigidly vinylogous CA-4 analogues, compounds 4d, 5b, 5i, 6c, 6e, 6g, 6i and 6k showed excellent antiproliferative activities against SGC-7901, A549 and HT-1080 cell lines with IC 50 values at the nanomolar level. Compound 6i showed the most highly active antiproliferative activity against the three human cancer cell lines with an IC 50 values of 0.011-0.015 µM, which are comparable to those of CA-4 (IC 50  = 0.009-0.013 µM). Interestingly, SAR studies revealed that 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl could replace the classic 3,4,5-trimethoxyphenyl in CA-4 structure and keep antiproliferative activity in this series of designed compounds. Tubulin polymerization experiments showed that 6i could effectively inhibit tubulin polymerization, which was corresponded with CA-4, and immunostaining experiments suggested that 6i significantly disrupted microtubule/tubulin dynamics. Furthermore, 6i potently induced cell cycle arrest at G 2 /M phase in SGC-7901 cells. Competitive binding assays and docking studies suggested that compound 6i binds to the tubulin perfectly at the colchicine binding site. Taken together, these results revealed that 6i may become a promising lead compound for new anticancer drugs discovery.

A new family of imidazo[4,5-c][1,2,6]thiadiazine 2,2-dioxide with antiproliferative Trypanosoma cruzi properties was identified from a neural network model published by our group. The synthesis and evaluation of this new class of trypanocidal agents are described. These compounds inhibit the growth of Trypanosoma cruzi, comparable with benznidazole or nifurtimox. In vitro assays were performed to study their effects on the growth of the epimastigote form of the Tulahuen 2 strain, as well as the epimastigote and amastigote forms of CL clone B5 of Trypanosoma cruzi. To verify selectivity towards parasite cells, the non-specific cytotoxicity of the most relevant compounds was studied in mammalian cells, i.e. J774 murine macrophages and NCTC clone 929 fibroblasts. Furthermore, these compounds were assayed regarding the inhibition of cruzipain. In vivo studies revealed that one of the compounds, 19, showed interesting trypanocidal activity, and could be a very promising candidate for the treatment of Chagas disease., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The aim of the present study was to examine how administration of a compound of 1,3,4- thiadiazine class 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17) with hypothermia inducing properties affects the brain metabolism. The mechanism by which L-17 induces hypothermia is unknown; it may involve hypothalamic central thermoregulation as well as act via inhibition of energy metabolism. We tested the hypothesis that L-17 may induce hypothermia by directly inhibiting energy metabolism. The study in vivo was carried out on Sprague-Dawley adult rats. Two doses of L-17 were administered (190 mg/kg and 760 mg/kg). Brain metabolites were analyzed in control and treated groups using magnetic resonance spectroscopy, along with blood flow rate measurements in carotid arteries and body temperature measurements. Further in vitro studies on primary cultures from rat hippocampus were carried out to perform a mitochondria function test of L-17 pre-incubation (100 μM, 30 min). Analysis of brain metabolites showed no significant changes in 190 mg/kg treated group along with a significant reduction in body temperature by 1.5°C. However, administration of L-17 in higher dose 760 mg/kg provoked changes in brain metabolites indicative of neurotoxicity as well as reduction in carotid arteries flow rate. In addition, a balance change of excitatory and inhibitory neurotransmitters was observed. The L-17 pre-incubation with cell primary cultures from rat brain showed no significant changes in mitochondrial function. The results obtained in the study indicate that acute administration of L-17 190 mg/kg in rats induces mild hypothermia with no adverse effects onto brain metabolism.

Previously, we demonstrated that certain heterocyclic compounds derived from 3-substituted-1,2,4-triazole-5-thiones had promising analgesic/anti-inflammatory activities together with low ulcerogenic properties. Therefore, we sought to design and synthesize new derivatives of triazol-5-thiones-fused heterocycles. In the present study, a series of novel bis-Mannich bases, namely 2,6-disubstituted-6,7-dihydro-5H-1,2,4-triazolo[3,2-b]-1,3,5-thiadiazines (1a-d, 2a-c, and 3a-d), were synthesized and characterized to assess their possible anti-inflammatory/analgesic properties. Additionally, their ability to induce gastric toxicity was also evaluated. Several of the condensed compounds produced a degree of analgesic activity comparable to reference drugs in both the hot plate and tail-flick tests. A strong anti-inflammatory effect was observed for the derivatives carrying a benzyl group at the second position (2a-c). The majority of the prepared compounds caused comparatively less gastrointestinal (GI) side effects than the reference drugs naproxen and indomethacin did. These results showed that 1,2,4-triazolo[3,2-b]-1,3,5-thiadiazine derivatives might afford a safer alternative to currently available analgesic/anti-inflammatory agents for the treatment and management of inflammatory disease and pain., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Former studies already revealed the anti-neoplastic properties of the anti-infective agent Taurolidine (TRD) against many tumor species in vitro and in vivo. Its anti-proliferative and cell death inducing capacity is largely due to its main derivative Taurultam (TRLT). In this study it could be demonstrated, that substance 2250 - a newly defined innovative structural analogue of TRLT - exhibits an anti-neoplastic effect on malignant pancreatic carcinoma in vitro and in vivo., Methods: The anti-neoplastic potential of substance 2250 as well as its mode of action was demonstrated in extensive in vitro analysis, followed by successful and effective in vivo testings, using xenograft models derived from established pancreatic cancer cell lines as well as patient derived tissue., Results: Our functional analysis regarding the role of oxidative stress (ROS) and caspase activated apoptosis showed, that ROS driven programmed cell death (PCD) is the major mechanisms induced by substance 2250 in pancreatic carcinoma. What is strongly relevant towards clinical practice is especially the observed inhibition of patient derived pancreatic cancer tumor growth in mice treated with this new substance in combination with its sharply higher metabolic stability., Conclusion: These encouraging results provide new therapeutical opportunities in pancreatic cancer treatment and build the basis for further functional analysis as well as first clinical studies for this promising agent.