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The aim of this work to study the feasibility of using phospholipid free vesicles with positive charge inducer in a slowly dissolving polymer ocular insert to successfully control intraocular pressure (IOP) for an extended period. Brinzolamide (BRNZ) was chosen as a model drug and a full factorial design was assembled to investigate the drug loading effect, ratio of cholesterol to fatty moiety and the type of the fatty moiety used on the vesicle size and entrapment efficiency. Linear regression models were constructed, and optimization of the formulation compositions yielded two formulae with palmitic acid as a negatively charged vesicles and cetrimide positively charged vesicles. Both formulae were studied in term of permeation efficiency through bovine corneal membranes. Positively charged vesicles although it didn't achieve the highest flux and cumulative amount permeated per unit surface area in the experiment time course, it achieved the highest retention of drug inside the corneal tissue, so it was chosen to be incorporated in a slowly dissolving polymer ocular insert. The insert was evaluated in term content, physical evaluation, and release properties. In vivo evaluation of the casted ocular inserts was conducted in male albino rabbits against market eye drop product and IOP readings were collected for 48 hours. The positively charged sterosomes containing BRNZ and formulated in polymer ocular inserts achieved extended control of IOP of the test animals compared to the market product., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

The goal of the present study was to prepare meloxicam (MX) entrapped hybrid particles (HPs) to enhance intestinal permeation and anti-inflammatory activity. MX-HPs were prepared by nanoprecipitation method using lipid, chitosan, poloxamer, and TPGS. The formulations (MX-HPs1, MX-HPs2, MX-HPs3) were evaluated for particle size, entrapment efficiency, and drug release to select the optimized composition and further evaluated for permeation study, stability study, morphology, interaction study, and anti-inflammatory activity by carrageenan-induced rat paw edema test. The prepared MX-HPs showed nano sized particles (198.5 ± 3.7 to 223.8 ± 2.1 nm) and PDI (<0.3), zeta potential (16.5 ± 2.7 to 29.1 ± 3.6 mV), and high entrapment efficiency (75.1 ± 4.7 to 88.5 ± 3.9%). The surface morphology was assessed by transmission electron microscopy and showed non-aggregated particles. Infra-red (IR) spectroscopy of pure MX as well as formulation revealed no drug-polymer interaction and X-ray diffraction confirmed the conversion of crystalline MX into amorphous form. The release study data revealed prolonged MX release for 24 h. The selected optimized hybrid particles (MX-HPs2) revealed a 2.3-fold improved enhancement ratio than free MX. The storage stability and gastrointestinal stability data demonstrated a stable formulation in SIF as well as SGF. The anti-inflammatory activity showed better therapeutic action than pure MX dispersion. From the study, it can be concluded that the prepared MX-HPs may be a promising delivery system for MX in treating inflammatory disorders., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Discovery and identification of a new endogenous metabolite are typically hindered by requirements of large sample volumes and multistage purifications to guide synthesis of the standard. Presented here is a metabolomics platform that uses chemical tagging and tandem mass spectrometry to determine structure, direct synthesis, and confirm identity. Three new homocysteine metabolites are reported: N-succinyl homocysteine, 2-methyl-1,3-thiazinane-4-carboxylic acid (MTCA), and homolanthinone.

With the spread of resistance to long-established insecticides targeting Anopheles malaria vectors, understanding the actions of compounds newly identified for vector control is essential. With new commercial vector-control products containing neonicotinoids under development, we investigate the actions of 6 neonicotinoids (imidacloprid, thiacloprid, clothianidin, dinotefuran, nitenpyram and acetamiprid) on 13 Anopheles gambiae nicotinic acetylcholine receptor (nAChR) subtypes produced by expression of combinations of the Ag α 1, Ag α 2, Ag α 3, Ag α 8 and Ag β 1 subunits in Xenopus laevis oocytes, the Drosophila melanogaster orthologues of which we have previously shown to be important in neonicotinoid actions. The presence of the Ag α 2 subunit reduces neonicotinoid affinity for the mosquito nAChRs, whereas the Ag α 3 subunit increases it. Crystal structures of the acetylcholine binding protein (AChBP), an established surrogate for the ligand-binding domain, with dinotefuran bound, shows a unique target site interaction through hydrogen bond formation and CH-N interaction at the tetrahydrofuran ring. This is of interest as dinotefuran is also under trial as the toxic element in baited traps. Multiple regression analyses show a correlation between the efficacy of neonicotinoids for the Ag α 1/Ag α 2/Ag α 8/Ag β 1 nAChR, their hydrophobicity and their rate of knockdown of adult female An. gambiae , providing new insights into neonicotinoid features important for malaria vector control.

The high efficient surface-enhanced Raman scatterring (SERS) methods to detect thiacloprid and imidacloprid were established using ZIF-8-wrapped Ag nanoparticles (AgNPs) modified with β-cyclodextrin (β-CD). The substrate of ZIF-8/β-CD@AgNPs was characterized by ultraviolet visible spectra (UV-vis), thermogravimetric analysis (TGA), X-ray diffraction (XRD), transmission electron microscopy (TEM) and scanning transmission electron microscopy (STEM). The interaction between the substrate and thiacloprid/imidacloprid was also explored. The optimum measurement conditions were obtained by response surface model based on single-factor experiments. Enhancement factors (EFs) of thiacloprid and imidacloprid were respectively 2.29 × 10 6 and 2.60 × 10 6 . A good linearity between the scattering intensity and the concentration of thiacloprid/imidacloprid within 3-1000 nmol L -1 /6-400 nmol L -1 was established. The interference experiments indicated that the methods had good selectivity. The SERS methods were successfully applied to detect thiacloprid and imidacloprid in several vegetables samples. The recoveries ranged from 95.5 % to 105 % (n = 5). The detection limits (LODs) (S/N = 3) for thiacloprid and imidacloprid were 1.50 and 0.83 nmol L -1 , respectively., Competing Interests: Declaration of competing interest We would like to submit the enclosed manuscript entitled “ZIF-8-wrapped AgNPs modified with β-cyclodextrin for sensitive detection of thiacloprid and imidacloprid by SERS technology”, which we wish to be considered for publication in “Talanta”. No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part., (Copyright © 2024 Elsevier B.V. All rights reserved.)

With projections suggesting an increase in the global use of neonicotinoids, contemporary farmers can get caught on the "pesticide treadmill", thus creating ecosystem side effects. The aim of this study was to investigate the sorption/desorption behavior of acetamiprid, imidacloprid, and thiacloprid that controls their availability to other fate-determining processes and thus could be useful in leveling the risk these insecticides or their structural analogues pose to the environment, animals, and human health. Sorption/desorption isotherms in four soils with different organic matter (OC) content were modelled by nonlinear equilibrium models: Freundlich's, Langmuir's, and Temkin's. Sorption/desorption parameters obtained by Freundlich's model were correlated to soil physico-chemical characteristics. Even though the OC content had the dominant role in the sorption of the three insecticides, the role of its nature as well as the chemical structure of neonicotinoids cannot be discarded. Insecticides sorbed in the glassy OC phase will be poorly available unlike those in the rubbery regions. Imidacloprid will fill the sorption sites equally in the rubbery and glassy phases irrespective of its concentration. The sorption of thiacloprid at low concentrations and acetamiprid at high concentrations is controlled by hydrophilic aromatic structures, "trapping" the insecticides in the pores of the glassy phase of OC.

The intricate structure of the eye poses difficulties in drug targeting, which can be surmounted with the help of nanoformulation strategies. With this view, brinzolamide nanosponges (BNS) were prepared using the emulsion solvent evaporation technique and optimized via Box-Behnken statistical design. The optimized BNS were further incorporated into a poloxamer 407 in situ gel (BNS-ISG) and evaluated. The optimized BNS showed spherical morphology, entrapment efficiency of 83.12 ± 1.2 % with particle size of 114 ± 2.32 nm and PDI of 0.11 ± 0.01. The optimized BNS-ISG exhibited a pseudoplastic behavior and depicted a gelling temperature and gelation time of 35 ± 0.5 °C and 10 ± 2 s respectively. In-vitro release and ex- vivo permeation studies of BNS-ISG demonstrated a sustained release pattern as compared to Brinzox®. Additionally, the HET-CAM and in vitro cytotoxicity studies (using SIRC cell line) ensured that the formulation was non-irritant and nontoxic for ophthalmic delivery. The in vivo pharmacodynamic study using rabbit model depicted that BNS-ISG treatment significantly lowers the intra ocular pressure for prolonged period of time when compared with Brinzox®. In conclusion, the BNS-ISG is an efficient and scalable drug delivery system with significant potential as the targeted therapy of posterior segment eye diseases., 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 © 2023 Elsevier B.V. All rights reserved.)

Thiazines are a sizable class of organic heterocycles that are notable for their skeletal versatility and relative chemical simplicity, making them among the most flexible sources of biologically active compounds. The term "green synthesis" refers to implementing energy-efficient procedures for the nature-friendly production of materials and chemicals using green solvents, catalysts, and suitable reaction conditions. Considering the importance of green chemistry and the outstanding therapeutic profile of thiazines, the present work was designed to review the recent advances in green chemistry-based synthetic strategies of thiazine and its derivatives. The green synthetic approaches, including microwave-assisted, ultrasound-assisted, and various other synthetic methods for thiazine and its derivatives, were discussed and generalized. In addition, applications of thiazine and its derivatives in pharmaceutical sciences were explained with examples of marketed drugs.The discussed sustainable synthetic methods for thiazines and their derivatives could be useful in developing other medicinally important lead molecules. They could also aid in developing new synthetic schemes and apparatuses that may simplify chemical manufacturing processes and enable novel reactions with minimal by-products while questing for optimal, green solvents. This review can help anyone interested in this fascinating class of heterocycles to make decisions about selecting targets and tasks for future research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Medical researchers have paid close attention to the green synthesis of oxazine and thiazine derivatives since they provided a lead molecule for the creation of numerous possible bioactive compounds. This review provides more information on green synthesis, which will be very helpful to researchers in creating the most effective, affordable, and clinically significant thiazine and oxazine derivatives that are anticipated to have strong pharmacological effects. This has resulted in the identification of several substances with a wide range of intriguing biological functions. This article's goal is to examine the numerous green chemical processes used to create oxazine and thiazine derivatives and their biological activity. We anticipate that researchers interested in oxazine and thiazine chemicals will find this material to be useful. We anticipate that medicinal chemists looking for new active medicinal components for drug discovery and advance progress will find this review of considerable interest., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: This study aims to explore potential of transniosomes, a hybrid vesicular system, as ocular drug-delivery vehicle. Materials & methods: Thin-film hydration technique was used to fabricate brinzolamide-loaded transniosomes (BRZ-TN) and optimized using Box-Behnken design, further exhaustively characterized for physicochemical evaluations, deformability, drug release, permeation and preclinical evaluations for antiglaucoma activity. Results: The BRZ-TN showed ultradeformability (deformability index: 5.71), exhibiting sustained drug release without irritation (irritancy score: 0) and high permeability compared with the marketed formulation or free drug suspension. The extensive in vivo investigations affirmed effective targeted delivery of transniosomes, with brinzolamide reducing intraocular pressure potentially. Conclusion: Our findings anticipated that BRZ-TN is a promising therapeutic nanocarrier for effectively delivering cargo to targeted sites by crossing corneal barriers.

Tuberculosis is the leading bacterial killer worldwide. 8-Nitro-4 H -benzo[ e ][1,3]thiazin-4-ones are a potent class of antitubercular agents with a new mechanism of action. BTZ043 and PBTZ169 (macozinone) have progressed to clinical studies. Herein, we give a comprehensive account of this important class of potential new drugs to treat tuberculosis. We present an overview of recent developments in the field of antitubercular benzothiazinones (BTZs) and summarize our own contributions. The review covers synthesis, structures and reactivity, mechanism of action, in vitro activity and structure activity relationships (SARs), physicochemical and pharmacokinetic properties as well as a brief summary of in vivo models and clinical studies. We address bioavailability issues and the challenge of the potentially toxic nitroaromatic moiety, including reactivity towards nucleophiles in vivo and highlight possible directions of further research into BTZs through chemical modification.

Meloxicam (MLX) is currently used in the therapeutic management of both acute and chronic inflammatory disorders such as pain, injuries, osteoarthritis, and rheumatoid arthritis in both humans and animals. Gastrointestinal toxicity and occasional renal toxicity were observed in patients taking it for a long-term period. Meloxicam's late attainment of peak plasma concentration results in a slow onset of action. The goal of the current study was to prepare and characterize chitosan encapsulated meloxicam nanoparticles (CEMNPs) with high bioavailability and less gastro intestinal toxicity in order to prevent such issues. The size of the prepared CEMNPs was approximately 110-220 nm with a zetapotential of +39.9 mV and polydispersity index of 0.268, suggesting that they were uniformly dispersed nanoparticles. The FTIR and UV-Vis spectroscopy have confirmed the presence of MLX in the prepared CEMNPs. The pharmacokinetics have been studied with three groups of male Wistar rats receiving either of the treatments, viz., 4 mg·kg -1 of MLX and 1 or 4 mg·kg -1 of CEMNPs. Plasma samples were collected until 48 h post administration, and concentrations of MLX were quantified by using reverse (C 18 ) phase HPLC. Non-compartmental analysis was applied to determine pharmacokinetic variables. Upon oral administration, the maximum concentration (C max ) was reached in 4 h for CEMNPs and 6 h for MLX. The mean area under the plasma MLX concentration-time curve from 'zero' to infinity (AUC 0-∞ ), half-life (t 1/2β ), and mean resident time (MRT) of 1 mg·kg -1 of CEMNPs was 1.4-, 2-, and 1.8-fold greater than 4 mg·kg -1 of MLX. The prepared CEMNPs demonstrated quicker absorption and prolonged release along with a significant improvement in the bioavailability of MLX, paving a prospective path for the development of drugs with enhanced bioavailability with less side effects., Competing Interests: The authors declare no conflict of interest.

Diabetes mellitus (DM) is a metabolic disorder that leads to hyperglycemia due to improper insulin secretion. The study aims to investigate the anti-diabetic potential of benzothiazine derivatives. Molecular docking and Molecular Dynamics simulation study revealed that Compound S6 (4-hydroxy-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide) and S7 (4-Hydroxy-2-methyl-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide) had less conformational changes during MD simulation analysis at 100 ns. Compound S6 and S7 showed potent activity with IC50 values of 5.93 μM, 6.91 μM and 75.17, 29.10 μM for α-glucosidase and α-amylase respectively and competitive type of inhibition was observed during enzyme kinetic study with a low value of Ki and Ki' for α-glucosidase and α-amylase, respectively. S6 has the lowest Ki (0.0736) and Ki' (-0.0982) for α-glucosidase. Furthermore, in vivo studies were carried out to distinguish the effects of the drug on the body. Histology analysis on mice model showed that compound S6 has a low necrosis rate in the liver, kidney, and pancreas compared to S7. Biochemical results of S6 revealed lower sugar level (112 mg/dL), increase insulin secretion (23, 25 μM/L), and low level of cholesterol (80, 85 mg/dL) and creatinine (1.6, 1.4 mg/dL). The results conclude that compound S6 is a new anti-diabetic agent that minimizes hyperglycemia complications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

8-Nitro-4H-benzo[e][1,3]thiazinones (BTZs) are potent in vitro antimycobacterial agents. New chemical transformations, viz. dearomatization and decarbonylation, of two BTZs and their influence on the compounds' antimycobacterial properties are described. Reactions of 8-nitro-2-(piperidin-1-yl)-6-(trifluoromethyl)-4H-benzo[e][1,3]thiazin-4-one and the clinical drug candidate BTZ043 with the Grignard reagent CH 3 MgBr afford the corresponding dearomatized stable 4,5-dimethyl-5H- and 4,7-dimethyl-7H-benzo[e][1,3]thiazines. These methine compounds are structurally characterized by X-ray crystallography for the first time. Reduction of the BTZ carbonyl group, leading to the corresponding markedly non-planar 4H-benzo[e][1,3]thiazine systems, is achieved using the reducing agent (CH 3 ) 2 S ⋅ BH 3 . Double methylation with dearomatization and decarbonylation renders the two BTZs studied inactive against Mycobacterium tuberculosis and Mycobacterium smegmatis, as proven by in vitro growth inhibition assays., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

This paper describes the structure-activity-relationships of novel fluoroalkyl substituents at the C2 position of iminothiazine dioxide beta secretase inhibitors. Key discoveries include reduced amidine basicity and its effect on Pgp, cell potency, and efficacy in various preclinical in vivo efficacy animal models. Findings from these structure-activity-relationships are discussed., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We report a series of compounds 1-17 derived from the antiepileptic drug Sulthiame (SLT) from which both the benzenesulfonamide and the sultam moiety were retained. All compounds were tested in vitro for their inhibition activity against the human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, VII, IX and XII isoforms. Among the series, derivatives 1 and 11 showed great enhancement of both inhibition potency and selectivity towards the hCA VII isoform, when compared to the reference SLT drug. The binding mode of 11 within the hCA VII active site was deciphered by means of X-ray crystallography and revealed the sultam moiety being exposed to the rim of the active site. In vivo experiments on a model of neuropathic pain induced by oxaliplatin clearly showed 11 being an effective pain relieving agent and therefore worth of further exploitation towards the validation of the hCA VII as new target for the management of neuropathies., 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.)

Hepatitis C Virus (HCV) is a viral infection posing a severe global threat that left untreated progresses to end-stage liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Moreover, no prophylactic approach exists so far enabling its prevention. The NS5B polymerase holds special significance as the target of intervention against HCV infection. The current study kindles benzothiazine derivatives against HCV NS5B polymerase through in silico and experimental approaches. Following docking, the compound 2-(3,4-dimethyl-5,5-dioxidobenzo[e]pyrazolo[4,3-c][1,2]thiazin-2(4H)-yl)-N-(2-fluorobenzyl)acetamide was revealed to form effective binding interaction in the proposed site of HCV NS5B with a score of -10 kcal/mol and subsequently was deciphered through molecular dynamics (MD) simulation study which indicated interaction of residues TYR&#95;382, VAL&#95;381 and HIS&#95;467 through hydrophobic interaction and two residues such as GLU&#95;202 and LYS&#95;209 contributed in the formation of water bridges. The subsequent in silico pharmacological analysis revealed its safe drug profile. The cytotoxicity activity of compound 6c indicated to be non-toxic in HepG2 cells at concentration ranges from 0.001-1.0 µmol/L with >80% cell viability and diminished expression of the HCV NS5B to 98% at the dose of 1.0 µmol/L and 90% at 0.5µmol/L. Thus the hit compound 6c might be a potent NS5B polymerase inhibitor required to be validated further through in vivo and preclinical studies., (© 2021 John Wiley & Sons Australia, Ltd.)

Heat shock proteins HSPA1/Hsp70α and HSP90AA1/Hsp90α are crucial for cancer growth but their expression pattern in colorectal polyps or whether they can be modulated by oxicams is unknown. We quantified (RTqPCR) HSPA1 and HSP90AA1 expression in 50 polyp-normal pairs in relation to polyp malignancy potential and examined the effect of piroxicam, meloxicam and five novel analogues on HSPA1 and HSP90AA1 expression (mRNA/protein) in colorectal adenocarcinoma lines. HSPA1 and HSP90AA1 were upregulated in polyps by 3- and 2.9-fold. Expression ratios were higher in polyps with higher dysplasia grade and dominant villous growth pattern, mostly a result of diminished gene expression in normal tissue. Classic oxicams had negligible/non-significant effect on HSP expression. Their most effective analogue inhibited HSPA1 protein and gene by 2.5-fold and 5.7-fold in Caco-2 and by 11.5-fold and 6.8-fold in HCT116 and HSPA1 protein in HT-29 by 1.9-fold. It downregulated HSP90AA1 protein and gene by 1.9-fold and 3.7-fold in Caco-2 and by 2-fold and 5.0-fold in HCT116. HSPA1 and HSP90AA1 are upregulated in colorectal polyps reflecting their potential for malignancy. HSPA1 in cancer cells and, to lesser degree, HSP90AA1 can be reduced by oxicam analogues with thiazine ring substituted via propylene linker by arylpiperazine pharmacophore with fluorine substituents and by benzoyl moiety.

We prepared a series of free NH and N-substituted dibenzonthiazines with potential anti-tumor activity from N-aryl-benzenesulfonamides. A biological test of synthesized compounds (59 samples) was performed in vitro measuring their antiproliferative activity against a panel of six human solid tumor cell lines and its tubulin inhibitory activity. We identified 6-(phenylsulfonyl)-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide and 6-tosyl-6H-dibenzo[c,e][1,2]thiazine 5,5-dioxide as the best compounds with promising values of activity (overall range of 2-5.4 μM). Herein, we report the dibenzothiazine core as a novel building block with antiproliferative activity, targeting tubulin dynamics., (© 2021 Wiley-VCH GmbH.)

Intrinsically disordered proteins (IDPs) are emerging as attractive drug targets by virtue of their physiological ubiquity and their prevalence in various diseases, including cancer. NUPR1 is an IDP that localizes throughout the whole cell, and is involved in the development and progression of several tumors. We have previously repurposed trifluoperazine (TFP) as a drug targeting NUPR1 and, by using a ligand-based approach, designed the drug ZZW-115 starting from the TFP scaffold. Such derivative compound hinders the development of pancreatic ductal adenocarcinoma (PDAC) in mice, by hampering nuclear translocation of NUPR1. Aiming to further improve the activity of ZZW-115, here we have used an indirect drug design approach to modify its chemical features, by changing the substituent attached to the piperazine ring. As a result, we have synthesized a series of compounds based on the same chemical scaffold. Isothermal titration calorimetry (ITC) showed that, with the exception of the compound preserving the same chemical moiety at the end of the alkyl chain as ZZW-115, an increase of the length by a single methylene group (i.e., ethyl to propyl) significantly decreased the affinity towards NUPR1 measured in vitro, whereas maintaining the same length of the alkyl chain and adding heterocycles favored the binding affinity. However, small improvements of the compound affinity towards NUPR1, as measured by ITC, did not result in a corresponding improvement in their inhibitory properties and in cellulo functions, as proved by measuring three different biological effects: hindrance of the nuclear translocation of the protein, sensitization of cells against DNA damage mediated by NUPR1, and prevention of cancer cell growth. Our findings suggest that a delicate compromise between favoring ligand affinity and controlling protein function may be required to successfully design drugs against NUPR1, and likely other IDPs.

This study investigates the combination of two waves emitted from a single-piezoelectric crystal by use of a dual-frequency generator in a sonochemical reactor. The dual-frequency configurations analyzed were the double-modulated fundamental frequency (376-376 kHz), resonant and second harmonic, termed 376D, 376R and 376H respectively. The effect of the phase shift (Φ) and the percentage of modulation between added waves were described by the total acoustic power distribution (P t ) measured inside the sonoreactor. Moreover, optimal angle alignment and modulation between dual-frequency waves for 376D, 376R and 376H cases were selected in order to evaluate the ultrasonic synergy by sonochemical reactivity in production of H 2 O 2 , in degradation rate of a model emerging pollutant ACE, and in the TOC and biodegradability evolution in the treated effluent. Phase shift and percentage of modulation had strong effect on the resulted waveform and on the sonochemical efficiency for all, harmonic and non-harmonic, dual-frequency combinations created. In the 376D case, the best reinforcement conditions are founded at 0° and 360°. In the 376H the maximum power distribution presents a 90° period. Shift phase does not determines any cyclic pattern in the total power distribution for the 376R case. The highest H 2 O 2 production rate was observed for the 376H case followed for 376D and 376R configurations with 1.61, 1.12 and 0.58 μM/min by angle alignment in 105, 0 and 110° respectively. The highest initial degradation rate of ACE was observed for the 376D case followed for 376H and 376R with 0.56, 0.42 and 0.33 μM/min at 100% modulation. Reduced mineralization was observed in all dual-frequency configurations (8.54% for 376D and approximately 4.5% for 376R and 3756H modes). Contrasting results are observed regard to biodegradability ratio following the next sequence 376D < 376H≈376R with 0.9, 2.30 and 2.33 respectively. Relevant intensification in hydroxyl radicals production is observed by the UV-US system increasing up three folds the ACE removal and mineralization and two folds higher biodegradability of effluent in particular for 376R and 376H cases at optimal operation condition of dual-frequency signal., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this paper, we report an efficient one-pot three-component reaction sequences comprising Cu(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC) followed by Cu-catalyzed arylation of resulting 1,2,3-triazole in the presence of ionic liquid [Emim]BF 4 under microwave conditions involving. The newly synthesized derivatives were screened for in vitro antibacterial inhibition potency against both gram +ve and gram -ve strains. Among the tested compounds, 4f exhibited significant inhibition activity with MIC value 3.12 µg/mL against B. subtilis and S. epidermidis which is two-fold higher than the standard ciprofloxacin (6.25 µg/mL) and also displayed equipotent activity to that of the positive control against S. aureus with MIC value 6.25 µg/mL. Conjugates of the series viz. 3f and 4b against S. aureus, and 4e against E. coli have also displayed promising results with MIC values 6.25 µg/mL which is comparable to the ciprofloxacin. Also we report the anti-biofilm profiles for the potent compounds and it was observed from the results that the active derivatives 4b and 4f were not only potent antibacterial agents but also efficient inhibitors of B. subtilis and S. aureus biofilm growth. Furthermore, in silico-ADME and pharmacokinetic profiles demonstrated the druggability of the hybrids., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In recent years, the hydrophobic active substances have led researchers to develop new formulations to enhance bioavailability and dissolution rate; brinzolamide, a lipophilic drug belongs to carbonic anhydrase inhibitors, which cause reduction of intraocular pressure in patients suffering from glaucoma. Currently, the marketed product of brinzolamide is in the form of ocular drops; nonetheless, the conventional drops provide decreased therapeutic efficacy owing to their low bioavailability and pulsed drug release. Thus, the development of novel ocular formulations such as topical microemulsions is of high importance. In this work, the preparation of new microemulsions containing brinzolamide (0.2, 0.5 and 1% w/w) and comprised from isopropyl myristate, tween 80 and span 20 and Cremophor EL was performed. The obtained microemulsions were further characterized for their physicochemical properties. In addition, Fourier Transformed-Infrared spectroscopy was used touate the compatibility of active ingredients and components. In vitro release studies along with kinetic modeling were performed using the dialysis membrane method in simulated tear fluid. Bioadhesion studies were performed using Texture analysis. Finally, in vitro ocular irritation based on EpiOcular™ Eye Irritation Test and cytocompatibility studies was performed to examine any possible harm on ocular cells and predict in vivo safety profile.

Plasma proteins play a fundamental role in living organisms. They participate in the transport of endogenous and exogenous substances, especially drugs. 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts, have been synthesized as potential anticancer substances used for cancer treatment. Most anticancer substances generate a toxic effect on the human body. In order to check the toxicity and therapeutic dosage of these chemicals, the study of ligand binding to plasma proteins is very relevant. The present work presents the first comparative analysis of the binding of one of the 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium derivatives (Salt1) with human serum albumin (HSA), α-1-acid glycoprotein (AGP) and human gamma globulin (HGG), assessed using fluorescence, UV-Vis and CD spectroscopy. In order to mimic in vivo ligand-protein binding, control normal serum (CNS) was used. Based on the obtained data, the Salt1 binding sites in the tertiary structure of all plasma proteins and control normal serum were identified. Both the association constants (K a ) and the number of binding site classes ( n ) were calculated using the Klotz method. The strongest complex formed was Salt1-AGP complex (K a = 7.35·10 4 and 7.86·10 4 mol·L -1 at excitation wavelengths λ ex of 275 and 295 nm, respectively). Lower values were obtained for Salt1-HSA complex (K a = 2.45·10 4 and 2.71·10 4 mol·L -1 ) and Salt1-HGG complex (K a = 1.41·10 4 and 1.33·10 4 mol·L -1 ) at excitation wavelengths λ ex of 275 and 295 nm, respectively, which is a positive phenomenon and contributes to the prolonged action of the drug. Salt1 probably binds to the HSA molecule in Sudlow sites I and II; for the remaining plasma proteins studied, only one binding site was observed. Moreover, using circular dichroism (CD), fluorescence and UV-Vis spectroscopy, no effect on the secondary and tertiary structures of proteins in the absence or presence of Salt1 has been demonstrated. Despite the fact that the conducted studies are basic, from the scientific point of view they are novel and encourage further in vitro and in vivo investigations. As a next part of the study (Part 2), the second new synthetized quinobenzothiazine derivative (Salt2) will be analyzed and published.

Triple negative breast cancer (TNBC) remains challenging because of heterogeneous responses to chemotherapy. Incomplete response is associated with a greater risk of metastatic progression. Therefore, treatments that target chemotherapy-resistant TNBC and enhance chemosensitivity would improve outcomes for these high-risk patients. Breast cancer stem cell-like cells (BCSCs) have been proposed to represent a chemotherapy-resistant subpopulation responsible for tumor initiation, progression and metastases. Targeting this population could lead to improved TNBC disease control. Here, we describe a novel multi-kinase inhibitor, 108600, that targets the TNBC BCSC population. 108600 treatment suppresses growth, colony and mammosphere forming capacity of BCSCs and induces G2M arrest and apoptosis of TNBC cells. In vivo, 108600 treatment of mice bearing triple negative tumors results in the induction of apoptosis and overcomes chemotherapy resistance. Finally, treatment with 108600 and chemotherapy suppresses growth of pre-established TNBC metastases, providing additional support for the clinical translation of this agent to clinical trials., (© 2021. The Author(s).)

New, tricyclic compounds containing a sulfonyl moiety in their structure, as potential safer COX inhibitors, were designed and synthesized. New derivatives have three conjugated rings and a sulfonyl group. A third ring, i.e., an oxazine, oxazepine or oxazocin, has been added to the 1,2-benzothiazine skeleton. Their anti-COX-1/COX-2 and cytotoxic effects in vitro on NHDF cells, together with the ability to interact with model membranes and the influence on reactive oxygen species and nitric oxide, were studied. Additionally, a molecular docking study was performed to understand the binding interaction of the compounds with the active site of cyclooxygenases. For the abovementioned biological evaluation of new tricyclic 1,2-benzothiazine derivatives, the following techniques and procedures were employed: the differential scanning calorimetry, the COX colorimetric inhibitor screening assay, the MTT, DCF-DA and Griess assays. All of the compounds studied demonstrated preferential inhibition of COX-2 compared to COX-1. Moreover, all the examined tricyclic 1,2-thiazine derivatives interacted with the phospholipid model membranes. Finally, they neither have cytotoxic potency, nor demonstrate significant influence on the level of reactive oxygen species or nitric oxide. Overall, the tricyclic 1,2-thiazine derivatives are good starting points for future pharmacological tests as a group of new anti-inflammatory agents.

Thiazine formation during the conjugation of N-terminal cysteine peptides to maleimides is an underreported side reaction in the peptide literature. When the conjugation was performed at neutral and basic pH, we observed the thiazine isomer as a significant by-product. Nuclear magnetic resonance (NMR) spectroscopy confirmed the structure of the six-membered thiazine and ultra-high performance liquid chromatography (UHPLC) combined with tandem mass spectrometry (MS/MS) allowed for facile, unambiguous detection due to a unique thiazine mass fragment. Furthermore, substitution of various amino acids adjacent to the N-terminal cysteine in a tripeptide model system resulted in different rates of thiazine formation, albeit within the same order of magnitude. We also determined that varying the N-substitution of the maleimide affects the thiazine conversion rate. Altogether, our findings suggest that thiazine rearrangement for N-terminal cysteine-maleimide adducts is a general side reaction that is applicable to other peptide or protein systems. Performing the conjugation reaction under acidic conditions or avoiding the use of an N-terminal cysteine with a free amino group prevents the formation of the thiazine impurity., (© 2021 Bachem Americas,Inc. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

Calixarenes, which have a great place in supramolecular chemistry, have become the most prominent macrocyclic compounds in synthetic organic chemistry due to their easy synthesis and functionalization. In this study, p-tert-butyl calix[4]arene dihydrazide derivative was synthesized and then reacted with 3-oxo-3,4-dihydro-2 H-benzo[b][1,4] thiazin-2-ylideneacetyl chloride to prepare new calixarene based chromophore compound 4. The structure of the synthesized compound was elucidated by spectroscopic methods such as 1 H NMR 13 C NMR and FT-IR spectroscopy. Chromogenic and fluorescence properties of compound 4 were evaluated. It was observed from both studies that compound 4 was Co 2+ selective and shows fluorescence Switched-off behavior. Stoichiometry, binding constant and the detection limit were calculated. The stoichiometry between compound 4 and Co 2+ was found to be 1:1. The binding constant value (K) was calculated as 666.67 M - 1 using Benesi-Hildebrand equation, while the detection limit for Co 2+ ion was calculated as 0.0465 µM.

A series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in our lab, were designed and synthesized as new anti-TB agents. Many of the compounds exhibited excellent in vitro activity against both drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates (MIC: < 0.016 μg/mL), and good safety index (CC 50 : >64 μg/mL). Especially compound 1o displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its promising potential to be a lead compound for future antitubercular drug discovery., 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.)

Diabetes mellitus (DM) is a chronic disorder and has affected a large number of people worldwide. Insufficient insulin production causes an increase in blood glucose level that results in DM. To lower the blood glucose level, various drugs are employed that block the activity of the α-glucosidase enzyme, which&nbsp;is considered responsible for the breakdown of polysaccharides into monosaccharides leading to an increase in the intestinal blood glucose level. We have synthesized novel 2-(3-(benzoyl/4-bromobenzoyl)-4-hydroxy-1,1-dioxido-2 H -benzo[ e ][1,2]thiazin-2-yl)- N -arylacetamides and have screened them for their in silico and in vitro α-glucosidase inhibition activity. The derivatives 11c , 12a , 12d , 12e , and 12g emerged as potent inhibitors of the α-glucosidase enzyme. These compounds exhibited good docking scores and excellent binding interactions with the selected residues (Asp203, Asp542, Asp327, His600, Arg526) during in silico screening. Similarly, these compounds also showed good in vitro α-glucosidase inhibitions with IC 50 values of 30.65, 18.25, 20.76, 35.14, and 24.24 μM, respectively, which were better than the standard drug, acarbose (IC 50 = 58.8 μM). Furthermore, a good agreement was observed between in silico and in vitro modes of study.

In this article, we showed the synthesis of new polycyclic aromatic compounds, such as thienotriazolopyrimidinones, N -(thienotriazolopyrimidine) acetamide, 2-mercapto-thienotriazolo-pyrimidinones, 2-(((thieno-triazolopyrimidine) methyl) thio) thieno-triazolopyrimidines, thieno-pyrimidotriazolo-thiazines, pyrrolo-triazolo-thienopyrimidines, thienopyrimido-triazolopyrrolo-quinoxalines, thienopyrimido-triazolo-pyrrolo-oxathiino-quinoxalinones, 1,4-oxathiino-pyrrolo- triazolothienopyrimidinones, imidazopyrrolotriazolothienopyrimidines and 1,2,4-triazoloimidazo- pyrrolotriazolothienopyrimidindiones, based on the starting material 2,3-diamino-6-benzoyl-5- methylthieno[2,3-d]pyrimidin-4(3 H )-one ( 3 ). The chemical structures were confirmed using many spectroscopic ways (IR, 1 H, 13 C, -NMR and MS) and elemental analyses. A series of thiazine, imidazole, pyrrole, thienotriazolopyrimidine derivatives were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines, i.e., CNE2 (nasopharyngeal), KB (oral), MCF-7 (breast) and MGC-803 (gastric) carcinoma cells. The compounds 20 , 19 , 17 , 16 and 11 showed significant cytotoxicity against types of human cancer cell lines.

Sulthiame is an old antiepileptic medicine with controversial history, whose effectiveness and safety in use have been stated in some current studies. However, there is still a need for further clinical examinations for confirmation of its usefulness and tolerability in monotherapy and add-on therapy for epilepsy of various etiologies. A fully validated RP HPLC-UV method for determination of sulthiame in serum/plasma samples using desethylatrazine as the internal standard was developed. The biological fluid was prepared for analysis by a simple precipitation method with acetonitrile. The following validation parameters of the method were determined: selectivity/specificity, linearity range (0.2-50.0 μl/ml, R 2  > 0.9999), limits of detection (0.19 μl/ml) and quantification (0.58 μl/ml), precision (intra-day CV 1.06% and inter-day CV 1.25%), extraction recovery (~100%), accuracy (bias, -4.61-0.80%), carryover and ruggedness. Moreover, the stability of the medicine in plasma samples under different storage conditions was also tested. The usability of the method for clinical examinations was checked by analysis of serum samples originating from 19 patients treated with sulthiame. The proposed method is appropriate for determination of sulthiame in serum/plasma samples for drug monitoring purposes, as well as for pharmacokinetic studies., (© 2020 John Wiley & Sons, Ltd.)

An impurity in the color additives D&C Red No. 30 (R30) and D&C Red No. 30 lakes (R30L) was newly identified and characterized as 7-chloro-5-methyl-2H-1,4-benzothiazin-3(4H)-one (BTZ), and its extent and level in certified batches of these color additives was determined. BTZ was extracted from the dye with ethanol, resulting in a crude extract enriched to a concentration of over 60%. BTZ was then separated from a portion of the enriched extract by high-speed counter-current chromatography using a spiral-tube assembly column with intermittently pressed tubing of 60 ml capacity. It was the first reported use of such a column to separate a small, moderately hydrophobic compound. The two-phase solvent system was also moderately hydrophobic, consisting of hexane-ethyl acetate-methanol-water (5:2:5:2), and the retention of the organic stationary phase measured after the separation was 83.3%. The separation yielded BTZ of two purity grades, the higher of which (~95.5%) was used as a standard to quantify the impurity in 37 batches of R30 and R30L using an HPLC method developed and validated for that purpose. Analyses revealed a wide range of BTZ levels across batches, <0.05 - 0.84%, and suggested that BTZ contamination could be reduced by appropriate adjustments in the manufacturing process. An explanation of the likely source of BTZ - as a side-reaction product in a particular step of the manufacturing process - was also presented., 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., (Published by Elsevier B.V.)

The adaptor protein STING plays a major role in innate immune sensing of cytosolic nucleic acids, by triggering a robust interferon response. Despite the importance of this protein as a potential therapeutic target for serious unmet medical conditions including cancer and infectious disease there remains a paucity of STING ligands. Starting with a benzothiazinone series of weak STING activators (human EC 50 ∼10 μM) we identified several chemotypes with sub-micromolar STING activity across all the major protein polymorphs. An example compound 53 based on an oxindole core structure demonstrated robust on-target functional activation of STING (human EC 50 185 nM) in immortalised and primary cells and a cytokine induction fingerprint consistent with STING activation. Our study has identified several related series of potent small molecule human STING activators with potential to be developed as immunomodulatory therapeutics., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors are employees of Curadev Pharma., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Novel arylpiperazine-1,2-benzothiazine derivatives have been designed and synthesized as potential anti-inflammatory agents. Their structure and properties have been studied using spectroscopic techniques ( 1 H NMR, 13 C NMR, FT-IR), MS, elemental analyses, and single-crystal X-ray diffraction (SCXRD, for compound 7b). This study aimed to evaluate the inhibitory activity of new derivatives against both cyclooxygenase isoforms COX-1 and COX-2 due to the similarity of new compounds to oxicams drugs from the NSAIDs group. All new compounds were divided into two series - A and B - with a different linker between thiazine and piperazines nitrogens. Series A included the three-carbon aliphatic linker and series B - two-carbon with a carbonyl group. According to in vitro and molecular docking studies all new compounds exhibited cyclooxygenase inhibitory activity. The series of A compounds included COX-1 inhibitors only. In contrast, the B series showed inhibition of both COX-1 and COX-2, which suggested the importance of the acetoxy linker for COX-2 inhibition. Moreover, the most selective compound 7b, towards COX-2, was non-toxic for the normal human cell line (in concentration of 10 µM) comparable to reference drug meloxicam. Additionally, investigation of influence on model membranes confirmed the ability of the compound 7b to penetrate lipid bilayers which seemed to be important to the influence with membrane protein-cyclooxygenase., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Carbonic anhydrase (CA, EC 4.2.1.1) is an enzyme and a very omnipresent zinc metalloenzyme which catalyzed the reversible hydration and dehydration of carbon dioxide and bicarbonate; a reaction which plays a crucial role in many physiological and pathological processes. Carbonic anhydrase is present in human (h) with sixteen different isoforms ranging from hCA I-hCA XV. All these isoforms are widely distributed in different tissues/organs and are associated with a range of pivotal physiological activities. Due to their involvement in various physiological roles, inhibitors of different human isoforms of carbonic anhydrase have found clinical applications for the treatment of various diseases including glaucoma, retinopathy, hemolytic anemia, epilepsy, obesity, and cancer. However, clinically used inhibitors of CA (acetazolamide, brinzolamide, dorzolamide, etc.) are not selective causing the undesirable side effects. One of the major hurdles in the design and development of carbonic anhydrase inhibitors is the lack of balanced isoform selectivity which thrived to new chemotypes. In this review, we have compiled the recent strategies of various researchers related to the development of carbonic anhydrase inhibitors belonging to different structural classes like pyrimidine, pyrazoline, selenourea, isatin, indole, etc. This review also summarizes the structure-activity relationships, analysis of isoform selectivity including mechanistic and in silico studies to afford ideas and to provide focused direction for the design and development of novel isoform-selective carbonic anhydrase inhibitors with therapeutic implications., 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 Masson SAS. All rights reserved.)

The present study describes the synthesis of a novel series of thiazolidin-4-one and thiazinan-4-one using 1-(2-aminoethyl)pyrrolidine as amine precursor. All compounds were synthesised by one-pot three component cyclocondensation reaction from the amine, a substituted benzaldehyde and a mercaptocarboxylic acid. The compounds were obtained in moderate to good yields and were identified and characterised by 1 H, 13  C, 2 D NMR and GC/MS techniques. The compounds also were screened for their in vitro acetylcholinesterase (AChE) activity in hippocampus and cerebral cortex on Wistar rats. The six most potent compounds have been investigated for their cytotoxicity by cell viability assay of astrocyte primary culture, an important cell of central nervous system. We highlighted two compounds ( 6a and 6k ) that had the lowest IC 50 in hippocampus (5.20 and 4.46 µM) and cerebral cortex (7.40 and 6.83 µM). These preliminary and important results could be considered a starting point for the development of new AChE inhibitory agents.

Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4 . The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases.

Thiazinanes and its isomeric forms represent one of the most important heterocyclic compounds, and their derivatives represented a highly potent drug in disease treatment such as, 1,1-dioxido-1,2-thiazinan-1,6-naphthyridine, which has been shown to have anti-HIV activity by a mechanism that should work as anti-AIDS treatment, while ( Z )-methyl 3-(naphthalen-1-ylimino)- 2-thia-4-azaspiro[5 5]undecane-4-carbodithioate showed analgesic activity, cephradine was used as antibiotic and chlormezanone was utilized as anticoagulants. All publications were interested in the chemistry of thiazine (partially or fully unsaturated heterocyclic six-membered ring containing nitrogen and sulfur), but no one was dealing with thiazinane itself which encouraged us to shed new light on these interesting heterocycles. This review was focused on the synthetic approaches of thiazinane derivatives and their chemical reactivity.

Background: Trunk-boring pests (TBPs) are an important type of forest pest, TBPs not only feed on the branches and trunks of trees, but also spread quarantine diseases in forests. However, because the larvae of TBPs live inside the trunk and are well concealed, prevention and control are difficult. The lack of effective control methods leads to the death of many trees in forests. In this study, a novel nanopesticide featuring high bioactivity and slow-release properties was developed to control TBPs. Thiacloprid (THI), which is commonly used to control Coleoptera species, was used as a model pesticide., Results: The oleophobic properties of bovine serum albumin (BSA) were exploited to encapsulate the hydrophobic pesticide THI by self-assembly, and the size of the obtained nanoparticles, THI@BSA·NPs, was approximately 23 nm. The loading efficiency reached 70.4%, and THI@BSA·NPs could be released continuously for over 15 days, with the cumulative release reaching 93.5%. The fluorescein isothiocyanate (FITC)-labeled nanoparticles were evenly distributed in the digestive tract and body surface of a typical TBPs, M. alternatus, and the stomach and contact toxicities increased by 33.7% and 25.9%, respectively, compared with those of free THI. Furthermore, the results showed that the transport efficiency of THI@BSA·NPs was highest at a concentration of 50 μg/mL, and the THI@BSA·NPs content in the trunk, from to lower to higher layers, was 8.8, 8.2, 7.6, and 5.8 μg/g. At the same time, THI@BSA·NPs also exhibited high transport efficiency in dead trees., Conclusion: The transport efficiency and toxicity of the active ingredients are the key factors for the control of TBPs. This work provided idea for the application of biological delivery system encapsulated hydrophobic pesticides. The novel self-assembled THI@BSA·NPs have promising potential for sustainable control of TBPs.

A general regioselective one-pot synthesis of 1,2-benzothiazine 1,1-dioxides from 2-iodo benzenesulfonamide moieties and allenylstannanes is described using a domino Stille-like/Azacyclization reaction. The conditions developed also opened a novel access to β-carbolinones, indolopyranones, thienopyranones and pyrano-imidazopyridines.

A piperazine-containing benzothiazinones lead compound PBTZ169, served as DprE1 inhibitor, displays nanomolar bactericidal activity against Mycobacteria tuberculosis. Here, we systematically evaluate anti-tuberculosis activity of one of PBTZ169 analogues, TZY-5-84, in vitro and in vivo. The MIC value of TZY-5-84 against M. tuberculosis H37Rv ranged from 0.014 to 0.015 mg/L, lower than those of INH, RFP and BDQ. Five susceptible and thirteen drug-resistant clinical isolates were also susceptive to TZY-5-84. It had anti-tuberculosis activity against intracellular bacilli in infected macrophage model. It exhibited its activity in time-dependent manner and against intracellular bacilli in infected macrophage cells. However, the MIC of TZY-5-84 against three laboratory PBTZ169-induced resistant isolates increased four-fold increment compared to that of H37Rv. No antagonism was observed in any combination between TZY-5-84 and seven commonly used anti-tuberculosis drugs in an in vitro checkerboard assay. In murine infection model, TZY-5-84 at lower dosage (12.5 mg/kg) was found to be comparatively efficacious as PBTZ169 at 25 mg/kg. Our research suggests TZY-5-84 can be a promising preclinical candidate for further study on TB treatment., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A series of novel benzothiazinone derivatives containing a N-((methylene)amino)piperazine moiety, inspired by rifampicin/rifapentine, were designed and synthesized. Seven compounds 1a and 1e-j show excellent in vitro activity against both drug-sensitive MTB strain H37Rv and drug-resistant clinical isolates (MIC: <0.029-0.110 μM), and accepted selective index (>1100->4000). Compound 1h displays good safety and pharmacokinetic profiles, suggesting its promising potential to be lead compound for future antitubercular drug discovery., 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.)

Drug particle size distribution (PSD) and dispersion viscosity are two critical quality attributes that govern the performance of topical ophthalmic suspensions, such as suspension physical stability, ocular retention, and drug release characteristics.. An in-depth knowledge of the effects of formulation and manufacturing process on these critical quality attributes may facilitate the product and process development, quality control, as well as support regulatory policy and approval. The current study has investigated the effect of formulation and process parameters on the quality attributes of brinzolamide ophthalmic suspensions. In the first step, three milling techniques (probe sonication, microfluidization, and media milling with a planetary centrifugal mixer) were evaluated for manufacturing of brinzolamide suspension. Out of the three techniques, the planetary centrifugal media milling yielded the narrowest PSD and thus was considered the most viable lab-scale technique for this purpose. In the next step, various process parameters of media milling were evaluated using a central-composite experimental design. The independent variables included bead size, agitating intensity, and process time while the PSD of drug particles (D 50 ) was the response variable. The effect of shear rate and shear time of the homogenization process and the concentration of carbomer on the rheological properties of the suspension were studied using a Box-Behnken design. Additionally, effects of sodium chloride and mannitol concentration on the rheological properties of the suspension was also investigated. Sodium chloride was found to exert a pronounced effect on rheology of the suspension. Despite variations in the carbomer concentration, a suspension of comparable rheology could be prepared by controlling the process parameters namely the shear rate and process time., 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., (Published by Elsevier B.V.)

A series of new benzothiazinone derivatives containing a symmetric 2-benzyl-2,7-diazaspiro[3.5]nonane moiety, based on the structure of LK02 discovered in our lab, were designed and synthesized. With one exception 3, all of them show excellent in vitro activity against both drug-sensitive and clinically isolated multidrug-resistant Mycobacterium tuberculosis (MTB) strains (MIC: < 0.016 μg/mL). Compound 2d with a methyl group at the benzylic carbon, was identified to have good safety and significant efficacy in an acute mouse model of TB, as well as better PK profiles than PBTZ169., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

In this work, the binding interaction of an artificial sweetener, acesulfame (ACS) with human serum albumin (HSA) are investigated at the molecular level by using spectral methods and molecular modeling. ACS has the ability to induce static quenching of the intrinsic fluorescence of HSA by a complex formed between HSA and ACS through weak multi-noncovalent forces including hydrophobic, hydrogen bond and van der Waals forces. ACS enters subdomain IIA of HSA to induce the tertiary structure changes of HSA and decreased the hydrophobicity of protein. In addition, ACS binding does not obviously alter the secondary structure of HSA. This study is hoped to provide some crucial information for further investigations of the biosafety of sweetener., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in the manuscript entitled “Comprehensive investigations about the binding interaction of acesulfame with human serum albumin”., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The global concern related with growing number of bacterial pathogens, resistant to numerous antibiotics, prone scientific environment to search for new antimicrobials. Antiseptics appear to be suitable candidates as adjunctive agents to antibiotics or alternative local treatment option aiming to prevent and treat infections. 1,2-benzothiazines are considered one the most promising of them. In this research twenty 1,2-benzothiazine 1,1-dioxide derivatives were scrutinized with regard to their biological activity. Three of them are new. For evaluation of compounds' activity against microbial pathogens, disk diffusion method and serial microdilution method was applied. To establish the cytotoxicity profile of tested 1,2-benzothiazines 1,1-dioxides derivatives, the cytotoxicity assay using fibroblasts L292 was performed. Antimicrobial activity of all tested compounds against Gram-positive Staphylococcus aureus and Enterococcus faecalis strains was higher than antimicrobial activity of DMSO solvent, which possesses antimicrobial activity itself. Gram-negative P. aeruginosa , E. coli and K. pneumoniae have shown susceptibility only to compounds 3e , 7i and 7l . None of tested compounds was effective against C. albicans. Compound 6g has demonstrated the strongest antimicrobial potency (MIC = 0.00975 mg/mL) among compounds of series 6 . Compounds of series 7 , namely 7d , 7f , 7g had the lowest minimum inhibitory concentration (MIC). Compound 7f displayed also the lowest cytotoxic effect against fibroblast cell line among series 7 compounds. All tested derivatives displayed lower MIC against Gram-positive bacteria than commercially applied antiseptic, povidone iodine, which MIC value range for tested Gram-positive bacteria was 1.56-6.25 mg/mL.

The inverse correlation observed between Alzheimer's disease (AD) and cancer has prompted us to look for cholinesterase-inhibiting activity in phenothiazine derivatives that possess anticancer properties. With the use of in silico and in vitro screening methods, our study found a new biological activity in anticancer polycyclic, tricyclic, and tetracyclic compounds. The virtual screening of a library of 120 ligands, which are the derivatives of azaphenothiazine, led to the identification of 25 compounds that can act as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Biological assays revealed the presence of selective inhibitors of ee AChE ( electric eel AChE) or eq BuChE ( equine serum BuChE) and nonselective inhibitors of both enzymes among the tested compounds. Their potencies against ee AChE were in a submicromolar-to-micromolar range with IC 50 values from 0.78 to 19.32 μM, while their IC 50 values against eq BuChE ranged from 0.46 to 10.38 μM. The most potent among the compounds tested was the tetracyclic derivative, 6-(4-diethylaminobut-2-ynyl)-9-methylthioquinobenzothiazine 24 , which was capable of inhibiting both enzymes. 9-Fluoro-6-(1-piperidylethyl)quinobenzothiazine 23 was found to act as a selective inhibitor of eq BuChE with an IC 50 value of 0.46 μM. Compounds with such a dual antitumor and cholinesterase-inhibitory activity can be considered as a valuable combination for the treatment of both cancer and AD prevention. The results presented in this study might open new directions of research on the group of tricyclic phenothiazine derivatives.

Aim: Brinzolamide (BNZ) is a carbonic anhydrase inhibitor commonly used for the treatment of glaucoma. The aim of this study was to prepare BNZ loaded chitosan-pectin mucoadhesive nanocapsules (CPNCs) by polyelectrolyte complex coacervation method for ocular delivery and evaluated for its anti glaucoma efficacy., Methods: The prepared CPNCs were characterized for their particle size, polydispersity index, zeta-potential, surface morphology, entrapment efficiency, drug loading efficiency, mucoadhesive strength in-vitro and ex-vivo release. The pharmacodynamic studies were conducted for CPNCs on glaucoma induced rabbit eye model and compared with marketed product., Result and Discussion: All the formulated CPNCs exhibited the size range from 217.01 ± 0.21 to 240.05 ± 0.08 nm and appropriate physico-chemical parameters, and depicted a couple of erosion- diffusion release of BNZ over a time of 8 h. Ex-vivo corneal permeation study concluded that BNZ loaded CPNCs crosses the cornea potentially higher rate as compared to the marketed product. In pharmacodynamic study, greater intraocular pressure lowering effect was achieved by CPNCs as compared to marketed drug product., Conclusion: The result concluded that CPNCs are a feasible choice to conventional eye drops because of its ability to improve the bioavailability via its longer precorneal retention time and its ability to sustained release of the drug., Competing Interests: Financial & competing interest disclosure Financial support grand was received from the AICTE, New Delhi, India in the respect of Fellowship for PG programme. The authors report no conflicts of interest. The authors alone are responsible for writing content of this article., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A series of 1,3-benzothiazinone derivatives were designed and synthesized for pharmacological assessments. Among the synthesized 19 compounds, some compounds showed high activities on inhibiting LPS-induced nitrite oxide and TNF-α production, down-regulating COX-2 and increasing IL-10 production in RAW264.7 cells. All the compounds had no obvious cytotoxicity in in vitro assay. LD 50 value of compound 25 was greater than 2000 mg/kg, which was safer than meloxicam. Compound 25 significantly inhibited phosphorylation of NF-κB and STAT3 in LPS-induced RAW264.7 cells. Inhibition of synthesized compounds on COX activity was weaker than meloxicam. Compound 25 displayed lower gastrointestinal toxicity than meloxicam. Besides, compound 25 decreased the swelling in carrageenan-induced paw edema models of inflammation and reduced PGE 2 level significantly. In summary, 1,3-benzothiazinone derivatives are unique scaffolds with anti-inflammatory activity and low toxicity., Competing Interests: Declaration of Competing Interest The authors confirm that this article content has no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)