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COVID-19 infection is associated with a variety of vascular occlusive morbidities. However, a comprehensive understanding of how this virus can induce vascular complications remains lacking. Here, we show that a peptide fragment of SARS-CoV-2 spike protein, S192 (sequence 192-211), is capable of forming amyloid-like aggregates that can induce agglutination of red blood cells, which was not observed with low- and non-aggregated S192 peptide. We subsequently screened eight amyloid-binding molecules and identified BAM1-EG6, a benzothiazole amphiphile, as a promising candidate capable of binding to aggregated S192 and partially inhibiting its agglutination activity. These results provide new insight into a potential molecular mechanism for the capability of spike protein metabolites to contribute to COVID-19-related blood complications and suggest a new therapeutic approach for combating microvascular morbidities in COVID-19 patients.

PURPOSE: To investigate the impact of reduced injected doses on the quantitative and qualitative assessment of the amyloid PET tracers [18F]flutemetamol and [18F]florbetaben. METHODS: Cognitively impaired and unimpaired individuals (N = 250, 36% Aβ-positive) were included and injected with [18F]flutemetamol (N = 175) or [18F]florbetaben (N = 75). PET scans were acquired in list-mode (90-110 min post-injection) and reduced-dose images were simulated to generate images of 75, 50, 25, 12.5 and 5% of the original injected dose. Images were reconstructed using vendor-provided reconstruction tools and visually assessed for Aβ-pathology. SUVRs were calculated for a global cortical and three smaller regions using a cerebellar cortex reference tissue, and Centiloid was computed. Absolute and percentage differences in SUVR and CL were calculated between dose levels, and the ability to discriminate between Aβ- and Aβ + scans was evaluated using ROC analyses. Finally, intra-reader agreement between the reduced dose and 100% images was evaluated. RESULTS: At 5% injected dose, change in SUVR was 3.72% and 3.12%, with absolute change in Centiloid 3.35CL and 4.62CL, for [18F]flutemetamol and [18F]florbetaben, respectively. At 12.5% injected dose, percentage change in SUVR and absolute change in Centiloid were  80% for both tracers. CONCLUSION: This proof-of-concept study showed that for both [18F]flutemetamol and [18F]florbetaben, adequate quantitative and qualitative assessments can be obtained at 12.5% of the original injected dose. However, decisions to reduce the injected dose should be made considering the specific clinical or research circumstances.

Synthesis of novel benzothiazoles via intramolecular CS bond formation reactions is increasingly being explored since they have been found in a wide range of natural products and pharmaceutical agents. Sharma et al. reported the ruthenium‐catalyzed preparation of novel benzothiazole derivatives from N‐arylthiourea precursors, with a range of reaction yields and selectivity being observed. We have employed a density functional theory‐based computational model to investigate the reaction mechanism leading to the benzothiazole product and help uncover the origin of the differing experimental yields and substrate specificities. We proposed a modified mechanistic scheme where the rate‐determining step to be the synchronized breaking of the peroxide bond of the oxidizing agent with the concomitant proton‐coupled electron transfer from the haloarene urea and a Ru‐bound water molecule, not electrophilic RuC bond activation. Evidence for this being the rate‐determining step is (a) the barrier is consistent with a lack of kinetic isotope effects associated with the ortho‐H atom and (b) the computed rate‐determining barriers for 10 N‐arylthiourea substrates show good correlation with the observed yield. [ABSTRACT FROM AUTHOR]

A straightforward, metal‐free multicomponent tandem cyclization/aromatization approach for the synthesis of naphthothiazoles and benzothiazoles is described. This method employs α‐tetralones and cyclohexenones as the starting materials, styrene derivatives as a one‐carbon synthon, an ammonium salt as the N source, elemental sulfur as the S source and an oxidant. This approach offers a broad substrate scope, including α‐tetralones and cyclohexenones adorned with different functional groups, resulting in moderate to high yields of the desired products. [ABSTRACT FROM AUTHOR]

Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Accumulated evidence has shown that Shigella species are the most prevalent bacteria responsible for diarrhea in developing countries. Antimicrobial therapy is necessary for Shigella infections; however, the development of resistance against current drugs justifies the pressing need to search for alternative medications. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing a benzothiazole backbone, and their combination with certain antibiotics. As a result, two acetaminophen derivatives containing a benzothiazole backbone (4a and 4b) inhibited the growth of Shigella flexneri with a common MIC value of 12.5 µg/mL. These compounds were established through a time-kill kinetics study to be potentially bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a and b) were found to be poorly active (MIC: 100 µg/mL) against this pathogen. Combination studies of 4a and 4b with the least effective antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity with MIC values decreasing from 12.5 to 0.781 μg/ mL. The present study demonstrates that the azobenzothiazole dyes 4 (a and b) can be repurposed as potential anti-Shigella compounds, thus providing potential chemical pharmacophores for the discovery of drugs against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries.

The synthesis of 2-(benzo[d]thiazol-2-yl)-N-arylacetamide derivatives was achieved by cyclocondensation reaction of 2-aminothiophenol and different cyanoacetamide derivatives in solvent free condition and without any catalyst. The resultant products were used as a precursor for synthesis novel acetamide, acrylamide, pyrazole and pyridine derivatives via reaction with different reagents. All reaction products have been tested for their antioxidant activities compared with ascorbic acid. Some on novel synthesized products furnished promising results. [ABSTRACT FROM AUTHOR]

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds—4a, 4f, 4l, and 4r—demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 µM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77–66.22 µM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 µM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib. [ABSTRACT FROM AUTHOR]

Diarrhea remains one of the leading causes of mortality worldwide, especially among children. Accumulated evidence has shown that Shigella species are the most prevalent bacteria responsible for diarrhea in developing countries. Antimicrobial therapy is necessary for Shigella infections; however, the development of resistance against current drugs justifies the pressing need to search for alternative medications. In this study, we have applied antibacterial phenotypic screening to identify potent anti-Shigella compounds across a broad chemical diversity, including selected acetaminophen derivatives containing a benzothiazole backbone, and their combination with certain antibiotics. As a result, two acetaminophen derivatives containing a benzothiazole backbone (4a and 4b) inhibited the growth of Shigella flexneri with a common MIC value of 12.5 µg/mL. These compounds were established through a time-kill kinetics study to be potentially bactericidal. Meanwhile, the 2-aminobenzothiazoles (1a and 1b) used for the synthesis of compounds 4 (a and b) were found to be poorly active (MIC: 100 µg/mL) against this pathogen. Combination studies of 4a and 4b with the least effective antibiotics (ceftriaxone and cotrimoxazole) demonstrated synergistic anti-Shigella activity with MIC values decreasing from 12.5 to 0.781 μg/ mL. The present study demonstrates that the azobenzothiazole dyes 4 (a and b) can be repurposed as potential anti-Shigella compounds, thus providing potential chemical pharmacophores for the discovery of drugs against infectious diarrhea caused by Shigella and other enteric pathogens, especially in developing countries. [ABSTRACT FROM AUTHOR]

Soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are potential targets for several diseases. Previous studies have reported that concomitant selective inhibition of sEH and FAAH produced antinociception effects in an animal model of pain. However, the co-administration of a selective sEH inhibitor and a selective FAAH inhibitor might produce serious side effects due to drug-drug interactions that could complicate drug development in the long term. Thus, discovering dual sEH/FAAH inhibitors, single small molecules that can simultaneously inhibit both sEH and FAAH, would be a significant accomplishment in the medicinal chemistry field. Herein, we report the synthesis and biological evaluation of benzothiazole-phenyl-based analogs as potential dual sEH/FAAH inhibitors. This work represents a follow-up structure-activity relationship (SAR) and metabolic-stability studies of our best dual sEH/FAAH inhibitor identified previously, as well as in vivo evaluation of its effects on voluntary locomotor behavior in rats. Our SAR study indicates that trifluoromethyl groups on the aromatic rings are well tolerated by the targeted enzymes when placed at the ortho and para positions; however, they, surprisingly, did not improve metabolic stability in liver microsomes. Our behavioral studies indicate that doses of dual sEH/FAAH inhibitors that alleviate pain do not depress voluntary behavior in naïve rats, which is a common side effect of currently available analgesic drugs (e.g., opioids). Thus, dual sEH/FAAH inhibitors may be a safe and effective approach to treat pain.

Tire additives, such as benzothiazole and its derivatives (collectively called BTs), are large-volume chemicals that are constantly emitted into agricultural environment via tire-road wearing and other actions. The potential accumulation of BTs in food crops depends largely on their metabolism in plants, which is poorly understood. Herein, we evaluated uptake and metabolism of six BTs in carrot callus and intact carrot plants to understand their structure-specific metabolism. All BTs were readily taken up by carrot roots, with their root concentration factors (RCF) ranging from 1.66 ± 0.01 to 2.95 ± 0.05. Although the tested BTs exhibited poor upward translocation from root to leaves (translocation factors

An early exploration of the benzothiazole class against two kinetoplastid parasites, Leishmania infantum and Trypanosoma cruzi, has been performed after the identification of a benzothiazole derivative as a suitable antileishmanial initial hit. The first series of derivatives focused on the acyl fragment of its class, evaluating diverse linear and cyclic, alkyl and aromatic substituents, and identified two other potent compounds, the phenyl and cyclohexyl derivatives. Subsequently, new compounds were designed to assess the impact of the presence of diverse substituents on the benzothiazole ring or the replacement of the endocyclic sulfur by other heteroatoms. All compounds showed relatively low cytotoxicity, resulting in decent selectivity indexes for the most active compounds. Ultimately, the in vitro ADME properties of these compounds were assessed, revealing a satisfying water solubility, gastrointestinal permeability, despite their low metabolic stability and high lipophilicity. Consequently, compounds 5 and 6 were identified as promising hits for further hit‐to‐lead exploration within this benzothiazole class against L. infantum, thus providing promising starting points for the development of antileishmanial candidates. [ABSTRACT FROM AUTHOR]

We report the substrate and conditions switchable synthetic methods for the preparation of benzothiazoles, benzothiazines and benzothiazepines based on the reactions of o‐aminothiophenol with hetareno[e]pyrrole‐2,3‐diones, 1H‐pyrrole‐2,3‐diones fused at the [e]‐side to heterocycles. The series of novel five‐, six‐ and seven‐membered N,S‐heterocycles were prepared in fair to excellent yields. The reported reactions proceeded under mild, catalyst‐free conditions, and the products were isolated by simple workup procedures. [ABSTRACT FROM AUTHOR]

In this study, we synthesized sulfamic acid-functionalized Fe3O4 nanoparticles (Fe3O4@EDA-SO3H) as an effective nanomagnetic solid acid catalyst. This magnetically recoverable catalyst was well characterized by FT-IR, XRD, TGA, VSM, SEM, EDX, TEM, and CHN techniques. The prepared catalyst exhibited high efficiency in the synthesis of quinoxaline, benzothiazole, and benzoxazole derivatives such as 3,2-diphenylquinoxaline (97%), 2-phenyl-benzothiazole (97%), and 2-(4-chlorophenyl)benzoxazole (95%) via simple and mild conditions. The catalyst can be readily separated from the reaction medium by employing an external magnet and reused several times without significant loss of its catalytic activity. [ABSTRACT FROM AUTHOR]

Two halo‐benzothiazoles, namely, 2‐amino‐6‐bromo‐benzo[d]thiazole and 2‐amino‐6‐fluoro‐benzo[d]thiazole were utilized to modify poly(vinyl chloride) (PVC) and gave two modified PVC samples for biomedical applications. Prepared glucose‐fatty acid esters of palmitic, oleic, and octanoic acids were exploited as plasticizers to produce phthalate‐free eco‐friendly antimicrobial PVC. The chemical structures of all prepared compounds were confirmed via Fourier‐transform infrared spectroscopy. The thermal properties of modified PVC was determined using thermo gravimetric analysis and differential scanning calorimetry while weight loss and degree of discoloration were used to assess the photostability after UV irradiation whereas references heat and UV absorbers were applied for comparison. The plasticizing effect of each glucose‐fatty acid ester at 20% by weight on the mechanical properties of modified PVC was determined and referenced to diethylhexylphthalate. The results revealed that the mechanical properties as well as the thermal stability of plasticized modified PVCs were enhanced. Plasticizers migration from the polymeric matrix was also determined and the results showed low extent of migration of the prepared plasticizers. So, modified plasticized PVC samples exhibited improved physicochemical properties. Antimicrobial properties of all samples, using disc diffusion agar method, were evaluated against some Gram +ve bacteria like Staphylococcus aureus and Streptococcus mutans and Gram −ve bacteria like Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa and fungi strains used were Candida albicans, Aspergillus niger, and Aspergillus ochraceous. All investigated compounds showed improved antibacterial and antifungal activities. Highlights: PVC was chemically modified with two halo‐benzothiazoles to obtain antimicrobial PVC.Glucose‐fatty acids esters were prepared as eco‐friendly plasticizers for PVC.Halo‐benzothiazoles improved both the thermal‐ and photo‐stability of PVC.Glucose‐fatty acid plasticizers enhanced the mechanical properties of PVC.The extent of migration of prepared plasticizers is lower than that of reference plasticizer. [ABSTRACT FROM AUTHOR]

A convenient and efficient method for the synthesis of benzimidazoles, and benzothiazoles have been developed using recyclable magnetite polydopamine-supported copper nanoparticles (Fe3O4@PDA/CuCl2) under green and mild conditions. This catalytic system enables the one-pot synthesis of benzazoles by employing available, and easy to-handle aldehydes and o-phenylenediamine/o-aminothiophenol. Utilizing sustainable and mild conditions, a variety of functionalized benzazoles has been prepared in nearly quantitative yields (79–97%) within 5–30 min at 40 °C. The method offers advantages such as high yield, short reaction time, use of air as oxidant, ease of workup, avoiding toxic organic solvents, and a simple workup protocol. The catalyst could be recycled and reused up to five times without any loss of significant catalytic activity. The catalyst's great effectiveness can be seen in the fact that the TON reaches 2633–3233 and the TOF reaches 5266–38,800 h−1. [ABSTRACT FROM AUTHOR]

We present here a joint experimental and computational study on the formation of benzothiazoles. Our investigation reveals a green protocol for accessing benzothiazoles from acyl chlorides using either water alongside a reducing agent as the reaction medium or in combination with stoichiometric amounts of a weak acid, instead of the harsh conditions and catalysts previously reported. Specifically, we show that a protic solvent, particularly water, enables the formation of 2‐substituted benzothiazoles from N‐acyl 1,2‐aminothiophenols already at room temperature, without the need for strong acids or metal catalysts. DFT Molecular Dynamics simulations coupled with advanced enhanced sampling techniques provide a clear understanding of the catalytic role of water. We demonstrate how bulk water – due to its extended network of hydrogen bonds and an efficient Grotthuss mechanism – provides a reaction path that strongly reduces the reaction barriers compared to aprotic environments, namely more than 80 kJ/mol for the first reaction step and 250 kJ/mol for the second. Finally, we discuss the influence of different aliphatic and aromatic substituents with varying electronic properties on chemical reactivity. Besides providing in‐depth mechanistic insights, we believe that our findings pave the way for a greener route toward an important class of bioactive molecules. [ABSTRACT FROM AUTHOR]

This article discusses the need for new molecules with better antibacterial properties due to increasing drug resistance. The authors propose a copper-mediated synthesis of benzothiazoles, which have shown effectiveness against bacterial diseases. They present an efficient method for the synthesis of these compounds using copper oxide. The article also discusses the synthesis and antibacterial activity of the compounds, as well as their ability to inhibit biofilm formation. Compound 5r showed significant inhibitory effects and biofilm inhibition percentages comparable to a traditional antibiotic. Further research is needed to validate its therapeutic use. The document provides information on the synthesis and characterization of various compounds derived from benzo[d]thiazole. The compounds were tested against different bacteria strains and showed promising antibacterial and antibiofilm activities. Computational studies were conducted to analyze the interactions between the compounds and specific proteins. The authors acknowledge the support of the National Facility Single Crystal Laboratory. [Extracted from the article]

In this work, a new series of 1,2-diphenyl-3aH-spiro[benzo[d]pyrrolo[2,1-b]thaizol-3,5ʹ-pyrimidine (4) or 3,2ʹ-indendion (6) derivatives were efficiently designed and prepared using a novel and easy route in excellent yields by multicomponent-reactions between benzothiazoles, 2-chloro-2-phenylacetophenone, and 1,3-dicarbonyl compounds. These reactions were carried out in CH2Cl2 at ambient temperature under catalyst-free conditions for 3 h. The structure all of the synthesized compounds were established by NMR, IR, EI-MS and elemental analyses.

A catalyst-free synthesis of various 2-alkyl or aryl-substituted benzothiazoles and benzimidazoles has been developed at room temperature by simply combining alkyl or arylaldehydes with ortho-phenylenediamines and 2-aminothiophenols, respectively. The synthesis of these widely applicable fused heterocycles is often challenging and requires additives. The advantages of this new benign procedure include: products with nearly quantitative yields, high atom economy and no toxic waste formation, catalyst-free process with no need for catalyst separation and/or recycling, the use of a green and sustainable solvent, ethanol, and mostly room temperature reactions with moderate reaction times to ensure that the protocol is energetically favorable.

Evidence of the joint association between exposure to multiple environmental chemicals and non-alcoholic fatty liver disease (NAFLD) is scarce. In this study, 281 participants from Zhuhai, China (138 patients with NAFLD vs. 143 healthy participants) were recruited to explore the associations of 40 per- and polyfluoroalkyl substances (PFAS), 11 neonicotinoid insecticides (NEOs), and 8 benzotriazoles (BTRs) and benzothiazoles (BTHs) with the risk of NAFLD. Perfluorooctane sulfonate (PFOS) and its emerging alternatives (6:2 chlorinated polyfluorinated ether sulfonate [6:2 Cl-PFESA] and 8:2 fluorotelomer sulfonic acid [8:2 FTSA]), NEO metabolites (m-NEOs), BTR, and BTH were the predominant PFAS, NEOs, BTRs and BTHs, respectively. The total median concentrations of PFAS (20.4 ng/mL vs. 7.16 ng/mL) and NEOs (7.24 ng/mL vs. 6.23 ng/mL) in NAFLD group were significantly higher than those in healthy group. Sex differences in PFAS exposure have been observed among patients with NAFLD. 8:2 FTSA and short-chain PFAS were more predominant in female patients with NAFLD, whereas other emerging (i.e., 6:2 and 8:2 Cl-PFESA) and legacy PFAS (i.e., PFOS and long-chain perfluoroalkyl carboxylic acids) easily accumulated in male patients with NAFLD. The results of the multiple linear regression analysis indicated a significant positive association between PFOS and alanine transaminase (ALT) in serum samples from patients with NAFLD (β = 23.2, 95% confidence intervals (CI): 7.82, 38.5). Conversely, negative correlations were observed between 5-hydroxy-imidacloprid (5-OH-IMI) and γ-glutamyl transpeptidase (GGT) (β = −2.73, 95% CI: −5.29, −0.18), as well as between tolyltriazole (TTR) and total bilirubin (TBIL) (β = −0.70, 95% CI: −1.33, −0.08) and direct bilirubin (DBIL) (β = −0.59, 95% CI: −0.98, −0.20). The Bayesian kernel machine regression model revealed a positive joint effect of exposure to PFAS and NEO on elevated NAFLD outcomes, suggesting that exposure to PFAS and NEO might exacerbate the severity of NAFLD. This study fills the knowledge gap between multi-pollutant exposure and NAFLD risk.

Synthesis of 2-aryl substituted benzoxazoles, benzothiazoles, and quinoxalinones via decarboxylative coupling of α-keto acids with 2-aminophenol, 2-aminothiophenol, and OPD (o-phenylenediamine), using K2CO3 as a base in water at room temperature, and as well as solvent-free grinding and the synthesis of benzoxazinones from the reaction of α-keto acids with 2-aminophenol at 60 °C have been reported. Both the protocols afforded a wide range of desired products with excellent functional group tolerance in yields of 87-99%. The major advantages of these approaches are catalyst-free protocol, short reaction times, straightforward workup, and chromatographyfree processing of the products. Additionally, to test the translational demand of this methodology, the synthesis of 2-(3,5-dichlorophenyl)- 6-methylbenzo[d]oxazole was carried out which is a key structure of tafamidis, a commercially available drug. [ABSTRACT FROM AUTHOR]

Driven by the growing threat of cancer, many research efforts are directed at developing new chemotherapeutic agents, where the central role is played by transition metal complexes. The proper ligand design serves as a key factor to unlock the anticancer potential of a particular metal center. Following a recent trend, we have prepared unsymmetrical pincer ligands that combine benzothiazole and thiocarbamate donor groups. These compounds are shown to readily undergo direct cyclopalladation, affording the target S,C,N-type Pd(II) pincer complexes both in solution and in the absence of a solvent. The solid-phase strategy provided the complexes in an efficient and ecologically friendly manner. The resulting palladacycles are fully characterized using nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy and, in one case, by single-crystal X-ray diffraction (XRD). The solvent-free reactions are additionally analyzed by powder XRD. The pincer complexes exhibit remarkable cytotoxicity against several solid and blood cancer cell lines, including human colorectal carcinoma (HCT116), breast cancer (MCF7), prostate adenocarcinoma (PC3), chronic myelogenous leukemia (K562), multiple plasmacytoma (AMO1), and acute lymphoblastic leukemia (H9), with the dimethylamino-substituted derivative being particularly effective. The latter also induced an appreciable level of apoptosis in both parental and doxorubicin-resistant cells K562 and K562/iS9, vindicating the high anticancer potential of this type of palladacycles. [ABSTRACT FROM AUTHOR]

The benzothiazole nucleus is a major heterocyclic scaffold whose therapeutic potential has been thoroughly explored due to its structural simplicity and ease of synthesis. In fact, several benzothiazole derivatives have been synthesized over time, demonstrating numerous pharmacological properties such as anticancer, antimicrobial, anti-inflammatory, and antioxidant activities. Herein, we propose a new series of benzothiazole-phthalimide hybrids obtained by linking the phthalimide moiety to differently substituted benzothiazole nuclei through the N atom. These compounds have been screened for their anticancer properties against two human breast cancer cell lines. Furthermore, we delved into the mechanism of action of the most active hybrid, compound 3h, by assessing its capability to damage the nuclear DNA, trigger the apoptotic process in the high metastatic MDA-MB-231 cells, and prevent cellular migration. Moreover, in view of the documented antimicrobial activities of the two scaffolds involved, we explored the antibacterial and antifungal effects of the studied compounds by means of the broth microdilution method. Among the studied compounds, 3h showed the highest antimicrobial activity, both against gram-positive and gram-negative bacterial strains belonging to the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and against fungal strains of the Candida species with MICs values ranging from 16 to 32 µg/mL. [ABSTRACT FROM AUTHOR]

The emergence of a new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents an urgent public health crisis. Without available targeted therapies, treatment options remain limited for COVID-19 patients. Using medicinal chemistry and rational drug design strategies, we identify a 2-phenyl-1,2-benzoselenazol-3-one class of compounds targeting the SARS-CoV-2 main protease (Mpro). FRET-based screening against recombinant SARS-CoV-2 Mpro identified six compounds that inhibit proteolysis with nanomolar IC50 values. Preincubation dilution experiments and molecular docking determined that the inhibition of SARS-CoV-2 Mpro can occur by either covalent or noncovalent mechanisms, and lead E04 was determined to inhibit Mpro competitively. Lead E24 inhibited viral replication with a nanomolar EC50 value (844 nM) in SARS-CoV-2-infected Vero E6 cells and was further confirmed to impair SARS-CoV-2 replication in human lung epithelial cells and human-induced pluripotent stem cell-derived 3D lung organoids. Altogether, these studies provide a structural framework and mechanism of Mpro inhibition that should facilitate the design of future COVID-19 treatments.

Cancer remains a leading cause of death worldwide, often resulting from uncontrolled growth in various organs. Protein kinase inhibitors represent an important class of targeted cancer therapies. Recently, the kinases BRAF and VEGFR-2 have shown synergistic effects on tumor progression. Seeking to develop dual BRAF/VEGFR-2 inhibitors, we synthesized 18 amino-benzothiazole derivatives with structural similarities to reported dual inhibitors. Four compounds—4a, 4f, 4l, and 4r—demonstrated remarkable cytotoxicity, with IC50 values ranging from 3.58 to 15.36 μM, against three cancer cell lines. Furthermore, these compounds showed IC50 values of 38.77–66.22 μM in the case of a normal cell line, which was significantly safer than the reference, sorafenib. Subsequent investigation revealed that compound 4f exhibited the capacity to inhibit the BRAF and VEGFR-2 enzymes, with IC50 values similar to sorafenib (0.071 and 0.194 μM, respectively). Moreover, compound 4f caused G2-M- and S-phase cycle arrest. Molecular modeling demonstrated binding patterns compatible with inhibition for both targets, where 4f exerted the critical interactions in the BRAF site and interacted in the VEGFR-2 site in a manner akin to sorafenib, demonstrating affinity similar to dabrafenib.

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.

Brain organoids represent a powerful tool for studying human neurological diseases, particularly those that affect brain growth and structure. However, many diseases manifest with clear evidence of physiological and network abnormality in the absence of anatomical changes, raising the question of whether organoids possess sufficient neural network complexity to model these conditions. Here, we explore the network-level functions of brain organoids using calcium sensor imaging and extracellular recording approaches that together reveal the existence of complex network dynamics reminiscent of intact brain preparations. We demonstrate highly abnormal and epileptiform-like activity in organoids derived from induced pluripotent stem cells from individuals with Rett syndrome, accompanied by transcriptomic differences revealed by single-cell analyses. We also rescue key physiological activities with an unconventional neuroregulatory drug, pifithrin-α. Together, these findings provide an essential foundation for the utilization of brain organoids to study intact and disordered human brain network formation and illustrate their utility in therapeutic discovery.

The study about how tyre-derived particles can potentially worsen the water quality and how traffic pollution markers can affect the environment is crucial for environmental management. Road emissions are known to contribute to pollution in various environments, and benzothiazoles and their derivates can be used to trace pollutant inputs related to surface runoff in the aquatic system. A total of eight benzothiazoles were determined in highway stormwater runoff and road dust collected from February to August 2022 near Venice (Casale sul Sile, Veneto Region, Italy). A new analytical method was validated, by using an UHPLC system coupled to a mass spectrometer (triple quadrupole). The target compounds were determined in both dissolved phase and suspended particulate matter of runoff, and the road dust samples were divided into seven fractions depending on particle diameters to understand the fraction partitioning. The results indicate that 2-SO3H-BTH was the most concentrated benzothiazole in all the analysed substrates, suggesting tyre debris as the main source because it is usually used in the vulcanization process. 2-SO3H-BTH reached a mean concentration of 115 ± 59 µg L−1, 4 ± 3 µg L−1, and 411 ± 441 µg Kg−1 for dissolved phase, suspended particulate matter, and road dust, respectively, while 2-OH-BTH and BTH showed values about an order of magnitude lower. The size distribution of most BTHs suggests that they are distributed in the finest fraction of road dust. An exception was given by 2-SCNMeS-BTH being present only in particles with a diameter > 1 mm. [ABSTRACT FROM AUTHOR]

Herein, we report the synthesis of sulfonic acid functionalized SBA-15 by post-synthetic functionalization of mesoporous SBA-15. The successful incorporation of sulfonic acid moiety into the SBA-15 framework could be confirmed by physico-chemical characterization. The nature of acidic sites was confirmed using temperature-programmed desorption of ammonia. A simple synthetic route for the synthesis of 2-aryl benzimidazoles and benzothiazoles using SBA-15-SO3H as a green heterogeneous catalyst at room temperature was investigated. 100% conversion and an isolated yield of 70–85% could be obtained. The green synthetic approach offers reaction under ambient conditions, a simple work-up procedure, good to excellent yield and easy product isolation along with good recyclability. [ABSTRACT FROM AUTHOR]

The molecular chaperone, Heat Shock Protein 70 (Hsp70), is an emerging drug target for neurodegenerative diseases, because of its ability to promote degradation of microtubule-associated protein tau (MAPT/tau). Recently, we reported YM-08 as a brain penetrant, allosteric Hsp70 inhibitor, which reduces tau levels. However, the benzothiazole moiety of YM-08 is vulnerable to metabolism by CYP3A4, limiting its further application as a chemical probe. In this manuscript, we designed and synthesized seventeen YM-08 derivatives by systematically introducing halogen atoms to the benzothiazole ring and shifting the position of the heteroatom in a distal pyridine. In microsome assays, we found that compound JG-23 has 12-fold better metabolic stability and it retained the ability to reduce tau levels in two cell-based models. These chemical probes of Hsp70 are expected to be useful tools for studying tau homeostasis.

Single-cell sequencing exposes previously unmeasurable complexity of tumor heterogeneity and clonal evolution on quizartinib. Single-cell sequencing reveals on- and off-target mechanisms of resistance to quizartinib, which can preexist therapy.

Oligonucleotide receptors (aptamers), which change conformation upon target recognition, enable electronic biosensing under high ionic-strength conditions when coupled to field-effect transistors (FETs). Because highly negatively charged aptamer backbones are influenced by ion content and concentration, biosensor performance and target sensitivities were evaluated under application conditions. For a recently identified dopamine aptamer, physiological concentrations of Mg2+ and Ca2+ in artificial cerebrospinal fluid produced marked potentiation of dopamine FET-sensor responses. By comparison, divalent cation-associated signal amplification was not observed for FET sensors functionalized with a recently identified serotonin aptamer or a previously reported dopamine aptamer. Circular dichroism spectroscopy revealed Mg2+- and Ca2+-induced changes in target-associated secondary structure for the new dopamine aptamer, but not the serotonin aptamer nor the old dopamine aptamer. Thioflavin T displacement corroborated the Mg2+ dependence of the new dopamine aptamer for target detection. These findings imply allosteric binding interactions between divalent cations and dopamine for the new dopamine aptamer. Developing and testing sensors in ionic environments that reflect intended applications are best practices for identifying aptamer candidates with favorable attributes and elucidating sensing mechanisms.

The present study reports the synthesis of 2-azidobenzothiazoles from substituted 2-aminobenzothiazoles using sodium nitrite and sodium azide under mild conditions. All the synthesized compounds were examined for their antibacterial activity against Gram (+) bacteria, Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 51299), Bacillus cereus (ATCC 10876) and Gram (−) bacteria, Escherichia coli (ATCC 10536), Pseudomonas aeruginosa (ATCC 10145), Klebsiella pneumonia (ATCC BAA-2146)and clinical isolates of Gram (+) Methicillin Resistant S. aureus (MRSA) and Multi Drug Resistant E. coli. The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) values by broth dilution method revealed that compound 2d exhibited significant antibacterial potential against E. faecalis and S. aureus with MIC of 8 μg/mL, while other synthesized compounds had only moderate effects against all the tested species. The compound significantly inhibited the biofilm formation of the bacterial strains below its MIC. The selective cytotoxicity of Compound 2d towards bacterial cells was evidenced on extended exposure of Human Embryonic Kidney-293 cell line to higher concentrations of the compound. Hence, the present study confirmed that compound 2d can be a potential drug candidate for future development as an antibacterial drug.

The development of bimetallic particles on a nano-scale for increasing catalytic activity has remained an enormous challenge in the catalytic arena. In this work, a new type of bimetallic particle catalyst was designed and prepared for the synthesis of benzothiazoles. First, mṣagnetic Fe3O4 nanoparticles (NPs) were produced using a co-precipitation method of working and next covered with a silica substrate. In addition, molybdenum trioxide (MoO3) crystals are used as outer shell precursors in order to stabilization of Cu2+. Using different techniques such as wide-angle XRD, FT-IR, TGA-DTG, VSM, BET, FESEM, and TEM spectroscopy, the core–shell nanocomposite structure was investigated. The proposed core–shell nanocomposites indicated excellent catalytic properties for the preparation of benzothiazole derivatives from various aldehydes and amino thiophenol that resulted in a product with higher efficiency, and high reaction speed, and high selectivity. The findings indicated that copper and MoO3 synergetic effects in the synthesis of benzothiazoles. The current study provided a rational design and synthesis of multifunctional catalysts for the development of green chemistry and green technologies. [ABSTRACT FROM AUTHOR]

An efficient Pd(II)N^N^S pincer type catalysts‐promoted sustainable construction of pharmaceutically important benzothiazole derivatives from primary alcohols and 2‐aminothiophenol via acceptorless dehydrogenative coupling (ADC) method has been described. The newly synthesized ligand L2 and the Pd(II) complexes in addition to L1 and L3 were characterized by analytical and Fourier transform infrared spectroscopy (FT‐IR), UV–visible (UV–vis), and nuclear magnetic resonance (NMR) spectral techniques. Further, the ORTEP views of the complexes 2 and 3 were established by a single crystal XRD study, which evidenced the coordination of the thiosemicarbazone ligands and disclose the square‐planar geometry around the Pd(II) ion. The present homogeneous catalytic system involves synthesizing a range of benzothiazoles via C−S and C−N bond formation with excellent yields up to 93%. The described methodology employs a sustainable, highly abundant, and inexpensive alcohol as starting material using 1 mol% catalyst loading, and water and hydrogen gas are the only by‐products. Furthermore, a plausible mechanism involving in situ aldehyde formation via dehydrogenation of primary alcohols has been proposed. A large‐scale synthesis of 2‐(4‐methoxyphenyl)benzo[d]thiazole illustrates the synthetic utility of the present catalytic protocol. [ABSTRACT FROM AUTHOR]

Small-molecule inhibitors of abnormal protein self-assembly are promising candidates for developing therapy against proteinopathies. Such compounds have been examined primarily as inhibitors of amyloid β-protein (Aβ), whereas testing of inhibitors of other amyloidogenic proteins has lagged behind. An important issue with screening compound libraries is that although an inhibitor suitable for therapy must be both effective and nontoxic, typical screening focuses on efficacy, whereas safety typically is tested at a later stage using cells and/or animals. In addition, typical thioflavin T (ThT)-fluorescence-based screens use the final fluorescence value as a readout, potentially missing important kinetic information. Here, we examined potential inhibitors of superoxide dismutase 1 (SOD1) using ThT-fluorescence including the different phases of fluorescence change and added a parallel screen of SOD1 activity as a potential proxy for compound toxicity. Some compounds previously reported to inhibit other amyloidogenic proteins also inhibited SOD1 aggregation at low micromolar concentrations, whereas others were ineffective. Analysis of the lag phase and exponential slope added important information that could help exclude false-positive or false-negative results. SOD1 was highly resistant to inhibition of its activity, and therefore, did not have the necessary sensitivity to serve as a proxy for examining potential toxicity.

The heat shock protein 70 (Hsp70) family of molecular chaperones are highly expressed in tumors. Inhibitors containing a pyridinium-modified benzothiazole, such as JG-98, bind to a conserved, allosteric site in Hsp70, showing promising anti-proliferative activity in cancer cells. When bound to Hsp70, the charged pyridinium makes favorable contacts; however, this moiety also increases the inhibitor's fluorescence, giving rise to undesirable interference in biochemical and cell-based assays. Here, we explore whether the pyridinium can be replaced with a neutral pyridine. We report that pyridine-modified benzothiazoles, such as compound 17h (JG2-38), have reduced fluorescence, yet retain promising anti-proliferative activity (EC50 values ~0.1 to 0.07 µM) in breast and prostate cancer cell lines. These chemical probes are expected to be useful in exploring the roles of Hsp70s in tumorigenesis and cell survival.

Aging represents an independent risk factor for the development of cardiovascular disease, and is associated with complex structural and functional alterations in the vasculature, such as endothelial dysfunction. Small- and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacological activators of these channels induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of such compounds are unknown. In our study, we hypothesized that such treatment would ameliorate aging-related cardiovascular deficits. Aged (∼18 months) male Sprague Dawley rats were treated daily with either vehicle or the KCa channel activator SKA-31 (10 mg/kg, intraperitoneal injection; n = 6/group) for 8 weeks, followed by echocardiography, arterial pressure myography, immune cell and plasma cytokine characterization, and tissue histology. Our results show that SKA-31 administration improved endothelium-dependent vasodilation, reduced agonist-induced vascular contractility, and prevented the aging-associated declines in cardiac ejection fraction, stroke volume and fractional shortening, and further improved the expression of endothelial KCa channels and associated cell signalling components to levels similar to those observed in young male rats (∼5 months at end of study). SKA-31 administration did not promote pro-inflammatory changes in either T cell populations or plasma cytokines/chemokines, and we observed no overt tissue histopathology in heart, kidney, aorta, brain, liver and spleen. SKA-31 treatment in young rats had little to no effect on vascular reactivity, select protein expression, tissue histology, plasma cytokines/chemokines or immune cell properties. Collectively, these data demonstrate that administration of the KCa channel activator SKA-31 improved aging-related cardiovascular function, without adversely affecting the immune system or promoting tissue toxicity.

Aging represents an independent risk factor for the development of cardiovascular disease, and is associated with complex structural and functional alterations in the vasculature, such as endothelial dysfunction. Small- and intermediate-conductance, Ca2+-activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacological activators of these channels induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of such compounds are unknown. In our study, we hypothesized that such treatment would ameliorate aging-related cardiovascular deficits. Aged (∼18 months) male Sprague Dawley rats were treated daily with either vehicle or the KCa channel activator SKA-31 (10 mg/kg, intraperitoneal injection; n = 6/group) for 8 weeks, followed by echocardiography, arterial pressure myography, immune cell and plasma cytokine characterization, and tissue histology. Our results show that SKA-31 administration improved endothelium-dependent vasodilation, reduced agonist-induced vascular contractility, and prevented the aging-associated declines in cardiac ejection fraction, stroke volume and fractional shortening, and further improved the expression of endothelial KCa channels and associated cell signalling components to levels similar to those observed in young male rats (∼5 months at end of study). SKA-31 administration did not promote pro-inflammatory changes in either T cell populations or plasma cytokines/chemokines, and we observed no overt tissue histopathology in heart, kidney, aorta, brain, liver and spleen. SKA-31 treatment in young rats had little to no effect on vascular reactivity, select protein expression, tissue histology, plasma cytokines/chemokines or immune cell properties. Collectively, these data demonstrate that administration of the KCa channel activator SKA-31 improved aging-related cardiovascular function, without adversely affecting the immune system or promoting tissue toxicity.

A novel magnetically recoverable copper nanocatalyst was fabricated via the immobilization of a copper complex on the surface of silica-coated magnetic nanoparticles modified with a novel Schiff base ligand [Fe3O4@SiO2-bis(aminopyridine)-Cu]. FT-IR spectroscopy, SEM, TEM, EDX, VSM, XRD, XPS, TGA and AAS, ICP-OES techniques were applied to characterize the structure of the as-fabricated [Fe3O4@SiO2-bis(aminopyridine)-Cu(II)] nanocomposite. TEM and SEM analysis confirmed that the typical silica shell thickness was assessed to be around 20 nm. Catalytic studies revealed that the Fe3O4@SiO2-bis(aminopyridine)-Cu(II) nanocomposite is a highly efficient and green nanocatalyst for the synthesis of benzothiazoles and polyhydroquinolines. The [Fe3O4@SiO2-bis(aminopyridine)-Cu(II)] nanocatalyst could be easily recovered by a simple magnetic separation and recycled at least 6 times without deterioration in catalytic activity. [ABSTRACT FROM AUTHOR]

Novel heterocyclic compounds containing a benzothiazole moiety (2–16) were synthesized via the reaction of benzothiazole cyanoacetamide derivative (2) with different types of reagents. All compounds were characterized by 1H NMR, MS, and IR techniques. The newly synthesized compounds were examined for their in vitro antibacterial activity against Gram-positive bacteria (Bacillus subtilis and Staphylococcus aureus), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and fungi (Candida albicans) microorganisms. Compounds (5, 6, 7, and 15) are promising antimicrobial agents and could be the lead compounds for more potent drugs. Binding modes of the synthesized compounds were analyzed by docking studies that showed good binding scores against the diverse amino acids of the two selected proteins (PDB Codes – 2EXB and 3HUN). The conducted docking studies were found to be consistent with antimicrobial results. Thus, the results indicate that the designed structures can be a potential lead as antimicrobial agents. [ABSTRACT FROM AUTHOR]

Novel 3-(3-benzyl-2,3-dihydrobenzo[ d ]thiazol-2-yl)benzo[ d ]oxazole-2(3 H)-thione derivatives are efficiently synthesized in excellent yields by reactions of benzothiazoles, benzyl bromides, and 2-mercaptobenzoxazole in acetone under catalyst-free conditions in the presence of triethylamine. The structures of the products are confirmed by nuclear magnetic resonance spectroscopy, infrared spectroscopy, electron ionization mass spectrometry, and elemental analyses. [ABSTRACT FROM AUTHOR]

A series of 2-substituted benzimidazole and benzothiazole derivatives were synthesized by condensation of aldehydes with o-phenylenediamine and 2-aminobenzenethiol, respectively, using a catalytic amount of wet zinc ferrite under solvent-free conditions. The characteristic features of the new protocol are clean reaction profile and the use of inexpensive and environmentally friendly catalyst. The method is operationally simple and applicable to aliphatic, aromatic, and heteroaromatic aldehydes without significant differences. [ABSTRACT FROM AUTHOR]

A well dispersed magnetically separable palladium complex (MNPs-phenanthroline-Pd) has been synthesized via the immobilization of palladium (II) complex on the surface of silica-coated magnetic nanoparticles modified with phenanthroline ligand. The as-fabricated MNPs-phenanthroline-Pd nanocatalyst was well characterized a series of spectroscopic techniques including FT-IR, SEM, TEM, EDX, TGA, XRD, VSM, AAS and ICP-OES. The SEM and TEM images of MNPs-phenanthroline-Pd at different magnification show that the catalyst is formed of nanometer-sized particles. The MNPs-phenanthroline-Pd nanocomposite was found to be an efficient catalyst for the synthesis of benzoxazoles, benzothiazoles and cyanation of aryl halides. The high efficiency and the ability to be recovered and reused for at least up to seven consecutive runs are some superior properties of the catalyst. SEM images of reused catalyst confirmed that there was no significant change in the morphology and dispersion of the particles. MNPs- phenanthroline-Pd catalyzed synthesis of benzoxazoles, benzothiazoles and nitriles [ABSTRACT FROM AUTHOR]

Driven by the growing threat of cancer, many research efforts are directed at developing new chemotherapeutic agents, where the central role is played by transition metal complexes. The proper ligand design serves as a key factor to unlock the anticancer potential of a particular metal center. Following a recent trend, we have prepared unsymmetrical pincer ligands that combine benzothiazole and thiocarbamate donor groups. These compounds are shown to readily undergo direct cyclopalladation, affording the target S,C,N-type Pd(II) pincer complexes both in solution and in the absence of a solvent. The solid-phase strategy provided the complexes in an efficient and ecologically friendly manner. The resulting palladacycles are fully characterized using nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy and, in one case, by single-crystal X-ray diffraction (XRD). The solvent-free reactions are additionally analyzed by powder XRD. The pincer complexes exhibit remarkable cytotoxicity against several solid and blood cancer cell lines, including human colorectal carcinoma (HCT116), breast cancer (MCF7), prostate adenocarcinoma (PC3), chronic myelogenous leukemia (K562), multiple plasmacytoma (AMO1), and acute lymphoblastic leukemia (H9), with the dimethylamino-substituted derivative being particularly effective. The latter also induced an appreciable level of apoptosis in both parental and doxorubicin-resistant cells K562 and K562/iS9, vindicating the high anticancer potential of this type of palladacycles.