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We present our results on the synthesis and preliminary in silico and in vitro studies of the toxicology and antioxidant properties of selenylated analogs of Tacrine. Initially, we synthesized 2-aminobenzonitriles containing an organic selenium moiety, resulting in sixteen compounds with various substituents linked to the portion derived from diorganyl diselenide. These compounds were then used as substrates in reactions with cyclic ketones, in the presence of 1.4 equivalents of trifluoroboroetherate as a Lewis acid, to synthesize selenylated analogs of Tacrine with yields ranging from 20 % to 87 %. In silico studies explored computational parameters related to antioxidant activity and hepatotoxicity. In vitro studies elucidated the antioxidant effects of Tacrine and its selenium hybrid (TSe) in neutralizing ABTS radicals, scavenging DPPH radicals, and reducing iron ions. Additionally, the acute oral toxicity of one synthesized compound was evaluated., (© 2024 Wiley-VCH GmbH.)

The dyshomeostasis of metal ions in the brain leads to the accumulation of excess metals in extracellular and inter-neuronal locations and the Amyloid β peptide (Aβ) binds these transition metals, which ultimately cause the Aβ aggregation and severe oxidative stress in the brain. The aggregation of Aβ and oxidative stress are important factors to trigger Alzheimer's disease (AD). Metal chelation therapy is a promising approach to removing metals from Aβ-M species and relieve the oxidative stress. Therefore, 4 tetrahydrosalens containing benzothiazole moiety were designed and synthesized. Their biological activities for Alzheimer's disease therapy in vitro were determined by Turbidity assay, BCA protein assay, MTT assay and fluorescent probe of DCFH-DA. The results were comparing with that of non-specific chelator (cliquinol, CQ) and non-benzothiazole functionalized tetrahydrosalens, the results demonstrated that benzothiazole functionalized chelators had more efficient bio-activities in preventing Cu 2+ -induced Aβ aggregation, attenuating cytotoxicity mediated by Aβ-Cu 2+ species and decrease the level of reactive oxygen species (ROS) in Cu 2+ -Aβ treated PC12 cells than that of cliquinol and non-benzothiazole functionalized analogues., Competing Interests: Declaration of competing interest We solemnly promise that this manuscript is the original paper, and that all or part of contents of this manuscript has never published in any other publication in any form, and that there is no problem of multiple contributions. We also declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our works, 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, or the review of, the manuscript entitled., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC 50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC 50 value of 0.88 μM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C 2 -symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Benzothiazoles are a class of heterocycles with multiple applications as anticancer, antibiotic, antiviral, and anti-inflammatory agents. Benzothiazole is a privileged scaffold in drug discovery programs for modulating a variety of biological functions. This review focuses on the design and synthesis of new benzothiazole derivatives targeting hypoxic tumors. Cancer is a major health problem, being among the leading causes of death. Tumor-hypoxic areas promote proliferation, malignancy, and resistance to drug treatment, leading to the dysregulation of key signaling pathways that involve drug targets such as vascular endothelial growth factor, epidermal growth factor receptor, hepatocyte growth factor receptor, dual-specificity protein kinase, cyclin-dependent protein kinases, casein kinase 2, Rho-related coil formation protein kinase, tunica interna endothelial cell kinase, cyclooxygenase-2, adenosine kinase, lysophosphatidic acid acyltransferases, stearoyl-CoA desaturase, peroxisome proliferator-activated receptors, thioredoxin, heat shock proteins, and carbonic anhydrase IX/XII. In turn, they regulate angiogenesis, proliferation, differentiation, and cell survival, controlling the cell cycle, inflammation, the immune system, and metabolic alterations. A wide diversity of benzothiazoles were reported over the last years to interfere with various proteins involved in tumorigenesis and, more specifically, in hypoxic tumors. Many hypoxic targets are overexpressed as a result of the hypoxia-inducible factor activation cascade and may not be present in normal tissues, providing a potential strategy for selectively targeting hypoxic cancers., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Compounds with sulfhydryl substituents and azole compounds exhibit potent anti-tyrosinase potency. 2-Thiobenzothiazole (2-TBT), a hybrid structure of sulfhydryl and azole, exists in two tautomeric forms, with the thione form being predominant according to several studies. 2-TBT derivatives were synthesized as potential tyrosinase inhibitors as the thione tautomeric form has the same N-CS moiety as phenylthiourea (PTU), which is suitable for chelation with the copper ions present in the tyrosinase active site. Eight of the ten 2-TBT derivatives inhibited the monophenolase and diphenolase activities of mushroom tyrosinase, with IC 50 values of 0.02-0.83 μM. Kinetic studies and molecular dynamics simulations were performed to determine their mode of action and confirm that the 2-TBT derivatives bind to the tyrosinase active site with high stability. Derivatives 3, 4, 8, and 10 strongly inhibited melanogenesis in B16F10 cells in a pattern similar to the results of cellular tyrosinase inhibition, thereby suggesting that their ability to inhibit melanogenesis was due to their tyrosinase inhibitory activity. In a depigmentation experiment using zebrafish embryos, all 2-TBT derivatives showed better potency than kojic acid, even at 400 to 2000 times lower concentration, and 1 and 10 reduced zebrafish larva pigmentation more strongly than PTU even at 20 times lower concentration. Experiments investigating the changes in tyrosinase inhibitory activity of 2-TBT derivatives in the presence and absence of CuSO 4 and their copper chelating ability supported that these derivatives exert their anti-melanogenic effect by chelating the copper ions of tyrosinase. These results suggest that 2-TBT derivatives are promising candidates for the treatment of hyperpigmentation-related disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Inhibition of quorum sensing (QS) is an impending approach for targeting bacterial infection. Fourteen benzo[d]thiazole and 2-pyrazolo[1,5-a]pyrimidin-3-yl)benzo[d]thiazoles analogues were designed and synthesized as promising LasR antagonists with QS inhibition activity. Among the investigated compounds, compounds 3c, 3e, and 8d exhibited the highest percentage inhibition in biofilm formation (77 %, 63.9 %, 69.4 %), pyocyanin production (74.6 %, 64.9, 69.4 %), and rhamnolipids production (58.5 %, 51 %, 54.3 %) in P. aeruginosa, respectively. Additionally, compounds 3c, 3e and 8d achieved IC 50 values against Las R equal 1.37 ± 0.35, 1.55 ± 0.24, 1.1 ± 0.15 μM respectively. Also, molecular docking of the target compounds into the LasR binding site co-crystalized "odDHL" revealed their binding with the essential residues for protein inhibition. Additionally, molecular dynamics simulation (MDS) experiments over 200 ns of compound 3c showed its ability to interact with the LasR binding site with dissociation of the protein's dimer confirming its action as a LasR antagonist. The obtained findings inspire further investigation for benzo[d]thiazole and 2-pyrazolo[1,5-a]pyrimidin-3-yl)benzo[d]thiazoles aiming to design and synthesize more potential QS inhibitors., Competing Interests: Declaration of competing interest There are no interests to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Aim: The present study describes benzothiazole derived thiazolidinone based thiadiazole derivatives ( 1-16 ) as anti-Alzheimer agents. Materials & methods: Synthesis of benzothiazole derived thiazolidinone based thiadiazole derivatives was achieved using the benzothiazole bearing 2-amine moiety. These synthesized compounds were confirmed via spectroscopic techniques ( 1 H NMR, 13 C NMR and HREI-MS). These compounds were biologically evaluated for their anti-Alzheimer potential. Binding interactions with proteins and drug likeness of the analogs were explored through molecular docking and ADMET analysis, respectively. In the novel series, compound- 3 emerged as the most potent inhibitor when compared with other derivatives of the series. Conclusion: The present study provides potent anti-Alzheimer's agents that can be further optimized to discover novel anti-Alzheimer's drugs.

In the present study, naphthalimide-pyrazole-benzothiazole based fluorescent analogs were synthesized by substituting different primary and secondary amines on the naphthalimide nucleus and were evaluated for their sensitivity and selectivity towards serum albumin. Among various synthesized analogues compound 25 showed the most significant change with serum albumin and was further studied for selective detection and mode of interaction with serum albumin. Here, we compared the binding interaction of fluorescent probe 25 for variation/detection of two 76 % structurally resembling proteins HSA and BSA, by spectroscopic experiments. The compound shows more selectivity for HSA and BSA with a higher binding constant and evident visible change in the emission spectra of two serum albumins among different bioanalytes. The mode of interaction of 25 with human serum albumin and bovine serum albumin was investigated by FT-IR, circular dichroism, and DLS techniques to find out the change in the microenvironment and variation in the structure of serum albumin proteins. Higher binding affinity and specific selectivity of 25 with a limit of detection of 0.69 μM and 1.4 μM towards HSA and BSA compared to other bioanalytes make it a significant fluorescent probe for quantitatively detecting serum albumins at the very early stage of many fatal diseases., (© 2024 Wiley-VCH GmbH.)

New 2-(4-benzothiazol-2-yl-phenoxy)-1-(3,5-diphenyl-4,5-dihydro-pyrazol-1-yl)-ethanones (9a-o) have been designed and synthesized. All the synthesized compounds were characterized by thin layer chromatography and spectral analysis. The antiepileptic potential of the synthesized compounds has been tested by following standard animal screening models, including maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) models. The neurotoxic and antidepression effects of the synthesized compounds were checked by utilizing rotarod apparatus, and motor impairment test (by actophotometer) respectively. The study concluded that compounds 9c, 9d, 9f, 9i, 9n, and 9o possessed good antiepileptic potential compared to standard drugs like carbamazepine and phenytoin. The results of the rotarod performance test also established them without any neurotoxicity. The motor impairment test revealed that the synthesized compounds are also good antidepressants. In-silico studies have been performed for calculation of pharmacophore pattern, prediction of pharmacokinetic properties which determine the eligibility of synthesized compounds as orally administered molecules and interactions with the target proteins. The result of in-silico studies reinforced results obtained by in vivo study of the synthesized compounds and their possible mechanism of antiepileptic action i. e. via inhibiting voltage-gated sodium channels (VGSCs) and gamma-aminobutyric acid-A receptor., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

In this review, we present a systematic and comprehensive summary of the recent developments in the synthetic strategies of 2-(2-hydroxyarylsubstituted)-benzothiazole (HBT) framework along with incorporation of various substituents on phenolic and benzothiazole rings which affect the emission process. The literature, spanning the years 2015-2024, on excited-state intramolecular proton transfer (ESIPT)-based studies of HBT derivatives comprising the effects of solvent polarity, substituents, and extended conjugation on fluorophores has been searched. ESIPT, intramolecular charge transfer, and aggregation-induced emissions enable these fluorescent probes to specifically interact with analytes, thereby altering their luminescence characteristics to achieve analyte detection. These fluorescent probes exhibit large Stokes shifts, high quantum yields, and excellent color transitions. Finally, the applications of HBTs as ESIPT-based fluorescent probes for the detection of cations, anions, and biomolecules have been summarized. We anticipate that this review will provide a comprehensive overview of the current state of research in this field and encourage researchers to develop novel ESIPT-based fluorophores with new applications., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Benzothiazole compounds are known as an important bicyclic ring system with multiple applications. These compounds have a wide range of biological activities, including anticancer, antimicrobial, anti-inflammatory and antiviral activities. In this study, benzothiazole compounds were synthesized and their various biological activities were examined. The synthesized benzothiazoles were evaluated for their antimicrobial properties against various bacterial and fungal strains. The compound 6e is most active ligand in the series against bacteria and fungi as compared to standard antibiotics. Especially, this compound significant effect against Staphylococcus aureus (32.00 ± 1.73 mm). These compounds exhibited potent anticancer activity against gastrointestinal cancer cells, demonstrating their potential as therapeutic agents. The lowest antiproliferative response after administration of the compounds was observed in HCT116 cells, while the most effective antiproliferative response was observed in AGS cells (> 10 µg/mL). In all cell lines, 40 and 100 µg/mL application values of the selected compounds showed significant increases in the expression of caspase-3, 8 and 9. We also utilized a computational docking approach to investigate the interaction of these benzothiazoles with VEGFR-2 kinase. Our docking studies showed that compounds 6a and 6d may be promising therapeutic agents against gastrointestinal system cancers due to their ability to bind to VEGFR-2 kinase.

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 IC 50 values ranging from 3.58 to 15.36 μM, against three cancer cell lines. Furthermore, these compounds showed IC 50 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 IC 50 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.

Leishmaniasis is a disease caused by protozoa Leishmania spp., considered as a significant and urgent public health problem mainly in developing countries. In the absence of an effective vaccine, the treatment of infected people is one of the most commonly prophylactic measures used to control this disease. However, the therapeutic arsenal is reduced to a few drugs, with serious side effects and variability in efficacy. Attempting to this problem, in this work, a series of benzothiazole derivatives was synthetized and assayed against promastigotes and intracellular amastigotes of L. amazonensis, as well as the toxicity on macrophages. In addition, studies about the mechanism of action were also performed. Among the synthesized molecules, the substitution at position 4 of the aromatic ring appears to be critical for activity. The best compound exhibited IC 50 values of 28.86 and 7.70 μM, against promastigotes and amastigotes of L. amazonensis, respectively, being more active than miltefosine, used as reference drug. The in silico analysis of physicochemical and pharmacokinetic (ADMET) properties of this compound suggested a good profile of oral bioavailability and safety. In conclusion, the strategy of using benzothiazole nucleous in the search for new antileishmanial agents was advantageous and preliminar data provide information about the mechanism of action as well as in silico parameters suggest a good profile for preclinical studies., (© 2024 John Wiley & Sons Ltd.)

The coupling reaction of diazonium ion of 2-amino-6-nitrobenzothiazole at 0-5 °C with distinctly substituted 2-aminobenzothiazole derivatives produced new 1,2,3,5-tetrazine derivatives. It was found that diazotized 2-amino-6-nitrobenzo[d]thiazol reacts with the ring nitrogen atom of varyingly substituted 2-aminobenzothiazole derivatives to yield tetrazine nucleus. The benzene ring of benzothiazole bearing electron donor group and annelated to the tetrazine was further substituted in situ by other 6-nitrobenzo[d]thiazol-2-yl) diazinyl to yield the final product. The structure of the prepared compounds was elucidated using their physical, elemental, and spectroscopic data. The synthesized compounds were tested for their antimicrobial and antibiofilm activities against Staphylococcus aureus and Escherichia coli bacteria. Two of the synthesis tetrazine derivatives exhibited interesting antibiofilm potential.

Nuclear imaging of aggregated α-synuclein pathology is an urgent clinical need for Parkinson's disease, yet promising tracers for brain α-synuclein aggregates are still rare. In this work, a class of compact benzothiazole derivatives was synthesized and evaluated for α-synuclein aggregates. Among them, azobenzothiazoles exhibited specific and selective detection of α-synuclein aggregates under physiological conditions. Fluoro-pegylated azobenzothiazole NN-F further demonstrated high-affinity binding to α-synuclein aggregates and efficient 18 F-radiolabeling via nucleophilic displacement of a tosyl precursor. [ 18 F]NN-F was stable in plasma in vitro and showed efficient brain uptake with little defluorination in vivo .

In this study, the synthesis of N-(5,6-methylenedioxybenzothiazole-2-yl)-2-[(substituted)thio/piperazine]acetamide/propanamide derivatives (3a-3k) and to investigate their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase 1 (BACE-1) inhibition activity were aimed. Mass, 1 H NMR, and 13 C NMR spectra were utilized to determine the structure of the synthesized compounds. Compounds 3b, 3c, 3f, and 3j showed AChE inhibitory activity which compound 3c (IC 50  = 0.030 ± 0.001 µM) showed AChE inhibitory activity as high as the reference drug donepezil (IC 50  = 0.0201 ± 0.0010 µM). Conversely, none of the compounds showed BChE activity. Compounds 3c and 3j showed the highest BACE-1 inhibitory activity and IC 50 value was found as 0.119 ± 0.004 µM for compound 3j whereas IC 50 value was 0.110 ± 0.005 µM for donepezil, which is one of the reference substance. Molecular docking studies have been carried out using the data retrieved from the server of the Protein Data Bank (PDBID: 4EY7 and 2ZJM). Using in silico approach behavior active compounds (3c and 3j) and their binding modes clarified., (© 2024 The Author(s). Drug Development Research published by Wiley Periodicals LLC.)

α-Glycosidase inhibition is one of the main approaches to treat Diabetes mellitus. Polyphenolic moieties are known to be responsible for yielding exhibit potent α-glycosidase inhibitory effects. In addition, compounds containing benzothiazole and Schiff base functionalities were previously reported to show α-glycosidase inhibition. In this paper, the synthesis of seven new phloroglucinol-containing benzothiazole Schiff base derivatives through the reaction of 6-substituted-2-aminobenzothiazole compounds with 2,4,6-trihydroxybenzaldehyde using acetic acid as a catalyst was reported. The synthesized compounds were characterized using spectroscopic methods such as FT-IR, 1 H NMR, 13 C NMR, and elemental analysis. The synthesized compounds were evaluated for their inhibitory effects on α-glycosidase, compounds 3f and 3g were found to show significant inhibitory properties when compared to the positive control. The IC 50 values of 3f and 3g were calculated as 24.05 ± 2.28 and 18.51 ± 1.19 µM, respectively. Kinetic studies revealed that compounds 3f and 3g exhibited uncompetitive mode of inhibition against α-glycosidase. Molecular modeling predicted druglikeness for the title compounds and underpinned the importance of phloroglucinol hydroxyls for interacting with the key residues of α-glycosidase., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The misfolding and aggregation of α-Syn play a pivotal role in connecting diverse pathological pathways in Parkinson's disease (PD). Preserving α-Syn proteostasis and functionality by inhibiting its aggregation or disaggregating existing aggregates using suitable inhibitors represents a promising strategy for PD prevention and treatment. In this study, a series of benzothiazole-polyphenol hybrids was designed and synthesized. Three identified compounds exhibited notable inhibitory activities against α-Syn aggregation in vitro, with IC 50 values in the low micromolar range. These inhibitors demonstrated sustained inhibitory effects throughout the entire aggregation process, stabilizing α-Syn proteostasis conformation. Moreover, the compounds effectively disintegrated preformed α-Syn oligomers and fibers, potentially by binding to specific domains within the fibers, inducing fibril instability, collapse, and ultimately resulting in smaller-sized aggregates and monomers. These findings offer valuable insights into the therapeutic potential of polyphenol hybrids with 2-conjugated benzothiazole targeting α-Syn aggregation in the treatment of PD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Recent evidence suggests that histone deacetylases (HDACs) are important regulators of autosomal dominant polycystic kidney disease (ADPKD). In the present study, a series of benzothiazole-bearing compounds were designed and synthesized as potential HDAC inhibitors. Given the multiple participation of HDACs in ADPKD cyst progression, we embarked on a targeted screen using HeLa nuclear extracts to identify potent pan-HDAC inhibitors. Compound 26 emerged as the most efficacious candidate. Subsequent pharmacological characterization showed that compound 26 effectively inhibits several HDACs, notably HDAC1, HDAC2, and HDAC6 (IC 50  < 150 nM), displaying a particularly high sensitivity towards HDAC6 (IC 50  = 11 nM). The selected compound significantly prevented cyst formation and expansion in an in vitro cyst model and was efficacious in reducing cyst growth in both an embryonic kidney cyst model and an in vivo ADPKD mouse model. Our results provided compelling evidence that compound 26 represents a new HDAC inhibitor for the treatment of ADPKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Aim: The extensive utilization of 2-phenylbenzothiazole due to their wide array of biological activities, particularly in cancer therapy, has caused great attention to explore more potent derivatives. Materials & methods: We report the synthesis of 2-phenylbenzothiazole tagged 1,2,3-triaozle (8) through Cu(I)-catalyzed cycloaddition of alkyne side chain with aryl-substituted azides. Results: The in vitro experiments, using MTT and 99mTc-MIBI cell uptake methods, demonstrated the remarkable anticancer activity of these compounds against A549, SKOV3 and MCF7 cell lines. Conclusion: Compounds 8b , 8f and 8i possessed high cytotoxic activity as compared with doxorubicin. Compound 8g has a similar inhibitory effect on the proliferation of breast cancer cells as doxorubicin. In silico study indicated that compound 8 would be a good lead for the development of new potent anticancer agents.

Background: Cyclodextrins selectively bind with reactants and facilitate chemical reactions through supramolecular catalysis, similar to the mechanisms employed by enzymes. In this paper, β-cyclodextrin was used as a supramolecular catalyst in water as a green, reusable, and ecofriendly solvent system to synthesize spiro-benzimidazoquinazolinones and spiro-benzothiazoloquinazolinones., Objective: A supramolecular catalyst β-cyclodextrin (β-CD) is used to synthesize spiro- benzimidazoquinazolinones and spiro-benzothiazoloquinazolinones via multicomponent reaction involving the condensation of dimedone, isatin, and 2-aminobenzimidazole/2-aminobenzothiazole., Methods: In a 50 mL round bottom flask were added the respective mixture of substituted isatin (1 mmol), dimedone (1mmol), and 2-aminobenzimidazole/2-aminobenzothiazole (1 mmol) in water (5 ml) containing β-CD (113 mg, 10 mol. %) was stirred at 60oC for 30 min. The desired product was obtained with excellent yield. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with water and extracted with ethyl acetate (4X5 ml). The combined organic layers were washed with brine solution, dried over anhydrous Na 2 SO 4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography., Results: β-cyclodextrin catalyst showed very good efficiency in the synthesis of the desired compounds and can be easily recovered and reused at least five times with minimal deactivation in catalytic activity., Conclusion: The catalyst demonstrated remarkable effectiveness in producing the target compounds and conducting the reaction with different initial substances, resulting in excellent yields of the products, thereby confirming the broad applicability and versatility of this method., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: The objective of the present investigation was to design and synthesize new heterocyclic hybrids comprising benzothiazole and indenopyrazolone pharmacophoric units in a single molecular framework targeting α-amylase and α-glucosidase enzymatic inhibition. Materials & methods: 20 new benzothiazole-appended indenopyrazoles, 3a-t , were synthesized in good yields under environment-friendly conditions via cycloaddition reaction, and assessed for antidiabetic activity against α-amylase and α-glucosidase, using acarbose as the standard reference. Results: Among all the hydroxypyrazolones, 3p and 3r showed the best inhibition against α-amylase and α-glucosidase, which finds support from molecular docking and dynamic studies. Conclusion: Compounds 3p and 3r have been identified as promising antidiabetic agents against α-amylase and α-glucosidase and could be considered valuable leads for further optimization of antidiabetic agents.

Aim: Efficient synthesis of precursor from commercially available starting materials and automated radiosynthesis of [ 11 C]PiB using commercially available dedicated [ 11 C]- Chemistry module from the synthesized precursor., Background: [ 11 C]PiB is a promising radiotracer for PET imaging of β-Amyloid, advancing Alzheimer's disease research. The availability of precursors and protocols for efficient radiolabelling foster the applications of any radiotracer. Efficient synthesis of PiB precursor was performed using anisidine and 4-nitrobenzoyl chloride as starting materials in 5 steps, having addition, substitutions, and cyclization chemical methodologies. This precursor was used for fully automated radiosynthesis of [ 11 C]PiB in a commercially available synthesizer, MPS-100 (SHI, Japan). The synthesized [ 11 C]PiB was purified via solid-phase methodology, and its quality control was performed by the quality and safety criteria required for clinical use., Methods: The synthesis of desired precursors and standard authentic compounds started with commercially available materials with 70-80% yields. The standard analytical methods were characterized all synthesized compounds. The fully automated [ 11 C]-chemistry synthesizer (MPS-100) used for radiosynthesis of [ 11 C]PiB with [ 11 C]CH 3 OTf acts as a methylating agent. For radiolabelling, varied amounts of precursor and time of reaction were explored. The resulting crude product underwent purification through solid-phase cartridges. The synthesized radiotracer was analyzed using analytical tools such as radio TLC, HPLC, pH endo-toxicity, and half-life., Results: The precursor for radiosynthesis of [ 11 C]PiB was achieved in excellent yield using simple and feasible chemistry. A protocol for radiolabelling of precursor to synthesized [ 11 C]PiB was developed using an automated synthesizer. The crude radiotracer was purified by solid-phase cartridge, with a decay-corrected radiochemical yield of 40±5% and radiochemical purity of more than 97% in approx 20 minutes (EOB). The specific activity was calculated and found in a 110-121 mCi/μmol range., Conclusion: A reliable methodology was developed for preparing precursor followed by fully automated radiolabeling using [ 11 C]MeOTf as a methylating agent to synthesize [ 11 C]PiB. The final HPLC-free purification yielded more than 97% radiochemical purity tracer within one radionuclide half-life. The method was reproducible and efficient for any clinical center., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

To discover new agrochemicals with prominent pesticidal properties, a series of novel β -naphthol derivatives containing benzothiazolylamino and various heteroaryl groups ( 8a-q ) were efficiently synthesised via Betti reaction. The bioassay results showed that most of the synthesised compounds exhibited favourable insecticidal potentials, particularly towards oriental armyworm (50-100% at 200 mg·L -1 ) and diamondback moth (50-95% at 10 mg·L -1 ). Compounds 8 b , 8f , 8 g , 8j , 8k , 8n , and 8o possessed LC 50 values of 0.0988-5.8864 mg·L -1 against diamondback moth. Compounds 8i , 8 l , and 8 m also displayed lethality rates of 30-90% against spider mite at the concentration of 100 mg·L -1 . Overall, some compounds could be considered as new insecticidal/acaricidal leading structures for further investigation. The calcium imaging experiments revealed that 8 h , 8i , and viii could activate the release of calcium ions in insect ( M. separata ) central neurons at a higher concentration (50 mg·L -1 ). The SAR analysis provided valuable information for further structural modifications.

Novel PPARδ agonists, 2-(1-piperidinyl)-1,3-benzothiazole derivatives were discovered by our proprietary docking-based virtual screening technique. Compound 1 as the initial hit was effectively modified to acquire PPARδ agonist activity, resulting in the discovery of compound 12 with high agonistic potency for PPARδ and selectivity over PPARα and PPARγ. Compound 12 also had good ADME profiles and showed in vivo efficacy as a lead., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

A novel series of benzothiazole-based derivatives linked to various amino acids and their corresponding ethyl ester analogues were prepared and were initially evaluated for their anticancer activity againstMCF-7 and HepG-2 and were further assessed as VEGFR-2 inhibitors. All the newly synthesized benzothiazole derivatives showed promising cytotoxic activities against the tested cell lines. Derivatives exhibited potent cytotoxic and VEGFR-2 inhibitory activities were then evaluated further as anticancer agents against the resistant MDA-MB-231 and as EGFR inhibitors. The carboxylic acid derivatives 10-12 and their ester analogues 21-23 displayed the highest anticancer activities with IC 50 of 0.73-0.89 µM, against MCF-7 and IC 50 of 2.54-2.80 µM, against HepG-2; compared to doxorubicin (IC 50  = 1.13 and 2.75 µM, respectively); also they showed safety towards the normal cell line, the ethyl ester derivatives 21-23 showed a potent activity against the resistant MDA-MB-231 cell line with IC 50 of 5.45-7.28 µM, relative to doxorubicin (IC 50  = 7.46 µM) surpassing their carboxylic acid analogues 10-12 (IC 50 of 8.88-11.02 µM). Furthermore, the promising derivatives 10-12 and 21-23 displayed promising VEGFR-2 inhibitory activity (IC 50  = 0.15-0.19 µM) comparable to that of sorafenib (IC 50  = 0.12 µM). Against EGFR, the ethyl ester derivatives 21-23 showed superior inhibitory activity relative to the used reference standard, erlotinib, with IC 50 of 0.11-0.16 vs. 0.18 µM, respectively. The QSAR study revealed that the molecular bulkiness and molecular partial charge distribution govern the kinase inhibition potency in this series. Furthermore, the molecular docking study in VEGFR-2 active site showed that the novel synthesized benzothiazole derivatives adopted the common binding pattern of type II PK inhibitors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

In our attempt towards the synthesis and development of effective antimicrobial, anticancer and antioxidant agents, a novel series of 2,3-dihydropyrido[2,3-d]pyrimidin-4-one 7a - e and pyrrolo[2,1-b][1,3]benzothiazoles 9a - e were synthesized. The synthesis of 2-(1,3-benzo thiazol-2-yl)-3-(aryl)prop-2-enenitrile ( 5a - e ) as the key intermediate was accomplished by a microwave efficient method. Via a new variety oriented synthetic microwave pathway, these highly functionalized building blocks allowed access to numerous fused heteroaromatic such as 7-amino-6-(1,3-benzo thiazol-2-yl)-5-(aryl)-2-thioxo-2,3dihydropyrido [2,3-d]pyrimidin-4(1H)-one 7a - e and 1-amino-2-(aryl)pyrrolo[2,1-b][1,3]benzothiazole-3-carbonitrile derivatives 9a - e in order to study their antimicrobial and anticancer activity. The present investigation offers effective and rapid new procedures for the synthesis of the newly polycondensed heterocyclic ring systems. All the newly synthesized compounds were evaluated for antimicrobial, anticancer and antioxidant activity. Compounds 7a , d , and 9a , d showed higher antimicrobial activity than cefotaxime and fluconazole while the remaining compounds exhibited good to moderate activity against bacteria and fungi. An anticancer evaluation of the newly synthesized compounds against the three tumor cell lines (lung cell NCI-H460, liver cancer HepG2 and colon cancer HCT-116) exhibited that compounds 7a , d , and 9a , d have higher cytotoxicity against the three human cell lines compared to doxorubicin as a reference drug. These compounds also exhibited higher antioxidant activity and a great ability to protect DNA from damage induced by bleomycin.

This work deals with the design and synthesis of a series of new substituted 2-arylbenzothiazole compounds attached to 4-oxothiazolidin-2-ylidene ring 2-12 and chain elongation with different amino acids and their corresponding ester derivatives 13-18. All prepared derivatives were screened for their in vitro cytotoxicity activities against two cancer cell lines (HepG-2 and MCF-7) in comparison with doxorubicin; in addition to their safety towards thenormal cell line. Furthermore, all compounds 2-18 were evaluated as FGFR-1 inhibitors using AZD4547 as a reference. The 4-oxothiazolidin-2-ylidene derivatives 3 and 8 exhibited the highest cytotoxic activity (IC 50 HepG-2  = 2.06, 2.21 µM and IC 50 MCF-7  = 0.73, 0.77 µM, respectively) through their promising FGFR-1 suppression effects (IC 50  = 16.31 and 18.08 nM, respectively) in comparison to AZD4547 (IC 50  = 21.45 nM). Cell cycle and apoptosis analysis indicated that compounds 3 and 8 induce pronounced increase in the cell percentages at pre-G 1 and G 2 /M phase compared to the untreated MCF-7 cancer cells, in addition to their up regulation of caspase-3/7/9. The molecular docking simulation was created to elucidate the binding modes of benzothiazole derivatives 1-18 bearing various scaffolds within the ATP-binding pocket of FGFR-1 enzyme compared with AZD4547., (Copyright © 2021. Published by Elsevier Inc.)

To discover an efficient and convenient method to synthesize C2-arylacylated benzothiazoles as potential drug scaffolds, a novel [bis(trifluoroacetoxy)iodo]benzene(PIFA)/KOH synergistically promoted direct ring-opening C2-arylacylation reaction of 2H -benzothiazoles with aryl methyl ketones has been developed. Various substrates were tolerated under optimized conditions affording the C2-arylacylation products in 70-95% yields for 38 examples. A plausible mechanism was also proposed based on a series of controlled experiments.

Newly synthesised benzimidazole/benzotiazole derivatives bearing amidino, namely 3,4,5,6-tetrahydropyrimidin-1-ium chloride, substituents have been evaluated for their potential antitumor activity in vitro . Compounds and standard drugs (doxorubicin, staurosporine and vandetanib) were tested on three human lung cancer cell lines A549, HCC827 and NCI-H358. We tested compounds in MTS citotoxicity assay and in BrdU proliferative assay performed on 2 D and 3 D assay format. Because benzmidazole scaffold is similar to natural purines, we tested the most active compounds for ability to induce cell apoptosis of A549 by binding to DNA in comparison with doxorubicin and saturosporine. Additionally, the ADME properties of the most active benzothiazole/benzimidazole and non-active compounds were determined to see if the different ADME properties are the cause of different activity in 2 D and 3 D assays, as well as to see if the tested active compounds have drug like properties and potency for further profilation. ADME characterisation included solubility, lipophilicity, permeability, metabolic stability and binding to plasma proteins. In general, the benzothiazole derivatives were more active in comparison to their benzimidazole analogues. The exception was 2-phenyl substituted benzimidazole 6a being active with very pronounced activity especially towards HCC827 cells. All active compounds have similar mode of action on A549 cell line as standard compound doxorubicin, which binds to nucleic acids with the DNA double helix. Tested active benzothiazole compounds were characterised by moderate to good solubility, good metabolic stability, low permeability and high binding to plasma proteins. One tested active benzimidazole derivative showed ADME properties, but lower lipophilicity resulted in low PPB and higher metabolic instability. In addition, no significant difference was observed in ADME profile between active and non-active compounds.

The synthesis, in silico molecular docking, and in vitro urease inhibition studies of a novel series of benzothiazole derivatives are reported. The title compounds in the two series, namely, 2-({5-[(benzothiazol-2-ylthio)methyl]-1,3,4-oxadiazol-2-yl}thio)-1-(4-substituted-phenyl)ethan-1-one and 2-(benzothiazol-2-ylthio)-1-(4-substituted-phenyl)ethan-1-one oxime, were synthesized by the reaction of benzo[d]thiazole-2-thiol with different kinds of intermediates in several steps using both conventional and microwave techniques. All compounds were found to have an excellent degree of urease-inhibitory potential ranging between 16.16 ± 0.54 and 105.32 ± 2.10 µM when compared with the standard inhibitor acetohydroxamic acid with IC 50  = 320.70 ± 4.24 µM. The structure-activity relationship was established in detail. The binding interactions of the compounds with the enzyme were confirmed through molecular docking. Further, 100 -ns molecular dynamics simulations were performed to investigate the stability and structural perturbations experienced by the most potent compound over the urease active site., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Targeted therapy plays a pivotal role in cancer therapeutics by countering the drawbacks of conventional treatment like adverse events and drug resistance. Over the last decade, heterocyclic derivatives have received considerable attention as cytotoxic agents by modulating various signaling pathways. Benzothiazole is an important heterocyclic scaffold that has been explored for its therapeutic potential. Benzothiazole-based derivatives have emerged as potent inhibitors of enzymes such as EGFR, VEGFR, PI3K, topoisomerases, and thymidylate kinases. Several researchers have designed, synthesized, and evaluated benzothiazole scaffold-based enzyme inhibitors. Of these, several inhibitors have entered various phases of clinical trials. This review describes the recent advances and developments of benzothiazole architecture-based derivatives as potent anticancer agents., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

A series of 6-amidinobenzothiazoles, linked via phenoxymethylene or directly to the 1,2,3-triazole ring with a p -substituted phenyl or benzyl moiety, were synthesised and evaluated in vitro against four human tumour cell lines and the protozoan parasite Trypanosoma brucei . The influence of the type of amidino substituent and phenoxymethylene linker on antiproliferative and antitrypanosomal activities was observed, showing that the imidazoline moiety had a major impact on both activities. Benzothiazole imidazoline 14a , which was directly connected to N -1-phenyl-1,2,3-triazole, had the most potent growth-inhibitory effect (IC 50 = 0.25 µM) on colorectal adenocarcinoma (SW620), while benzothiazole imidazoline 11b , containing a phenoxymethylene linker, exhibited the best antitrypanosomal potency (IC 90 = 0.12 µM). DNA binding assays showed a non-covalent interaction of 6-amidinobenzothiazole ligands, indicating both minor groove binding and intercalation modes of DNA interaction. Our findings encourage further development of novel structurally related 6-amidino-2-arylbenzothiazoles to obtain more selective anticancer and anti-HAT agents.

The death caused by pathogenic bacteria has always been a severe threat to mankind. The prevalence of drug resistance among bacteria underscores an urgent goal for new antibacterial agents with novel mode of action. Here we first designed and synthesized a class of benzothiazolyl-5-methylphenanthridium derivatives and evaluated their antibacterial activity. On this basis, we further designed and synthesized another class of novel indolyl-5-methylphenanthridium derivatives by optimizing the benzothiazolyl-5-methylphenanthridium core and evaluated their antibacterial activity targeting the bacterial cell division protein FtsZ. The results showed that the indolyl-5-methylphenanthridium derivatives had greatly improved activity against various drug-resistant bacterial strains including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus (VRE). Among them, compound C5 displayed excellent antibacterial activity against susceptible (MIC = 1 μg/mL), methicillin-resistant and clinical isolated S. aureus (MIC = 2 μg/mL). With low hemolytic activity towards mice red blood cells, C5 exhibited good antibacterial effect in vivo in preliminary pharmacodynamic assay. More importantly, C5 was difficult to induce bacterial resistance. Further mechanism studies proved that C5 could inhibit bacterial cell division by promoting FtsZ polymerization, leading to disorderly polymerization and disordered knots. Therefore, our findings suggest that this class of novel indolyl-5-methylphenanthridium derivatives are promising for future antibacterial agents., 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.)

We have synthesized a cyan fluorescent benzothiazole-pyridinium salt composite based on D-π-A architecture. This salt was found to work as not only a two- and three-photon excitable fluorophore but also a degradation agent against amyloid fibrils under LED irradiation conditions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In recent years, dengue virus (DENV) and Zika virus (ZIKV), both mosquito-borne members of the Flaviviridae family, have emerged as intercontinental health issues since their vectors have spread from their tropical origins to temperate climate zones due to climate change and increasing globalization. DENV and ZIKV are positive-sense, single-stranded RNA viruses, whose genomes consist of three structural (capsid, membrane precursor, envelope) and seven non-structural (NS) proteins, all of which are initially expressed as a single precursor polyprotein. For virus maturation, the polyprotein processing is accomplished by host proteases and the viral NS2B/NS3 protease complex, whose inhibitors have been shown to be effective antiviral agents with loss of viral pathogenicity. In this work, we elucidate new structure-activity relationships of benzo[d]thiazole-based allosteric NS2B/NS3 inhibitors. We developed a new series of Y-shaped inhibitors, which, with its larger hydrophobic contact surface, should bind to previously unaddressed regions of the allosteric NS2B/NS3 binding pocket. By scaffold-hopping, we varied the benzo[d]thiazole core and identified benzofuran as a new lead scaffold shifting the selectivity of initially ZIKV-targeting inhibitors to higher activities towards the DENV protease. In addition, we were able to increase the ligand efficiency from 0.27 to 0.41 by subsequent inhibitor truncation and identified N-(5,6-dihydroxybenzo[d]thiazol-2-yl)-4-iodobenzamide as a novel sub-micromolar NS2B/NS3 inhibitor. Utilizing cell-based assays, we could prove the antiviral activity in cellulo. Overall, we report new series of sub-micromolar allosteric DENV and ZIKV inhibitors with good efficacy profile in terms of cytotoxicity and protease inhibition selectivity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A new anticancer benzo[d]thiazolo[3,2-a]quinolin-10-ium derivatives were synthesized and characterized. Anticancer evaluation in vitro against four cancer cell lines including adenocarcinomic human alveolar basal epithelial cells (A549), hepatocellular carcinoma (HepG2), prostate cancer (PC3) and breast cancer (MCF7) indicated that some of prepared compounds shows higher selectivity in comparison with doxorubicin. DNA interaction studies by optical, CD, NMR spectroscopies showed the high affinity of benzothiazole ligands towards the dsDNA. The ligand-DNA interaction occurs through the intercalation of benzo[d]thiazolo[3,2-a]quinolin-10-ium derivatives with nucleic acid. The investigation of formed ligand - DNA complexes by docking and molecular dynamic calculations was applied for analysis of the relationship between structure and anticancer activity. The results suggested that benzo[d]thiazolo[3,2-a]quinolin-10-ium derivatives might serve as a novel scaffold for the future development to new antitumor agents., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The upregulation of the CB 2 receptors in neuroinflammation and cancer and their potential visualization with PET (positron emission tomography) could provide a valuable diagnostic and therapy-monitoring tool in such disorders. However, the availability of reliable CB 2 -selective imaging probes is still lacking in clinical practice. We have recently identified a benzothiazole-2-ylidine amide hit (6a) as a highly potent CB 2 ligand. With the aim of enhancing its CB 2 over CB 1 selectivity and introducing structural sites suitable for radiolabeling, we herein describe the development of fluorinated and methoxylated benzothiazole derivatives endowed with extremely high CB 2 binding affinity and an exclusive selectivity to the CB 2 receptor. Compounds 14, 15, 18, 19, 21, 24 and 25 displayed subnanomolar CB 2 K i values (ranging from 0.16 nM to 0.68 nM) and interestingly, all of the synthesized compounds completely lacked affinity at the CB 1 receptor (K i  > 10,000 nM for all compounds), indicating their remarkably high CB 2 over CB 1 selectivity factors. The fluorinated analogs, 15 and 21, were evaluated for their in vitro metabolic stability in mouse and human liver microsomes (MLM and HLM). Both 15 and 21 displayed an exceptionally high stability (98% and 91% intact compounds, respectively) after 60 min incubation with MLM. Contrastingly, a 5- and 2.8-fold lower stability was demonstrated for compounds 15 and 21, respectively, upon incubation with HLM for 60 min. Taken together, our data present extremely potent and selective CB 2 ligands as credible leads that can be further exploited for 18 F- or 11 C-radiolabeling and utilization as PET tracers., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Newly designed and synthesized cyano, amidino and acrylonitrile 2,5-disubstituted furane derivatives with either benzimidazole/benzothiazole nuclei have been evaluated for antitumor and antimicrobial activity. For potential antitumor activity, the compounds were tested in 2D and 3D cell culture methods on three human lung cancer cell lines, A549, HCC827 and NCI-H358, with MTS cytotoxicity and BrdU proliferation assays in vitro. Compounds 5 , 6 , 8 , 9 and 15 have been proven to be compounds with potential antitumor activity with high potential to stop the proliferation of cells. In general, benzothiazole derivatives were more active in comparison to benzimidazole derivatives. Antimicrobial activity was evaluated with Broth microdilution testing (according to CLSI (Clinical Laboratory Standards Institute) guidelines) on Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus . Additionally, Saccharomyces cerevisiae was included in testing as a eukaryotic model organism. Compounds 5 , 6 , 8 , 9 and 15 showed the most promising antibacterial activity. In general, the compounds showed antitumor activity, higher in 2D assays in comparison with 3D assays, on all three cell lines in both assays. In natural conditions, compounds with such an activity profile (less toxic but still effective against tumor growth) could be promising new antitumor drugs. Some of the tested compounds showed antimicrobial activity. In contrast to ctDNA, the presence of nitro group or chlorine in selected furane-benzothiazole structures did not influence the binding mode with AT-DNA. All compounds dominantly bound inside the minor groove of AT-DNA either in form of monomers or dimer and higher-order aggregates.

The formation of biofilms by clinical pathogens typically leads to chronic and recurring antibiotic-resistant infections. High cellular levels of cyclic diguanylate (c-di-GMP), a ubiquitous secondary messenger of bacteria, have been proven to be associated with a sessile biofilm lifestyle of pathogens. A promising antibiofilm strategy involving the induction of c-di-GMP to form dysfunctional G-quadruplexes, thereby blocking the c-di-GMP-mediated biofilm regulatory pathway, was proposed in this study. In this new strategy, a series of novel c-di-GMP G-quadruplex inducers were designed and synthesized for development of therapeutic biofilm inhibitors. Compound 5h exhibited favorable c-di-GMP G-quadruplex-inducing activity and 62.18 ± 6.76% biofilm inhibitory activity at 1.25 μM without any DNA intercalation effect. Moreover, the favorable performance of 5h in interfering with c-di-GMP-related biological functions, including bacterial motility and bacterial extracellular polysaccharide secretion, combined with the reporter strain and transcriptome analysis results confirmed the c-di-GMP signaling-related action mechanism of 5h .

Molecules that exhibit solid-state luminescence enhancement, i.e. the rare property to be more strongly emissive in the solid state than in solution, find an increasing number of applications in the fields of optoelectronic and nanophotonic devices, sensors, security papers, imaging, and theranostics. Benzazole (BZ) heterocycles are of particular value in this context. The simple enlargement of their π-electron system using a -C=C-Ar or -N=C-Ar moiety is enough for intrinsic solid-state luminescence enhancement (SLE) properties to appear. Their association with a variety of polyaromatic motifs leads to SLE-active molecules that frequently display attractive electroluminescent properties and are sensitive to mechanical stimuli. The excited-state intramolecular proton transfer (ESIPT) process that takes place in some hydroxy derivatives reinforces the SLE effect and enables the development of new sensors based on a protection/deprotection strategy. BZ may also be incorporated into frameworks that are prototypical aggregation-induced enhancement (AIE) luminogens, such as the popular tetraphenylethene (TPE), leading to materials with excellent optical and electroluminescent performance. This review encompasses the various ways to use BZ units in SLE systems. It underlines the significant progresses recently made in the understanding of the photophysical mechanisms involved. A brief overview of the synthesis shows that BZ units are robust building blocks, easily incorporated into a variety of structures. Generally speaking, we try to show how these small heterocycles may offer advantages for the design of increasingly efficient luminescent materials., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Organic small molecules with near-infrared (NIR) absorption hold great promise as the phototheranostic agents for clinical translation by virtue of their inherent merits such as well-defined chemical structure, high purity and good reproducibility. Probes that happen to be based on cyanine dyes exhibit strong NIR-absorbing and efficient photothermal conversion, representing a new class of photothermal agents (PAs) for photothermal therapy (PTT), and taking into account the heat susceptibility of Mitochondria (Mito), we designed and prepared a mitochondria-targeted organic small molecule (Mito-BWQ) based on thiazole orange maternal unit that can effectively kill tumor cells through the hyperpyrexia generated in the lesions under exogenous laser irradiation. The Confocal laser scanning microscope was employed to determine the preferential targeting of Mito-BWQ to the mitochondria of MCF-7 cells and U87 cells. When subjected to 600 nm laser radiation, Mito-BWQ produced an increase in temperature in test systems and this increase was dependent on both the laser power and probe concentration. In vitro tests, cytotoxicity was observed when cells were incubated with Mito-BWQ and exposed to laser irradiation. The PTT in vivo also showed that Mito-BWQ performed remarkably in tumor inhibition. This study thus provides a vital starting point for the creation of thiazole orange-based PTT formulations and promotes further advances in the field of PAs-based anticancer research and therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Necroptosis is a form of programmed cell death that contributes to the pathophysiology of multiple diseases. Development of small-molecule anti-necroptosis agents has great promising clinical therapeutic relevance. The benzothiazole compounds were discovered by our group from an in-house fluorine-containing compound library as potent necroptosis inhibitors. Herein, a chiral dimethylcyclopropyl benzothiazole necroptosis inhibitor was developed and the enantiomeric profiling resulted that the (S) form was generally more potent than the (R) counterpart in 2 ~ 4-fold toward cell necroptosis, receptor-interacting protein (RIP) kinases 1 and 3. The chiral compounds could significantly inhibit the expression of the phosphorylation of RIPK1, RIPK3 and MLKL in necroptotic cells. The molecular modelling studies predicted the binding modes of the enantiomers with RIP and explained their activity differences, guiding further rational design of the chiral necroptosis inhibitors., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Myotonic dystrophy type 2 (DM2) is one of >40 microsatellite disorders caused by RNA repeat expansions. The DM2 repeat expansion, r(CCUG) exp (where "exp" denotes expanded repeating nucleotides), is harbored in intron 1 of the CCHC-type zinc finger nucleic acid binding protein (CNBP). The expanded RNA repeat causes disease by a gain-of-function mechanism, sequestering various RNA-binding proteins including the pre-mRNA splicing regulator MBNL1. Sequestration of MBNL1 results in its loss-of-function and concomitant deregulation of the alternative splicing of its native substrates. Notably, this r(CCUG) exp causes retention of intron 1 in the mature CNBP mRNA. Herein, we report druglike small molecules that bind the structure adopted by r(CCUG) exp and improve DM2-associated defects. These small molecules were optimized from screening hits from an RNA-focused small-molecule library to afford a compound that binds r(CCUG) exp specifically and with nanomolar affinity, facilitates endogenous degradation of the aberrantly retained intron in which it is harbored, and rescues alternative splicing defects.

Receptor-related orphan receptor γ (RORγ) has emerged as an attractive therapeutic target for the treatment of cancer and inflammatory diseases. Herein, we report our effort on the discovery, optimization, and evaluation of benzothiazole and benzimidazole derivatives as novel inverse agonists of RORγ. The representative compound 27h (designated as XY123) potently inhibited the RORγ transcription activity with a half-maximal inhibitory concentration (IC 50 ) value of 64 nM and showed excellent selectivity against other nuclear receptors. 27h also potently suppressed cell proliferation, colony formation, and the expression of androgen receptor (AR)-regulated genes in AR-positive prostate cancer cell lines. In addition, 27h demonstrated good metabolic stability and a pharmacokinetic property with reasonable oral bioavailability (32.41%) and moderate half-life ( t 1/2 = 4.98 h). Significantly, oral administration of compound 27h achieved complete and long-lasting tumor regression in the 22Rv1 xenograft tumor model in mice. Compound 27h may serve as a new valuable lead compound for further development of drugs for the treatment of prostate cancer.

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Five nucleic acid binding cyanine dyes were synthesized and their photophysical properties were evaluated. Changing a single heteroatom in the chromophore causes major differences both in brightness and photostability between the dyes. With such alteration, the brightness of the chromophore increased two-fold compared to the one found in SYBR Green I.

The review is devoted to modern trends in the chemistry of 2-amino and 2-mercapto substituted benzothiazoles covering the literature since 2015. The reviewed heterocycles belong to biologically active and industrially demanded compounds. Newly developed synthesis methods can be divided into conventional multistep processes and one-pot, atom economy procedures, realized using green chemistry principles and simple reagents. The easy functionalization of the 2-NH 2 and 2-SH groups and the benzene ring of the benzothiazole moiety allows considering them as highly reactive building blocks for organic and organoelement synthesis, including the synthesis of pharmacologically active heterocycles. The review provides a summary of findings, which may be useful for developing new drugs and materials and new synthetic approaches and patterns of reactivity.

With the aim to obtain potent adenosine A 2A receptor (A 2A R) ligands, a series of eighteen derivatives of 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide (SYN-115, Tozadenant) were designed and synthesized. The target compounds were obtained by a chemical building block principle that involved reaction of the appropriate aminobenzothiazole phenyl carbamates with either commercially available or readily synthesized functionalized piperidines. Their affinity and subtype selectivity with regard to human adenosine A 1 -and A 2A receptors were determined using radioligand binding assays. K i values for human A 2A R ranged from 2.4 to 38 nM, with more than 120-fold selectivity over A 1 receptors for all evaluated compounds except 13k which had a K i of 361 nM and 18-fold selectivity. The most potent fluorine-containing derivatives 13e, 13g and 13l exhibited K i values of 4.9 nM, 3.6 nM and 2.8 nM for the human A 2A R. Interestingly, the corresponding values for rat A 2A R were found to be four to five times higher. Their binding to A 2A R was further confirmed by radiolabeling with 18 F and in vitro autoradiography in rat brain slices, which showed almost exclusive striatal binding and complete displacement by the A 2A R antagonist ZM 241385. We conclude that these compounds represent potential candidates for the visualization of the A 2A receptor and open pathways to novel therapeutic treatments of neurodegenerative disorders or cancer., 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.)