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The present study aims to create spiro-N-(4-sulfamoyl-phenyl)-1,3,4-thiadiazole-2-carboxamide derivatives with anticancer activities. The in vitro anticancer evaluation showed that only the novel spiro-acenaphthylene tethered-[1,3,4]-thiadiazole (compound 1 ) exhibited significant anticancer efficacy as a selective inhibitor of tumor-associated isoforms of carbonic anhydrase. Compound 1 demonstrated considerable efficacy against the renal RXF393, colon HT29, and melanoma LOX IMVI cancer cell lines, with IC 50 values of 7.01 ± 0.39, 24.3 ± 1.29, and 9.55 ± 0.51 µM, respectively. In comparison, doxorubicin exhibited IC 50 values of 13.54 ± 0.82, 13.50 ± 0.71, and 6.08 ± 0.32 µM for the corresponding cell lines. Importantly, compound 1 exhibited lower toxicity to the normal WI 38 cell line than doxorubicin, with IC 50 values of 46.20 ± 2.59 and 18.13 ± 0.93 µM, respectively, indicating greater selectivity of the target compound compared to the standard anticancer agent doxorubicin. Also, mechanistic experiments demonstrated that compound 1 exhibits inhibitory activity against human carbonic anhydrase hCA IX and XII, with IC 50 values of 0.477 ± 0.03 and 1.933 ± 0.11 μM, respectively, indicating enhanced selectivity for cancer-associated isoforms over cytosolic isoforms hCA I and II, with IC 50 values of 7.353 ± 0.36 and 12.560 ± 0.74 μM, respectively. Cell cycle studies revealed that compound 1 caused G1 phase arrest in RXF393 cells, and apoptosis experiments verified a substantial induction of apoptosis with significant levels of early and late apoptosis, as well as necrosis (11.69%, 19.78%, and 3.66%, respectively), comparable to those induced by the conventional cytotoxic agent doxorubicin, at 9.91%, 23.37%, and 6.16%, respectively. Molecular docking experiments confirmed the strong binding affinity of compound 1 to the active sites of hCA IX and XII, highlighting significant interactions with zinc-binding groups and hydrophobic residues. These findings underscore the target compound's potential as a viable anticancer agent via targeting CA.

A diverse set of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides 4(a-o) was synthesized via a one-pot reaction of 5-amino-[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4 e demonstrated superior efficacy against the Salinivibrio proteolyticus strain of Gram-negative bacteria compared to ciprofloxacin. Compound 4 d exhibited the highest potency against the fungal strain Candida albicans, surpassing amphotericin B. The physicochemical characteristics of 4 d and 4 e were assessed. According to docking analysis, DHTDAPy 4 e shows a higher binding affinity of -7.2 kcal/mol in the binding cavity of the receptor. These findings illustrate the safety, tolerability, and potency of the newly synthesized DHTDAPy compounds against fungal and bacterial infections., (© 2024 Wiley-VCH GmbH.)

The present study aimed to investigate the therapeutic effects of electroacupuncture (EA) on chronic cerebral hypoperfusion (CCH). We first applied the Morris water maze approach to determine the effects of EA and TGN-020 [an inhibitor of aquaporin 4 (AQP4)] on the learning and memory ability of CCH rats. The hematoxylin and eosin, and Nissl staining were further used to investigate the effects of EA and TGN-020 on the neuropathological changes of the dentate gyrus. Next, the ELISA kits were adopted to determine the effects of EA and TGN-020 on the content of amyloid-beta (Aβ) in the cerebrospinal fluid of CCH rats. Finally, we respectively employed technologies of immunohistochemical staining, quantitative real-time PCR, and Western blot to further explore the effects of EA and TGN-020 on the mRNA expression level of amyloid precursor protein (APP) and AQP4 as well as the protein expression level of Aβ1-42 and AQP4 in the dentate gyrus of CCH rats. Our results indicated that EA not only enhanced the learning and memory abilities of CCH rats but also improved the neuropathological damages of CCH rats by upregulating the mRNA and protein expression level of AQP4 to reduce the accumulation of Aβ, especially for the reduction of the mRNA expression level of APP and the protein expression level of Aβ1-42, but TGN-020 effectively reversed the therapeutic effects mentioned above of EA. In summary, we proved that EA, as the activator of AQP4, prevents the accumulation of Aβ during the treatment of CCH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Aim: Emerging resistance among pathogens necessitates the development of novel antimicrobial agents. As a result, we aimed to synthesize new coumarins and study their antimicrobial activity with the hope of obtaining effective drugs., Method: A series of coumarins were synthesized, characterized, and assessed for antimicrobial activity using broth microdilution and agar diffusion methods against Gram-positive ( Bacillus pumilis, Streptococcus faecalis ), Gram-negative ( Escherichia coli, Enterobacter cloacae ) bacteria, and fungi ( Saccharomyces cerevisiae, Candida albicans )., Results: Pyrazoles 15 and 16 revealed promising activities against all bacterial strains with MIC values ranging from 1.95 to 15.6 µg/ml. Notably, pyrazole 15 with CF 3 in 3-position of pyrazole ring demonstrated higher ability to inhibit Streptococcus faecalis strain with MIC value equal to penicillin G (3.91 µg/ml). It also exhibited the best bactericidal potency against Escherichia coli with MBC value of 15.6 µg/ml while, pyrazole 16 recorded the same MBC value against Enterobacter cloacae . Pyrazole 15 demonstrated the strongest antifungal activity against both fungal strains with MIC and MFC values of 15.6, 7.81, 62.5, and 31.3 µg/ml against Saccharomyces cerevisiae and Candida albicans , respectively., Conclusion: These findings underscore the potential of coumarins, particularly compounds 15 and 16 , as effective antimicrobial agents and provide critical insights into the design of bioactive molecules.

Tomato yellow leaf curl virus (TYLCV) poses a significant threat to tomato production, leading to severe yield losses. The current control strategies primarily rely on the use of pesticides, which are often nonselective and costly. Therefore, there is an urgent need to identify more environmentally friendly alternatives. Dufulin, a novel compound that has been effective in controlling viral diseases in tobacco and rice, has not yet been tested against TYLCV. This study assessed the efficacy of dufulin in controlling TYLCV over a three-year span from 2021 to 2023 through field trials, by monitoring disease symptoms and viral titers. Additionally, this study assessed the expression levels of genes associated with systemic acquired resistance (SAR), specifically proteinase inhibitor II ( PI II ) and non-expressor of pathogenesis-related genes 1 ( NPR1 ), using real-time qRT-PCR. The chlorophyll and nitrogen content in the leaves were also measured. Plants treated with dufulin showed reduced symptomatology and lower viral titers compared to the controls. Analysis of gene expression revealed that NPR1 was upregulated in the dufulin-treated plants, whereas PI II expression was consistently downregulated in the TYLCV-infected plants. Interestingly, PI II expression increased in the healthy plants following a seven-day post-treatment with dufulin. Moreover, the treated plants exhibited a higher chlorophyll content than the controls, though no significant differences in the nitrogen levels were observed between the dufulin-treated and water-treated plants. Overall, the application of dufulin significantly bolstered the plant's defense response, effectively reducing TYLCV symptoms and enhancing resistance.

This study explores the design, synthesis, and evaluation of a novel series of isobenzofuran-based imidazo[2,1-b][1,3,4]thiadiazole derivatives, targeting their antimicrobial and anticancer properties. These compounds integrate the pharmacologically significant 1,3,4-thiadiazole and imidazole moieties, which are known for their potential in drug development, although imidazo[2,1-b][1,3,4]thiadiazole-based drugs are not yet available on the market. Therefore, the aim of this study is to develop novel derivatives that could serve as promising candidates for future therapeutic applications. The derivatives were synthesized in two steps and thoroughly characterized using IR, 1 H NMR, 13 C NMR, and mass spectrometry. All the derivatives had shown fairly good antimicrobial activity against four microorganisms (Escherichia coli, Staphylococcus aureus, Mycobacterium smegmatis and Candida albicans) with minimum inhibition concentration's ranging from 0.14 to 0.59 mM. The anticancer activity of the compounds against MCF-7 cell lines showed promising activity, where three derivatives, 3a, 3c and 3d exhibited better inhibition than the standard, cisplatin. The highest anticancer activity was shown by the derivative 3c with an IC 50 value of 35.81 μM. Molecular docking was studied to determine the docking poses and binding interaction of the derivatives with the protein bearing PDB: 5BNS and 3ZNR; ADME properties of the derivatives are also inferred which gives insights into the bioavailability. The molecular dynamics simulation of the derivative 3c with HDAC7 protien (PDB: 3ZNR) was evalauted to determine the stability of the interaction between the protein and the ligand., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Given the significant prevalence of FLT3 receptor and its mutations in acute myeloid leukemia (AML) pathogenesis, we present a novel series of furo[2,3-d]pyrimidin-1,3,4-thiadiazole-urea derivatives, designed to exhibit FLT3-ITD inhibitory activity. These compounds demonstrated cytotoxicity in FLT3-ITD expressing AML cell lines MOLM-13 and MV4-11 in the nanomolar range, with significant selectivity over the K562 cell line. In-depth evaluations of example compound 49 revealed its efficacy in suppressing FLT3 phosphorylation and the downstream signaling molecules, including STAT5 and ERK1/2. Notably, compound 49 demonstrated cytotoxic effects in Ba/F3 cells expressing FLT3-ITD or FLT3-ITD-F691L mutant, exceeding the potency of both sorafenib and quizartinib. Molecular docking studies suggest that this compound binds to the active site of FLT3 in a type II manner. The study suggests that substituted furo[2,3-d]pyrimidines could be useful additions to the growing field of FLT3-targeted therapy for AML. These compounds have the potential to serve as novel FLT3-ITD inhibitors and may offer insights for developing future therapeutic strategies in AML., 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 Masson SAS.. All rights reserved.)

Ethnopharmacology Relevance: Lepidium meyenii Walp. (maca) has been traditionally used for centuries in the Central Andes region both as food and as medicine. In the last decades, its fertility enhancer properties have gained importance, with the majority of the scientific literature related to this topic. However, other traditional uses are less known as metabolic or infectious diseases., Aim of the Study: The main purpose of this study is to investigate the anti-infectious activity of L. meyenii, specifically in HIV-1 infection. There are previous reports of the transcriptional related activity of L. meyenii extracts in human T lymphocytes via transcription factors as NF-κB. Since T lymphocytes are the main target of HIV-1 infection and NF-κB is strongly involved in HIV-1 transcription, L. meyenii could display antiviral activity., Material and Methods: Chromatography and spectroscopy techniques were used to isolate and identify the compounds in the active extracts. An antiviral assay system based on recombinant viruses was used to evaluate the anti-HIV activity. Cell toxicity was tested for all the extracts and compounds. Viral entry was studied using VSV-HIV chimera viruses and reverse transcription and viral integration were studied by qPCR of viral DNA in infected cells. Finally, viral transcription was studied in primary lymphocytes transfected with HIV-1 or NF-κB luciferase reporter plasmids., Results: n-Hexane extracts of purple maca displayed anti-HIV activity in an in vitro assay. A bioassay-guided fractionation led to the identification of three thiadiazole alkaloids with antiviral activity. All the compounds were able to inhibit HIV infection of MT-2 cell lines and primary lymphocytes (PBMCs) with IC 50 values in the low micromolar range. The mechanism of action differs between the three compounds: one of them showed activity on viral entry, and all the three compounds inhibited viral integration at low concentrations. Remarkably, none of the compounds inhibited reverse transcription or viral transcription., Conclusions: n-Hexane extracts of the purple ecotype of L. meyenii inhibit HIV-1 infection in vitro and three active thiadiazole alkaloids were isolated acting mainly on viral integration and viral entry., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:L.A.T., J.A.G., J.A. P.B and L.M.B. participate as inventors in a patent application involving the antiviral activity of maca and thiadiazole compounds., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC 50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11's potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jungwook chin reports financial support was provided by National Research Foundation of Korea. Taeho Lee reports financial support was provided by National Research Foundation of Korea. Jungwook chin has patent #PCT/KR2023/003210 pending to Daegu-Gyeongbuk Medical Innovation Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Twenty chalcone derivatives containing morpholine-thiadiazole were designed and synthesized from the natural product chalcone. The bioactivity test results indicate that some compounds exhibit good antiviral activity against tobacco mosaic virus (TMV). In particular, the EC 50 values for the curative and protective activity of S14 against TMV were 91.8 and 130.6 μg/mL, which was better than that of the antiviral agent ningnanmycin (NNM, 237.8, 220.6 μg/mL). The results of preliminary mechanism study indicated that S14 had strong binding capacity and affinity to tobacco mosaic virus coat protein (TMV-CP). In the chlorophyll content assay, the chlorophyll content of tobacco leaves increased significantly after the action of S14, so that it can enhance the photosynthetic capacity of plants. In addition, the results of malondialdehyde (MDA) content assay also indicated that S14 could improve the disease resistance of tobacco., Competing Interests: Declaration of competing interest The authors declare that there are no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we present the design, synthesis, and evaluation of six new thiadiazole derivatives designed as VEGFR-2 inhibitors. The most promising compound, 18b, demonstrated promising inhibitory activity against VEGFR-2, with an IC 50 value of 0.165 µg/mL. The in vitro assessments on MCF-7 and HepG2 cell lines revealed the superior anti-proliferative effects of compound 18b, exhibiting IC 50 values of 0.06 and 0.17 µM, respectively. Further investigations into the cell cycle distribution of compound 18b on MCF-7 cells exhibited a cell cycle arrest at the S phase (52.96 %) and significantly reducing the percentage of cells in the G0-G1 and G2/M phases. Additionally, compound 18b demonstrated a remarkable pro-apoptotic effect, with 45.29 % total apoptosis, characterized by both early and late apoptosis, and minimal necrosis. These findings were corroborated by RT-PCR analysis, revealing a significant downregulation of the anti-apoptotic gene Bcl2 and upregulation of the pro-apoptotic gene BAX in compound 18b-treated cells compared to control MCF-7 cells. Moreover, in silico studies involving molecular docking, Density Functional Theory (DFT) calculations, Molecular Dynamics (MD) simulations, MM-GBSA, Principle Component Analysis of Trajectories (PCAT), in addition to Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions underscored the molecular interactions, energetics, and pharmacokinetic properties of compound 18b and the other derivatives further supporting its potential. Our integrated approach, combining in vitro experimens with in silico predictions provides valuable insights into the therapeutic potential of compound 18b as a robust VEGFR-2 inhibitor and lays the groundwork for future optimization., 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.)

Focal Adhesion Kinase (FAK) is a non-receptor protein tyrosine kinase that plays a crucial role in various oncogenic processes related to cell adhesion, migration, proliferation, and survival. The strategic targeting of FAK represents a burgeoning approach to address resistant tumours, such as pancreatic ductal adenocarcinoma (PDAC). Herein, we report a new series of twenty imidazo[2,1- b ][1, 3, 4]thiadiazole derivatives assayed for their antiproliferative activity against the National Cancer Institute (NCI-60) panel and a wide panel of PDAC models. Lead compound 10l exhibited effective antiproliferative activity against immortalised (SUIT-2, CAPAN-1, PANC-1, PATU-T, BxPC-3), primary (PDAC-3) and gemcitabine-resistant clone (PANC-1-GR) PDAC cells, eliciting IC 50 values in the low micromolar range (1.04-3.44 µM), associated with a significant reduction in cell-migration and spheroid shrinkage in vitro . High-throughput kinase arrays revealed a significant inhibition of the FAK signalling network, associated to induction of cell cycle arrest in G2/M phase, suppression of tumour cell invasion and apoptosis induction. The high selectivity index/toxicity prompted studies using PDAC mouse xenografts, demonstrating significant inhibition of tumour growth and safety. In conclusion, compound 10l displayed antitumor activity and safety in both in vitro and in vivo models, emerging as a highly promising lead for the development of FAK inhibitors in PDAC.

Spinal Cord Injury (SCI) is a severe condition that often leads to substantial neurological impairments. This study aimed to explore the role of Aquaporin-4 (AQP4) in regulating astrocyte autophagy and neuroinflammation post-SCI, as well as to evaluate the therapeutic potential of AQP4 inhibition using the specific inhibitor TGN-020. Using Western blot, CCK8 assays, immunofluorescence staining, histopathological assessments, and behavioral analyses, we investigated the effects of TGN-020 on SCI-induced alterations in autophagy, neuroinflammation, astrocyte proliferation, neuronal damage, and motor function recovery in both rat and astrocyte models. Our findings indicate that TGN-020 significantly enhances astrocyte autophagy, reduces neuroinflammation, thereby leading to mitigated astrocyte activation by suppressing AQP4 expression. These beneficial effects are associated with the activation of the peroxisome proliferator-activated receptor-γ/mammalian target of rapamycin (PPAR-γ/mTOR) signaling pathway. Notably, the introduction of the PPAR-γ specific inhibitor GW9662 abrogated the positive regulatory effects of TGN-020 on SCI-induced autophagy and neuroinflammation. Collectively, our in vivo and in vitro experiments demonstrate that TGN-020, by down-regulating AQP4, activates the PPAR-γ/mTOR pathway, ameliorates astrocyte autophagy, diminishes neuroinflammation, and ultimately enhances motor function recovery., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Thiosemicarbazide and also 1,3,4-thiadiazole derivatives have been garnering substantial attention from researchers worldwide due to their expansive range of biological activities, encompassing antimicrobial, anti-inflammatory, and anticancer properties. Herein, we embarked on a comprehensive investigation in this study, introducing a novel series of thiosemicarbazides (3a-3i) and their corresponding 1,3,4-thiadiazole (4a-4i) derivatives. The compounds were meticulously designed, synthesized, and subjected to meticulous characterization using various spectroscopic methods such as FT-IR, 1 H-NMR, 13 C-NMR, and elemental analysis. Afterward, their potential anti-proliferative effectiveness was assessed using MTT assay against two cancer cell lines (U87 and HeLa) and normal fibroblast cells (L929). Among the compounds, 4d showed the highest cytotoxic activity against U87 and 4i against HeLa. Compound 3b exhibited selective cytotoxic activity against both cancer cells. Among the molecules with selective activity against the U87 cell line; 3a, 3b, 4d and 4e were further evaluated by caspase-3 activity levels, Bax and Bcl-2 protein expression, and total oxidant status assay. Besides, carbonic anhydrase IX activity studies were also performed in order to understand the underlying mechanism of action. The results indicated that compound 4e showed higher efficacy than standard acetazolamide (IC 50  = 0.58 ± 0.02 µM) with an IC 50 value of 0.03 ± 0.01 µM. Furthermore, molecular docking studies were carried out using carbonic anhydrase IX crystals to determine the compound's interactions with the enzyme's active sites. This comprehensive investigation sheds light on the intricate interplay between molecular structure and biological activity, providing valuable insights into the therapeutic potential of these compounds., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Cobenfy, a co-formulation of xanomeline and trospium, is the first drug not acting on the dopaminergic system of the CNS approved for the treatment of schizophrenia by the FDA. Xanomeline is a muscarinic M1 and M4 receptor (CHRM1 and CHRM4) agonist whilst trospium is a peripherally active CHRM antagonist that reduces the unwanted peripheral side-effects of xanomeline. Relevant to this exciting development, this review details the human CNS cholinergic systems and how those systems are affected by the molecular pathology of schizophrenia in a way suggesting activating the CHRM1 and 4 would be beneficial in treating the disorder. The CNS distribution of CHRMs is presented along with findings using CHRM knockout mice and mice treated with drugs that activate the CHRM1 and / or M4, these data explain why these CHRMs could be involved in the genesis of the symptoms of schizophrenia. Next, the process leading to the formulation of Cobenfy and the preclinical data on xanomeline are reviewed showing why Cobenfy was expected to be useful in treating schizophrenia. The pipeline of drugs targeting CHRM1 and /or M4 receptors to treat schizophrenia are discussed. Finally, the molecular pathology of two sub-groups within schizophrenia, separated based on the presence or absence of a deficit of cortical CHRM1, are reviewed to show how such approaches could identify new drug targets. In conclusion, the history of the development of Cobenfy highlights how a growing understanding the pathophysiology of schizophrenia will suggest new treatment targets for the disorder and that pharmacologists can synthesise drugs to target these sites., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In an effort to explore new-type high-efficiency antifungal agents, 25 novel L -carvone-based 1,3,4-thiadiazole-amide derivatives were designed, synthesized, and structurally characterized by IR, 1 H NMR, 13 C NMR, and high-resolution mass spectrometry (HRMS) analyses. The antifungal activity of the target compounds was preliminarily assayed at a concentration of 50 μg/mL, and boscalid, a commercialized fungicide identified as a succinate dehydrogenase inhibitor (SDHI), was employed as the positive control. It was found that all of the target compounds showed moderate to potent antifungal activity against the tested fungi compared to boscalid. Surprisingly, compound 4b exhibited broad-spectrum and significant inhibition activity against the growth of eight phytopathogenic strains with inhibitory rates of 67-89%. Further, the results of the EC 50 value test suggested that the EC 50 values of compound 4b against Physalospora piricola and Colletotrichum orbiculare were 16.33 and 18.06 μg/mL, respectively, and both of them were better than those of boscalid (16.64 and >50). Therefore, compound 4b deserves further study as a lead compound for novel fungicides. In addition, the inhibitory activity of compound 4b against succinate dehydrogenase (SDH) was evaluated as well to prove that compound 4b (IC 50 = 3.38 μM) displayed higher SDH-inhibition activity than boscalid (IC 50 = 7.02 μM). The binding mode of compound 4b and SDH was simulated by molecular docking and found to be similar to that of boscalid. The structure-activity relationships (SARs) of the target compounds were analyzed by establishing a 3D-QSAR model. Besides, a 4b -loaded complex 4b/CSTA on a reported L -carvone-based nanochitosan carrier CSTA containing the 1,3,4-thiadiazole-amide group was constructed, and its sustained release performance was investigated in the EtOH-H 2 O system (1:9, v/v). The complex 4b/CSTA exhibited preferred sustained release performance, indicating its potential for developing environmentally friendly nanofungicides.

Objective: The African bush apple (Heinsia crinita) is a highly valued orphan shrub that supports the nutritional and natural medicine needs of many sub-Saharan African communities. However, the crop remains poorly conserved and without any known genetic improvement. Accordingly, the current study sought to develop for the first time, an in vitro regeneration system based on direct shoot proliferation from its stem and hypocotyledonary explants using combinations of two cytokinins (benzyl adenine - BA, thidiazuron - TDZ) and the auxin (naphthalene acetic acid (NAA), in Murashige and Skoog (MS) medium., Results: Combinations of BA and NAA effectively induced multiple shoot formation from stem and hypocotyledonary explants of the crop. The most effective treatment (1.0 mg/L BA + 0.1 mg/L NAA) induced an average of 13.77 and 30.32 shoots per responsive hypocotyl and stem explants, respectively. Combinations of TDZ and NAA were less effective in promoting shoot induction in the explants at the concentrations tested compared to BA and NAA combinations. Hypocotyledonary explants achieved complete plant regeneration without multiple shoot formation in a hormone-free MS medium. In vitro shoots regenerated from both stem and hypocotyledonary explants were 100% successfully rooted on a half-strength hormone-free medium, and acclimatized to produce H. crinita plants with over 90.0% efficiency., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Piezo1 plays a pivotal role in regulating bone remodeling and homeostasis and has emerged as a promising target for chemical intervention in disuse osteoporosis. Nevertheless, the development of small-molecule Piezo1 agonists is still in its infancy, and highly efficacious Piezo1 agonists are urgently required. In this study, by shedding light on the structural novelty of the canonical Piezo1 agonist Yoda1, we initiated a structural optimization campaign based on the (thiadiazol-2-yl)pyrazine scaffold. A deuterated compound 12a was identified to be the most potent candidate against Piezo1 with an EC 50 value of 2.21 μM, which was over 20-fold more potent than the reference Yoda1. This compound effectively activated Piezo1 and initiated Ca 2+ influx in MSCs and promoted MSC osteogenesis via activating the Ca 2+ -related Erk signaling pathway. Furthermore, compound 12a was found to alleviate disuse osteoporosis with a desirable safety profile in a HU (hindlimb-unloading) rat model, thus warranting it as a potential probe for further investigation.

The rapid emergence and spread of multidrug-resistant (MDR) Gram-positive pathogens present a significant challenge to global healthcare. Methicillin-resistant Staphylococcus aureus (MRSA) is a particular concern because of its high resistance to most antibiotics. Based on our previously reported chemical structure of compound 62, a series of novel derivatives were synthesized and evaluated for their antibacterial activities. We found that some of these derivatives displayed effective antibacterial activity against Gram-positive pathogens, with minimal cytotoxicity (CC 50 >100 μM) and hemolytic activity (HC 50 >200 μM). Among these derivatives, the minimum inhibitory concentration (MIC) of 62-7c against Gram-positive bacterial isolates ranged from 6.25 to 25 μM. This derivative also exhibited significant synergistic antibacterial effects with daptomycin both in vitro and in vivo, with an ability to eradicate planktonic and persister cells of MRSA. Additionally, 62-7c inhibited biofilm formation and eradicated mature biofilms of MRSA. Mechanistic studies revealed that 62-7c inhibited the YycG kinase activity and disrupted the cell membrane by binding to cardiolipin (CL), leading to cell death. Importantly, no development of drug resistance was observed even after 20 serial passages. Furthermore, 62-7c exhibited high biosafety and potent effectiveness in combating infections in both mouse pneumonia and mouse wound models infected with MRSA. Thus, our study revealed that 62-7c has the potential to serve as a novel antibacterial agent for treating MRSA infections., 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.)

Glutaminase inhibitors are currently being explored as potential treatments for cancer. This study aimed to elucidate the molecular mechanisms underlying the effects of CB-839 on lung tumor cell lines compared to non-tumor cell lines. Viability assays based on NADPH-dependent dehydrogenases activity, ATP energy production, or mitochondrial reductase activity were used to determine that CB-839 caused significant tumor cell specific inhibition of cellular functions. Clonogenic survival assay revealed a dose dependent reduction in clonogenic survival of various lung tumor cells presenting estimated IC 50 values between 10 and 90 nM, while no effect on non-tumor cells was observed. CB-839 led to a 20% reduction in glutaminase (GLS1, a mitochondrial enzyme that catalyzes the conversion of glutamine to glutamate) activity, and a dose-dependent reduced glutamine consumption in tumor cells and had no effect on non-tumor cells. Cell cycle analysis showed the CB-839 did not lead to cell cycle arrest. Apoptosis and necrosis assays revealed an only slight increase in apoptosis in tumor cells. Furthermore, a trypan blue exclusion assay revealed about 40% growth reduction in tumor cells at 0.1-1 μM CB-839 treatment. Surprisingly, treated cells resumed normal growth when re-plated in a drug-free medium, demonstrating reversibility. In hypoxic conditions, CB-839's effect on clonogenic survival was amplified in a dose dependent manner consistent with increased role of GLS1 for energy production under hypoxic conditions. In conclusion, these results suggest CB-839 efficacy is linked to temporary and reversible reduction in glutamine utilization suggesting induction of dormancy., 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 B.V.)

Rationale: The compound 5-((4-methoxyphenyl)thio)benzo[c][1,2,5]thiadiazole (MTDZ) has recently been shown to inhibit in vitro acetylcholinesterase activity, reduce cognitive damage, and improve neuropsychic behavior in mice, making it a promising molecule to treat depression., Objectives: This study investigated the antidepressant-like action of MTDZ in mice and its potential mechanisms of action., Results: Molecular docking assays were performed and suggested a potential inhibition of monoamine oxidase A (MAO-A) by MTDZ. The toxicity study revealed that MTDZ displayed no signs of toxicity, changes in oxidative parameters, or alterations to biochemistry markers, even at a high dose of 300 mg/kg. In behavioral tests, MTDZ administration reduced immobility behavior during the forced swim test (FST) without adjusting the climbing parameter, suggesting it has an antidepressant effect. The antidepressant-like action of MTDZ was negated with the administration of 5-HT1A, 5-HT1A/1B, and 5-HT3 receptor antagonists, implying the involvement of serotonergic pathways. Moreover, the antidepressant-like action of MTDZ was linked to the NO system, as L-arginine pretreatment inhibited its activity. The ex vivo assays indicated that MTDZ normalized ATPase activity, potentially linking this behavior to its antidepressant-like action. MTDZ treatment restricted MAO-A activity in the cerebral cortices and hippocampi of mice, proposing a selective inhibition of MAO-A associated with the antidepressant-like effect of the compound., Conclusions: These findings suggest that MTDZ may serve as a promising antidepressant agent due to its selective inhibition of MAO-A and the involvement of serotonergic and NO pathways., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We synthesized herein 16 compounds (SUT1-SUT16) as potential carbonic anhydrase (CA) inhibitors utilizing the tail-approach design. Based on this strategy, we connected benzenesulfonamide, the zinc-binding scaffold, to different urea moieties with the 1,3,4-thiadiazole ring as a linker. We obtained the target compounds by the reaction of 4-(5-amino-1,3,4-thiadiazol-2-yl)benzenesulfonamide with aryl isocyanates. Upon confirmation of their structures, the compounds were screened for their ability to inhibit the tumor-related human (h) isoforms human carbonic anhydrase (hCA) IX and XII, as well as the physiologically dominant hCA I and II. Most of the molecules demonstrated K i values ≤ 10 nM with different selectivity profiles. The binding modes of SUT9, SUT10, and SUT5, the most effective inhibitors of hCA II, IX, and XII, respectively, were predicted by molecular docking. SUT16 (4-{5-[3-(naphthalen-1-yl)ureido]-1,3,4-thiadiazol-2-yl}benzenesulfonamide) was found to be the most selective inhibitor of the cancer-associated isoforms hCA IX and XII over the off-target isoforms, hCAI and II. The interaction dynamics and stability of SUT16 within hCA IX and XII were investigated by molecular dynamics simulations as well as dynophore analysis. Based on computational data, increased hydrophobic contacts and hydrogen bonds in the tail part of these molecules within hCA IX and XII were found as favorable interactions leading to effective inhibitors of cancer-related isoforms., (© 2024 The Author(s). Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

The hyperactivity of urease enzyme leads to various complications including gastritis and peptic ulcer. A diverse variety of natural and synthetic inhibitors have shown a tremendous potential to inhibit the urease enzyme, thus decreasing the hyperactivity and reducing the risk for the development of urinary calculi and other similar problems. Therefore, we herein report a family of fused heterocycles such as triazolothiadiazoles ( 4a - h , 5a - f ) and triazolothiadiazines ( 6a - h ) as potential antiurease agents with IC 50 values in the range 10.41-41.20 µM. Several compounds were identified as potential lead candidates. Among them, compounds 4e and 4f from triazolothiadiazole series showed the highest inhibitory potential with IC 50 values of 11.62 ± 0.34 and 10.35 ± 0.14 µM), respectively, whereas 6e from triazolothiadiazine series emerged as the most potent inhibitor with an IC 50 value of 10.41 ± 0.13 µM. These compounds exhibited two-fold strong inhibitory efficacy against urease as compared to standard inhibitor, thiourea (IC 50 = 22.48 ± 0.67 µM). The mechanistic insights from kinetics experiments for compounds 4e , 4f , and 6e revealed the competitive mode of inhibition with K i values of 8.65 ± 0.004, 7.04 ± 0.012, and 8.31 ± 0.007 µM, respectively. The in vitro results were further explored through in silico computational docking analysis which reflects that binding of ligands with Ni ions and His492 play a crucial role in urease inhibition. In silico predicted physicochemical properties and ADME profile reflect drug-like nature of these molecules.Communicated by Ramaswamy H. Sarma.

Efficient clearance of hematomas is crucial for improving clinical outcomes in patients with intracerebral hemorrhage (ICH). The glymphatic system, facilitated by aquaporin-4 (AQP4), plays a crucial role in cerebrospinal fluid (CSF) entry and metabolic waste clearance. This study examined the role of the glymphatic system in ICH pathology, with a focus on AQP4. Collagenase-induced ICH models were established, with AQP4 expression regulated through mifepristone as an agonist, TGN-020 as an inhibitor, and Aqp4 gene knockout. Fluorescence tracing and multimodal magnetic resonance imaging (MRI) were employed to observe glymphatic system functionality, hematoma, and edema volumes. Neurological deficit scoring was performed using the modified Garcia Scale. AQP4 expression was quantified using RT-qPCR and Western blotting, and cellular localization was explored using immunofluorescence. The brain tissue sections were examined for neuronal morphology, degenerative changes, and iron deposition. Three days post-ICH, the AQP4 agonist group showed increased AQP4 protein expression and perivascular polarization, decreased hemoglobin levels, and reduced iron deposition. Conversely, the inhibition group exhibited contrasting trends. AQP4 activation improved glymphatic system function, leading to a wider distribution, improved neurological function, and reduced hematoma. Pharmacological inhibition and genetic knockout of AQP4 have opposing effects. The glymphatic system, facilitated by AQP4, plays a crucial role in hematoma clearance following cerebral hemorrhage. Upregulation of AQP4 improves glymphatic system function, facilitates hematoma clearance, and promotes brain tissue recovery., (© 2024 The Author(s). GLIA published by Wiley Periodicals LLC.)

Five series of new 1,3,4-thiadiazole hybrids were designed and synthesized as promising EGFR inhibitors. Three human cancer cell lines were employed for testing each hybrid's in vitro antiproliferative efficacy; colon HCT-116, liver HepG-2 and breast MCF-7 using MTT assay. Comparing compound 9a to the reference doxorubicin, 9a shown superior activity to that of Dox with respect to MCF-7 (IC 50 3.31 µM) while being secure for normal cells WI-38 (IC 50  = 43.99 µM). Further evaluation of the EGFR inhibitory activity of the most active candidates-4a, 6b, 8b, 9a, and 9 d-was performed. Of them, compounds 9a and 8b demonstrated the highest IC 50 values, 0.08 and 0.15 µM, respectively, relative to the reference gefitinib (IC 50  = 0.04 µM). Subsequent mechanistic analysis of compound 9a revealed a notable 14.24-fold increase in overall apoptosis and a 28.92% cell cycle arrest at G2/M. Additionally, research on apoptosis demonstrated that it triggered the mitochondrial apoptotic pathway. In MCF-7 cells, it also led to an increase in ROS buildup. For the most powerful EGFR inhibitors, 9a and 8b, a molecular docking research was conducted, and all of the findings agreed with the biological findings., (© 2024 Wiley Periodicals LLC.)

Androgen receptor (AR) is an important therapeutic target for prostate cancer (PCa) treatment, but prolonged use of AR antagonists has led to variant drug-resistant mutations. Since all marketed AR antagonists target the ligand binding pocket (LBP) of AR, to mitigate cross-resistance, a new drug pocket named Dimer Interface Pocket was discovered and a novel AR antagonist M17-B15 was identified. M17-B15 showed strong in vitro efficacy against PCa but had poor pharmacokinetic properties in vivo . In this study, through rational design and structure-activity relationship exploration, a series of thiadiazoleamide derivatives represented by N29 (IC 50 = 0.018 μM) were identified with dominant AR antagonistic activity and remarkable anti-PCa activity in vitro . Furthermore, N29 effectively inhibited a series of typical drug-resistant AR mutants. The improved oral bioavailability of N29 facilitated its efficacy via oral administration, significantly inhibiting LNCaP xenograft tumor in vivo , presenting a promising therapeutic application for PCa.

Plant pathogenic fungi frequently disrupt the normal physiological and biochemical functions of plants, leading to diseases, compromising plant health, and ultimately reducing crop yield. This study aimed to address this challenge by identifying antifungal agents with innovative structures and novel mechanisms of action. We designed and synthesized a series of flavonoid derivatives substituted with 5-sulfonyl-1,3,4-thiadiazole and evaluated their antifungal activity against five phytopathogenic fungi. Most flavonoid derivatives demonstrated excellent antifungal activity against Botrytis cinerea ( B. cinerea ), Alternaria solani ( A. solani ), Rhizoctorzia solani ( R. solani ), Fusarium graminearum ( F. graminearum ), and Colletotrichum orbiculare ( C. orbiculare ). Specifically, the EC 50 values of 38 target compounds against R. solani were below 4 μg/mL, among which the compounds C13 (EC 50 = 0.49 μg/mL), C15 (EC 50 = 0.37 μg/mL), and C19 (EC 50 = 0.37 μg/mL) had the most prominent antifungal activity, superior to that of the control drug carbendazim (EC 50 = 0.52 μg/mL). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of the cellular ultrastructures of R. solani mycelia and cells after treatment with the compound C19 revealed sprawling growth of hyphae, a distorted outline of their cell walls, and reduced mitochondrial numbers. Studying the 3D-QSAR between the molecular structure and antifungal activity of 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoid derivatives could significantly improve conventional drug molecular design pathways and facilitate the development of novel antifungal leads.

In the present work, we describe the synthesis of new 1,3,4-thiadiazole derivatives from natural (R)-carvone in three steps including, dichloro-cyclopropanation, a condensation with thiosemicarbazide and then a 1,3-dipolar cycloaddition reaction with various nitrilimines. the targeted compounds were structurally identified by 1 H & 13 C NMR and HRMS analyses. The cytotoxic assay demonstrated that some synthesized novel compounds were potent on certain cancer cell lines. Molecular modeling studies were undertaken to rationalize the wet lab study results. Furthermore, molecular docking was performed to unveil the binding potential of the most active derivatives, 3a and 6c, to caspase-3 and COX-2. The stabilities of the protein-compound complexes obtained from the docking were evaluated using MD simulation. Furthermore, FMO and related parameters of the active compounds and their stereoisomers were examined through DFT studies. The docking study showed compound 6c had a higher binding potential than caspase-3. However, the binding strength of 6c was found to be less than that of the standard drug, doxorubicin, as it formed lower conventional hydrogen bonds. On the other hand, compound 3a had a higher binding potential to COX-2. However, the binding potential 3a was much lower than that of the standard COX-2 inhibitor, celecoxib. The MD simulation demonstrated that the caspase-3-6c complex was less stable than the caspase-3-doxorubicin complex. In contrast, the COX-2-3a complex was stable, and 3a was anticipated to remain inside the protein's binding pocket. The DFT study showed that 3a had higher chemical stability than 6c. The electron exchange capacity, chemical stability, and molecular orbital distributions of the stereoisomers of the active compounds were also found to be alike., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Antiepileptic drugs (AEDs) are used in the treatment of epilepsy, a neurodegenerative disease characterized by recurrent and untriggered seizures that aim to prevent seizures as a symptomatic treatment. However, they still have significant side effects as well as drug resistance. In recent years, especially 1,3,4-thiadiazoles and 1,2,4-triazoles have attracted attention in preclinical and clinical studies as important drug candidates owing to their anticonvulsant properties. Therefore, in this study, which was conducted to discover AED candidate molecules with reduced side effects at low doses, a series of chiral 2,5-disubstituted-1,3,4-thiadiazoles (4a-d) and 4,5-disubstituted-1,2,4-triazole-3 thiones (5a-d) were designed and synthesized starting from l-phenylalanine ethyl ester hydrochloride. The anticonvulsant activities of the new chiral compounds were assessed in several animal seizure models in mice and rats for initial (phase I) screening after their chemical structures including the configuration of the chiral center were elucidated using spectroscopic methods and elemental analysis. First, all chiral compounds were pre-screened using acute seizure tests induced electrically (maximal electroshock test, 6 Hz psychomotor seizure model) and induced chemically (subcutaneous metrazol seizure model) in mice and also their neurotoxicity (TOX) was determined in the rotorad assay. Two of the tested compounds were used for quantitative testing, and (S)-(+)5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5b) and (S)-(+)-(5-[1-(4-fluorobenzamido)-2-phenylethyl]-4-(4-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (5c) emerged as the most promising anticonvulsant drug candidates and also showed low neurotoxicity. The antiepileptogenic potential of these compounds was determined using a chronic seizure induced electrically corneal kindled mouse model. Furthermore, all chiral compounds were tested for their neuroprotective effect against excitotoxic kainic acid (KA) and N-methyl-d-aspartate (NMDA) induced in vitro neuroprotection assay using an organotypic hippocampal slice culture. The KA-induced neuroprotection assay results revealed that compounds 5b and 5c, which are the leading compounds for anticonvulsant activity, also had the strongest neuroprotective effects with IC 50 values of 103.30 ± 1.14 and 113.40 ± 1.20 μM respectively. Molecular docking studies conducted to investigate the molecular binding mechanism of the tested compounds on the GABA A receptor showed that compound 5b exhibits a strong affinity to the benzodiazepine (BZD) binding site on GABA. It also revealed that the NaV 1.3 binding interactions were consistent with the experimental data and the reported binding mode of the ICA121431 inhibitor. This suggests that compound 5b has a high affinity for these specific binding sites, indicating its potential as a ligand for modulating GABA A and NaV 1.3 receptor activity. Furthermore, the ADME properties displayed that all the physicochemical and pharmacological parameters of the compounds stayed within the specified limits and revealed a high bioavailability profile., 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.)

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In this dispensation of rapid scientific and technological advancements, significant efforts are being made to curb health-related diseases. Research discoveries have highlighted the value of heterocyclic compounds, particularly thiadiazole derivatives, due to their diverse pharmacological activities. These compounds play a crucial role in therapeutic medicine and the development of effective drugs. Thiadiazoles are five-membered heterocyclic compounds consisting of one sulfur and two nitrogen atoms. This review explores advanced synthesis techniques, including the use of heterogeneous catalysts, microwave-assisted methods, ultrasound-assisted synthesis, solvent-free processes, multicomponent reactions, copper-catalyzed aerobic oxidative annulation, intramolecular cyclization, click-chemistry supported synthesis, and alkali-promoted, transition-metal-free mediated synthesis. These methods enhance the diversity and potential applications of thiadiazole compounds. Furthermore, this study provides up-to-date information on the key pharmacological activities of thiadiazole derivatives, highlighting their potential in therapeutic medicine for drug development. The structure-activity relationship (SAR) is also discussed to better understand their interactions and safety in biological systems. This work aims to expand on the reported chemistry and pharmacological potential of the thiadiazole moiety to validate their efficacy as promising pharmacophores in drug design and development., 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.)

In the search for new anticancer agents, we synthesized a new series of thiazole derivatives carried on thiadiazole-oxadiazole hybrid. Final compounds ( 5a-5i ) were analyzed via 1 H NMR, 13 C NMR, and HRMS. The pharmacokinetic profile of the targeted compounds was predicted via in silico calculations. Their anticancer properties were determined using MTT method against MCF7 and A549 cell lines. Compounds 5a , 5b and 5c were found more active against MCF7 cells than A549 cells while they were not cytotoxic on L929 healthy cells. Generally, it can be summarized that acetamide moiety has a pivotal role in anticancer activity. For further studies, their aromatase inhibitory activity was evaluated. After determination all these features, the binding modes of the active compounds and the stability and relation of the ligand-enzyme complex were investigated using molecular docking and molecular dynamics simulation studies, respectively. In vitro and in silico studies suggest two important structure-activity relationship (SAR) points that at least one azole ring is essential, and if there is approximately 8.0 ± 0.5 Å distance between the H-bond rich zone of ligand and the heteroaryl ring system of ligand has a major impact on aromatase inhibitory activity. Compounds with small group substitution on thiazole are found potentially may be used for the treatment of anti-breast cancer orally.Communicated by Ramaswamy H. Sarma.

The endoplasmic reticulum (ER) plays an important role in protein synthesis and its disruption can cause protein unfolding and misfolding. Accumulation of such proteins leads to ER stress, which ultimately promotes many diseases. Routine screening of ER activity in immune cells can flag serious conditions at early stages, but the current clinically used bio-probes have limitations. Herein, an ER-specific fluorophore based on a biocompatible benzothiadiazole-imine cage (BTD-cage) with excellent photophysical properties is developed. The cage outperforms commercially available ER stains in long-term live cell imaging with no fading or photobleaching over time. The cage is responsive to different levels of ER stress where its fluorescence increases accordingly. Incorporating the bio-probe into an immune disorder model, a 6-, 21-, and 48-fold increase in intensity is shown in THP-1, Raw 246.7, and Jurkat cells, respectively (within 15 min). These results strongly support that this system can be used for rapid visual and selective detection of ER stress. It is envisaged that tailoring molecular interactions and molecular recognition using supramolecular improved fluorophores can expand the library of biological probes for enhanced selectivity and targetability toward cellular organelles., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)

Background: Plant pathogens cause substantial crop losses annually, posing a grave threat to global food security. Fungicides have usually been used for their control, but the rapid development of pesticide resistance renders many ineffective, therefore the search for novel and efficient green pesticides to prevent and control plant diseases has become the top priority in crop planting., Results: The results of bioassay studies indicated that most of the target compounds showed certain antimicrobial activity in vitro. In particular, compound X7 showed high inhibitory activity against Xanthomonas oryzae pv. oryzae (Xoo), with an EC 50 value of 27.47 μg mL -1 , surpassing conventional control agents such as thiazole zinc (41.55 μg mL -1 ) and thiodiazole copper (53.39 μg mL -1 ). Further studies on molecular docking showed that X7 had a strong binding affinity with 2FBW. The morphological change observed by scanning electron microscopy indicated that the surface of Xoo appears wrinkled and cracked under X7 treatment and a total of 2662 proteins were identified by label-free proteomic analysis. Three experiments have elucidated the mechanism whereby X7 induced considerable changes in the physiological and biochemical properties of Xoo, which in turn affected the reproduction and growth of bacteria., Conclusion: This work represents a pivotal advancement, offering important reference for the research and development therapeutics in combating plant pathogens. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

In the current research study, we aim to design and synthesize highly potent hybrid analogs of benzimidazole derived thiadiazole based Schiff base derivatives which can combat the cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase) accountable for developing Alzheimer's disease. In this context, we have synthesized 15 analogs of benzimidazole based thiadiazole derivatives, which were subsequently confirmed through spectroscopic techniques including 1 H NMR, 13 C NMR and HREI-MS. Biological investigation of all the analogs revealed their varied acetylcholinesterase inhibitory potency covering a range between 3.20 ± 0.10 μM to 20.50 ± 0.20 μM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 ± 0.50 μM to 20.70 ± 0.50 μM when compared with the standard drug Donepezil having IC 50  = 6.70 ± 0.20 μM for AChE and 7.90 ± 0.10 μM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC 50  = 3.20 ± 0.10 μM for AChE and 4.30 ± 0.50 μM for BuChE), analog-4 (IC 50  = 4.30 ± 0.30 μM for AChE and 5.50 ± 0.20 μM for BuChE) and analog-5 (IC 50  = 4.10 ± 0.30 μM for AChE and 4.60 ± 0.40 μM for BuChE) were found as the lead candidates. Moreover, molecular docking and ADME analysis were conducted to explore the better binding interactions and drugs likeness respectively., Competing Interests: Declaration of competing interest It is declared that there is no conflict of interest between the authors of the current manuscripts and it is only submitting to Biochemical and Biophysical Research Communication and not submitted elsewhere., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Plant activators have emerged as promising alternatives to conventional crop protection chemicals for managing crop diseases due to their unique mode of action. By priming the plant's innate immune system, these compounds can induce disease resistance against a broad spectrum of pathogens without directly inhibiting their proliferation. Key advantages of plant activators include prolonged defense activity, lower effective dosages, and negligible risk of pathogen resistance development. Among the various defensive pathways targeted, the salicylic acid (SA) signaling cascade has been extensively explored, leading to the successful development of commercial activators of systemic acquired resistance, such as benzothiadiazole, for widespread application in crop protection. While the action sites of many SA-targeting activators have been preliminarily mapped to different steps along the pathway, a comprehensive understanding of their precise mechanisms remains elusive. This review provides a historical perspective on plant activator development and outlines diverse screening strategies employed, from whole-plant bioassays to molecular and transgenic approaches. We elaborate on the various components, biological significance, and regulatory circuits governing the SA pathway while critically examining the structural features, bioactivities, and proposed modes of action of classical activators such as benzothiadiazole derivatives, salicylic acid analogs, and other small molecules. Insights from field trials assessing the practical applicability of such activators are also discussed. Furthermore, we highlight the current status, challenges, and future prospects in the realm of SA-targeting activator development globally, with a focus on recent endeavors in China. Collectively, this comprehensive review aims to describe existing knowledge and provide a roadmap for future research toward developing more potent plant activators that enhance crop health.

Mechanosensitive ion channels, particularly Piezo channels, are widely expressed in various tissues. However, their role in immune cells remains underexplored. Therefore, this study aimed to investigate the functional role of Piezo1 in the human eosinophil cell line AML14.3D10. We detected Piezo1 mRNA expression, but not Piezo2 expression, in these cells, confirming the presence of the Piezo1 protein. Activation of Piezo1 with Yoda1, its specific agonist, resulted in a significant calcium influx, which was inhibited by the Piezo1-specific inhibitor Dooku1, as well as other nonspecific inhibitors (Ruthenium Red, Gd 3+ , and GsMTx-4). Further analysis revealed that Piezo1 activation modulated the expression and secretion of both pro-inflammatory and anti-inflammatory cytokines in AML14.3D10 cells. Notably, supernatants from Piezo1-activated AML14.3D10 cells enhanced capsaicin and ATP-induced calcium responses in the dorsal root ganglion neurons of mice. These findings elucidate the physiological role of Piezo1 in AML14.3D10 cells and suggest that factors secreted by these cells can modulate the activity of transient receptor potential 1 (TRPV1) and purinergic receptors, which are associated with pain and itch signaling. The results of this study significantly advance our understanding of the function of Piezo1 channels in the immune and sensory nervous systems.

Replicative senescence of mesenchymal stem cells (MSCs) caused by repeated cell culture undermines their potential as a cell therapy because of the reduction in their proliferation and therapeutic potential. Glutaminase-1 (GLS1) is reported to be involved in the survival of senescent cells, and inhibition of GLS1 alleviates age-related dysfunction via senescent cell removal. In the present study, we attempted to elucidate the association between MSC senescence and GLS1. We conducted in vitro and in vivo experiments to analyze the effect of GLS1 inhibition on senolysis and the therapeutic effects of MSCs. Inhibition of GLS1 in Wharton's jelly-derived MSCs (WJ-MSCs) reduced the expression of aging-related markers, such as p16, p21, and senescence-associated secretory phenotype genes, by senolysis. Replicative senescence-alleviated WJ-MSCs, which recovered after short-term treatment with bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3 (BPTES), showed increased proliferation and therapeutic effects compared to those observed with senescent WJ-MSCs. Moreover, compared to senescent WJ-MSCs, replicative senescence-alleviated WJ-MSCs inhibited apoptosis in serum-starved C2C12 cells, enhanced muscle formation, and hindered apoptosis and fibrosis in mdx mice. These results imply that GLS1 inhibition can ameliorate the therapeutic effects of senescent WJ-MSCs in patients with muscle diseases such as Duchenne muscular dystrophy. In conclusion, GLS1 is a key factor in modulating the senescence mechanism of MSCs, and regulation of GLS1 may enhance the therapeutic effects of senescent MSCs, thereby increasing the success rate of clinical trials involving MSCs., (© The Author(s) 2024. Published by Oxford University Press.)

Although the current cancer photothermal therapy (PTT) can produce a powerful therapeutic effect, tumor cells have been proved a protective mechanism through autophagy. In this study, a novel hybrid theranostic nanoparticle (CaCO 3 @CQ@pDB NPs, CCD NPs) is designed and prepared by integrating a second near-infrared (NIR-II) absorbed conjugated polymer DTP-BBT (pDB), CaCO 3, and autophagy inhibitor (chloroquine, CQ) into one nanosystem. The conjugated polymer pDB with asymmetric donor-acceptor structure shows strong NIR-II absorbing capacity, of which the optical properties and photothermal generation mechanism of pDB are systematically analyzed via molecular theoretical calculation. Under NIR-II laser irradiation, pDB-mediated PTT can produce powerful killing ability to tumor cells. At the same time, heat stimulates a large amount of Ca 2+ inflow, causing calcium overload induced mitochondrial damage and enhancing the apoptosis of tumor cells. Besides, the released CQ blocks the self-protection mechanism of tumor cells and greatly enhances the attack of PTT and calcium overload therapy. Both in vitro and in vivo experiments confirm that CCD NPs possess excellent NIR-II theranostic capacity, which provides a new nanoplatform for anti-tumor therapy and builds great potential for future clinical research., (© 2024 Wiley‐VCH GmbH.)

Benzothiadiazole (BTH) regulates grape development, ripening, volatiles, and phenolics. This study used metabolomics and transcriptomics to understand how exogenous BTH affects Chardonnay grapes' maturation and synthesis of isoprenoids. A 0.37 mM BTH solution was sprayed during the swelling and veraison stages, and then the ripe grapes were analyzed. Our results show that BTH application significantly increased levels of important isoprenoids such as free terpinen-4-ol, bound linalool, and 8'-apo-β-carotenal. Additionally, BTH was found to modulate several signaling pathways, including those involved in ethylene biosynthesis, salicylic acid synthesis, the abscisic acid pathway, and sugar metabolism, by regulating the expression of genes like VvACO4, VvTAR, VvPLD, VvTIP1-1, VvSTKs, VvPK, VvSUC2, VvGST4, and VvSTS. BTH also promoted grapevine resistance by up-regulating the expression of VvHSP20, VvGOLS4, VvOLP, and VvPR-10. Furthermore, BTH affected isoprenoids biosynthesis by regulating the expression of VvTPS35 and VvMYB24. Moreover, 13 hub genes in the MEgreen module were identified as crucial for the biosynthesis of isoprenoids. BTH application during the swelling stage remarkably promoted isoprenoid biosynthesis more effectively than veraison. Our study provides insights into the molecular mechanisms underlying BTH-induced regulation of grape development and offers a promising approach for enhancing the quality and resistance of grapes., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: Most of the subarachnoid hemorrhage (SAH) patients experienced the symptom of severe headache caused by intracranial hypertension. Piezo1 is a mechanosensitive ion channel protein. This study aimed to investigate the effect of Piezo1 on neurons in response to intracranial hypertension., Methods: The SAH rat model was performed by the modified endovascular perforation method. Piezo1 inhibitor GsMTx4 was administered intraperitoneally after SAH induction. To investigate the underlying mechanism, the selective Piezo1 agonist Yoda1, Piezo1 shRNA, and MY-875 were administered via intracerebroventricular injection before SAH induction. In vitro, we designed a pressurizing device to exclusively explore the effect of Piezo1 activation on primary neurons. Neurons were pretreated with Piezo1 inhibition followed by intracranial hypertension treatment, and then apoptosis-related proteins were detected., Results: Piezo1 inhibition significantly attenuated neuronal apoptosis and improved the outcome of neurological deficits in rats after SAH. The Hippo pathway agonist MY-875 reversed the anti-apoptotic effects of Piezo1 knockdown. In vitro, intracranial hypertension mimicked by the pressurizing device induced Piezo1 expression, resulting in Hippo pathway activation and neuronal apoptosis. The Hippo pathway inhibitor Xmu-mp-1 attenuated Yoda1-induced neuronal apoptosis. In addition, the combination of hypertension and oxyhemoglobin treatment exacerbated neuronal apoptosis., Conclusions: Intracranial hypertension induced Piezo1 expression, neuronal apoptosis, and the Hippo pathway activation; the Hippo signaling pathway is involved in Piezo1 activation-induced neuronal apoptosis in respond to intracranial hypertension. Primary neurons treated with intracranial hypertension and oxyhemoglobin together can better characterize the circumstance of SAH in vivo, which is contributed to construct an ideal in vitro SAH model., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Ovate Family Proteins (OFPs) are emerging as novel transcriptional regulators of fruit shape. Despite their established role in various species, their involvement in regulating grape fruit shape remains understudied. This study encompassed a comprehensive evaluation of 16 grape OFP genes in total at the whole genome level. Phylogenetic and synteny analyses established a close relationship between grape VvOFP genes and their tomato counterparts. Expression profiling post-treatment with gibberellic acid (GA 3 ) and thidiazuron (TDZ) revealed that certain OFP genes responded to these regulators, with VvOFP4 showing peak expression three days post-anthesis. Functional assays via overexpression of VvOFP4 in tobacco and tomato altered the morphology of both vegetative and reproductive organs, including leaves, stamens, and fruits/pods. Paraffin sections of transgenic tobacco stems and tomato fruits demonstrated that VvOFP4 overexpression modifies cell dimensions, leading to changes in organ morphology. Additionally, treatments with GA 3 and TDZ similarly influenced the shape of grape pulp cells and thereby the overall fruit morphology. These findings suggest that the VvOFP4 gene plays a crucial role in fruit shape determination by modulating cell shape and presents a potential target for future grape breeding programs aimed at diversifying fruit shapes., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A library of imidazole-thiadiazole compounds (1-24) was synthesized to explore their therapeutic applications. The compounds were subjected to meticulous in vitro evaluation against α-glucosidase, α-amylase, acetylcholinesterase (AChE), and butylcholinesterase (BChE) enzymes. Compounds were also investigated for antioxidant activities using cupric reducing antioxidant capacity (CUPRAC), ferric reducing antioxidant power (FRAP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) assays. Derivatives 5-7, 9-11, 18, and 19 displayed potent inhibitory activities with IC 50 values of 1.4 ± 0.01 to 13.6 ± 0.01 and 0.9 ± 0.01 to 12.8 ± 0.02 µM against α-glucosidase, and α-amylase enzymes, respectively, compared to the standard acarbose (IC 50  = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC 50  = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC 50  = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC 50  = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC 50  = 44.2 ± 0.05 µM). All compounds also demonstrated excellent antioxidant activities via CUPRAC, FRAP, and DPPH methods. Complementing the experimental studies, extensive kinetics, ADME/T, and molecular docking analysis were also conducted to unravel the pharmacokinetics and safety profiles of the designed compounds. These studies supported the experimental findings and facilitated the prioritization of hit candidates for subsequent stages of drug development., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity. We were able to enhance the in vitro activity and to maintain the specificity of the parent compound. We found the most active candidate to be quite stable in plasma, although it was metabolized by hepatic microsomes. This chemical probe should be useful for in vitro studies and needs to be tested for in vivo pharmacological activity. This could be an important lead toward the development of a first-in-class orally active agonist of the secretin receptor, which could be useful for multiple disease states., Competing Interests: Declaration of competing interest We declare no potential conflicts of interest with respect to research, authorship, and/or publication of this article., (Copyright © 2024. Published by Elsevier Inc.)

The aim of this work was to obtain and evaluate, as antiprotozoals, new derivatives of benzoate imidazo-1,3,4-thiadiazole 18 - 23 based on the concepts of molecular repositioning and hybridization. In the design of these compounds, two important pharmacophoric subunits of the fexnidazole prototype were used: metronidazole was used as a repositioning molecule, p-aminobenzoic acid was incorporated as a bridge group, and 1,3,4-thiadiazole group was incorporated as a second pharmacophore, which at position 5 has an aromatic group with different substituents incorporated. The final six compounds were obtained through a five-step linear route with moderate to good yields. The biological results demonstrated the potential of this new class of compounds, since three of them 19 - 21 showed inhibitory activity on proliferation, in the order of 50%, in the in vitro assay against epimastigotes of T. cruzi (Strain Y sensitive to nifurtimox and benznidazole) and promastigotes of L. donovani , at a single concentration of 50 μM.

Extracellular vesicles (EVs) can transfer antigens and immunomodulatory molecules, and such EVs released by antigen-presenting cells equipped with immunostimulatory functions have been utilized for vaccine formulations. A prior high-throughput screening campaign led to the identification of compound 634 ( 1 ), which enhanced EV release and increased intracellular Ca 2+ influx. Here, we performed systematic structure-activity relationship (SAR) studies to investigate the scaffold for its potency as a vaccine adjuvant. Synthesized compounds were analyzed in vitro for CD63 reporter activity (a marker for EV biogenesis) in human THP-1 cells, induction of Ca 2+ influx, IL-12 production, and cell viability in murine bone-marrow-derived dendritic cells. The SAR studies indicated that the ester functional group was requisite, and the sulfur atom of the benzothiadiazole ring replaced with a higher selenium atom ( 9f ) or a bioisosteric ethenyl group ( 9h ) retained potency. Proof-of-concept vaccination studies validated the potency of the selected compounds as novel vaccine adjuvants.

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.

α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson's disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1- b ][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [ 125 I] ITA-3 , with moderate binding affinity (IC 50 = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [ 125 I] ITA-3 , we developed a potential PET tracer, [ 18 F] FITA-2 (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC 50 = 245 nM), good brain uptake (SUV peak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [ 18 F] FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.

Protoporphyrinogen oxidase (PPO, EC 1.3.3.4) has a high status in the development of new inhibitors. To develop novel and highly effective PPO inhibitors, active substructure linking and bioisosterism replacement strategies were used to design and synthesize novel tetrahydrophthalimide derivatives containing oxadiazole/thiadiazole moieties, and their inhibitory effects on Nicotiana tobacco PPO ( Nt PPO) and herbicidal activity were evaluated. Among them, compounds B11 ( K i = 9.05 nM) and B20 ( K i = 10.23 nM) showed significantly better inhibitory activity against Nt PPO than that against flumiclorac-pentyl ( K i = 46.02 nM). Meanwhile, compounds A20 and B20 were 100% effective against three weeds ( Abutilon theophrasti , Amaranthus retroflexus , and Portulaca oleracea ) at 37.5 g a.i./ha. It was worth observing that compound B11 was more than 90% effective against three weeds ( Abutilon theophrasti , Amaranthus retroflexus , and Portulaca oleracea ) at 18.75 and 9.375 g a.i./ha. It was also safer to rice, maize, and wheat than flumiclorac-pentyl at 150 g a.i./ha. In addition, the molecular docking results showed that compound B11 could stably bind to Nt PPO and it had a stronger hydrogen bond with Arg98 (2.9 Å) than that of flumiclorac-pentyl (3.2 Å). This research suggests that compound B11 could be used as a new PPO inhibitor, and it could help control weeds in agricultural production.

Objective: The metabolic reprogramming of acute myeloid leukemia (AML) cells is a compensatory adaptation to meet energy requirements for rapid proliferation. This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells., Methods: SKM-1 cells (an AML cell line) were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES, a glutaminase inhibitor) or cytarabine. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, and cell apoptosis and reactive oxygen species (ROS) by flow cytometry. Western blotting was conducted to examine the levels of apoptotic proteins, including cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, the human long noncoding RNA (lncRNA) microarray was used to analyze gene expression after glutamine deprivation, and results were confirmed with quantitative RT-PCR (qRT-PCR). The expression of metallothionein 2A (MT2A) was suppressed using siRNA. Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry, respectively, in cells with MT2A knockdown., Results: Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells. The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation. MT2A knockdown increased apoptosis, while proliferation was not affected in SKM-1 cells. In addition, metformin inhibited cell growth and induced apoptosis in SKM-1 cells. Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine. Furthermore, the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells., Conclusion: Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML., (© 2024. Huazhong University of Science and Technology.)