Synthesis and Anti-Trypanosoma cruzi Activity of New Pyrazole-Thiadiazole Scaffolds.

Chagas disease, a silent but widespread disease that mainly affects a socioeconomically vulnerable population, lacks innovative safe drug therapy. The available drugs, benznidazole and nifurtimox, are more than fifty years old, have limited efficacy, and carry harmful side effects, highlighting the need for new therapeutics. This study presents two new series of pyrazole-thiadiazole compounds evaluated for trypanocidal activity using cellular models predictive of efficacy. Derivatives 1c (2,4-diCl) and 2k (4-NO2) were the most active against intracellular amastigotes. Derivative 1c also showed activity against trypomastigotes, with the detachment of the flagellum from the parasite body being a predominant effect at the ultrastructural level. Analogs have favorable physicochemical parameters and are predicted to be orally available. Drug efficacy was also evaluated in 3D cardiac microtissue, an important target tissue of Trypanosoma cruzi, with derivative 2k showing potent antiparasitic activity and a significant reduction in parasite load. Although 2k potentially reduced parasite load in the washout assay, it did not prevent parasite recrudescence. Drug combination analysis revealed an additive profile, which may lead to favorable clinical outcomes. Our data demonstrate the antiparasitic activity of pyrazole-thiadiazole derivatives and support the development of these compounds using new optimization strategies.

Investigation of 2,4-Dihydroxylaryl-Substituted Heterocycles as Inhibitors of the Growth and Development of Biotrophic Fungal Pathogens Associated with the Most Common Cereal Diseases.

Climate change forces agriculture to face the rapidly growing virulence of biotrophic fungal pathogens, which in turn drives researchers to seek new ways of combatting or limiting the spread of diseases caused by the same. While the use of agrochemicals may be the most efficient strategy in this context, it is important to ensure that such chemicals are safe for the natural environment. Heterocyclic compounds have enormous biological potential. A series of heterocyclic scaffolds (1,3,4-thiadiazole, 1,3-thiazole, 1,2,4-triazole, benzothiazine, benzothiadiazine, and quinazoline) containing 2,4-dihydroxylaryl substituents were investigated for their ability to inhibit the growth and development of biotrophic fungal pathogens associated with several important cereal diseases. Of the 33 analysed compounds, 3 were identified as having high inhibitory potential against Blumeria and Puccinia fungi. The conducted research indicated that the analysed compounds can be used to reduce the incidence of fungal diseases in cereals; however, further thorough research is required to investigate their effects on plant-pathogen systems, including molecular studies to determine the exact mechanism of their activity.

Discovery of novel dihydropyrrolidone-thiadiazole compound crosstalk between the YycG/F two-component regulatory pathway and cell membrane homeostasis to combat methicillin-resistant Staphylococcus aureus.

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 (CC50>100 µM) and hemolytic activity (HC50>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.

Structure-Activity Relationship Studies in Benzothiadiazoles as Novel Vaccine Adjuvants.

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 Ca2+ 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 Ca2+ 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.

Identification of Benzothiazoles Bearing 1,3,4-Thiadiazole as Antiproliferative Hybrids Targeting VEGFR-2 and BRAF Kinase: Design, Synthesis, BIO Evaluation and In Silico Study.

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

Discovery and Evaluation of Imidazo[2,1-b][1,3,4]thiadiazole Derivatives as New Candidates for α-Synuclein PET Imaging.

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 [125I]ITA-3, with moderate binding affinity (IC50 = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [125I]ITA-3, we developed a potential PET tracer, [18F]FITA-2 (radiochemical yield >25%, molar activity >110 GBq/µmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC50 = 245 nM), good brain uptake (SUVpeak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [18F]FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.

Near-Infrared II Fluorescence Imaging and Image-Guided siRNA Therapy of Atherosclerosis.

Targeting Ca2+/calmodulin-dependent protein kinase γ (CaMKIIγ) in macrophages using RNAi nanotechnology represents an innovative and promising strategy in the diagnosis and treatment of atherosclerosis. Nevertheless, it remains elusive because of the current challenges associated with the systemic delivery of siRNA nanoparticle (NP) to atheromatous plaques and the complexity of atherosclerotic plaques. Here, we demonstrate the potential of a thienothiadiazole-based near-infrared-II (NIR-II) organic aggregation-induced emission (AIE) platform encapsulated with the Camk2g siRNA to effectively target CaMKIIγ in macrophages for dynamic imaging and image-guided gene therapy of atherosclerosis. The nanoparticles effectively decreased CaMKIIγ expression and increased the expression of the efferocytosis receptor MerTK in plaque macrophages, leading to a reduction in the necrotic core area of the lesion in an aortic plaque model. Our theranostic approach highlights the substantial promise of near-infrared II (NIR-II) AIEgens for imaging and image-guided therapy of atherosclerosis.

Design, Synthesis, and Herbicidal Activity of Novel Tetrahydrophthalimide Derivatives Containing Oxadiazole/Thiadiazole Moieties.

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 (NtPPO) and herbicidal activity were evaluated. Among them, compounds B11 (Ki = 9.05 nM) and B20 (Ki = 10.23 nM) showed significantly better inhibitory activity against NtPPO than that against flumiclorac-pentyl (Ki = 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 NtPPO 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.

Development of new chiral 1,2,4-triazole-3-thiones and 1,3,4-thiadiazoles with promising in vivo anticonvulsant activity targeting GABAergic system and voltage-gated sodium channels (VGSCs).

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 IC50 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 GABAA receptor showed that compound 5b exhibits a strong affinity to the benzodiazepine (BZD) binding site on GABA. It also revealed that the NaV1.3 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 GABAA and NaV1.3 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.

Comparison of HPLC, HPTLC, and In Silico Lipophilicity Parameters Determined for 5-Heterocyclic 2-(2,4-Dihydroxyphenyl)-1,3,4-thiadiazoles.

The 5-heterocyclic 2-(2,4-dihydroxyphenyl)-1,3,4-thiadiazoles were obtained as potential biologically active compounds. Lipophilicity is one of the most important physicochemical properties of compounds and was already taken into account during the drug candidates design and development. The lipophilicity of compounds was determined using the computational (log P) and chromatography (log kw, RMw) methods. The experimental ones included the reverse-phase column high performance liquid chromatography RP (HPLC) with C8, C18, phosphatidylcholine (IAM), and cholesterol stationary phases and the thin layer chromatography (RP-HPTLC) with C8 and C18 stationary phases and various organic modifiers under the isocratic conditions. Descriptive statistics, correlation, and PCA analyses were used to compare the obtained results. For lipophilicity estimation of the tested compounds by HPTLC, dioxane and MeOH seem to be particularly beneficial as organic modifiers. The chromatographic lipophilicity parameters log kw (RMw) were well correlated and highly redundant (85%) compared with those calculated. Most compounds possess lipophilicity parameters within the recommended range for drug candidates.

A Benzothiadiazole-Based Zn(II) Metal-Organic Framework with Visual Turn-On Sensing for Anthrax Biomarker and Theoretical Calculation.

2,6-pyridine dicarboxylic acid (DPA) is an exceptional biomarker of notorious anthrax spores. Therefore, the rapid, sensitive, and selective quantitative detection of DPA is extremely significant and urgent. This paper reports a Zn(II) metal-organic framework with the formula of {[Zn6(NDA)6(DPBT)3] 2H2O·3DMF}n (MOF-1), which consists of 2,6-naphthalenedicarboxylic acid (2,6-NDA), 4,7-di(4-pyridyl)-2,1,3-benzothiadiazole (DPBT), and Zn(II) ions. Structural analysis indicated that MOF-1 is a three-dimensional (3D) network which crystallized in the monoclinic system with the C2/c space group, revealing high pH, solvent, and thermal stability. Luminescence sensing studies demonstrated that MOF-1 had the potential to be a highly selective, sensitive, and recyclable fluorescence sensor for the identification of DPA. Furthermore, fluorescent test paper was made to detect DPA promptly with color changes. The enhancement mechanism was established by the hydrogen-bonding interaction and photoinduced electron transfer transition between MOF-1 and DPA molecules.

Recent development and strategies towards target interactions: Synthesis, characterization and in silico analysis of benzimidazole based thiadiazole as potential anti-Alzheimer agents.

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 1H NMR, 13C 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 IC50 = 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 (IC50 = 3.20 ± 0.10 µM for AChE and 4.30 ± 0.50 µM for BuChE), analog-4 (IC50 = 4.30 ± 0.30 µM for AChE and 5.50 ± 0.20 µM for BuChE) and analog-5 (IC50 = 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.

Eco-synthesis route: Developing bis-hydrazono[1,2,4]-thiadiazoles via a green synthetic approach with calcium oxide-chitosan nanocomposite.

Modern environmental organic chemistry is focused on developing cost-efficient, versatile, environmentally acceptable catalytic chemicals that are also highly effective. Herein, hybrid calcium-chitosan nanocomposite films was prepared by doping calcium oxide molecules into a chitosan matrix at weight percentage (15, 20, and 25 % wt. chitosan­calcium) using an easy and affordable simple co-precipitation process. The CS-CaO nanocomposite's structure was elucidated using analytical techniques such as Fourier transform infrared (FTIR), scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). Based on the X ray diffraction (XRD) measurements, the crystallinity was reduced by the incorporation of the CaO molecules. Also, from the calculation of the Debye-Scherrer equation on this X-ray diffraction (XRD) pattern, the crystallite size was found to be 17.2 nm for the nanocomposite film with 20 % wt. The energy dispersive spectroscopy graph demonstrated the presence of the distinctive Ca element signals within the chitosan, with the amount in a sample of 20 % wt. being discovered to be 21.32 % wt. For the synthesis of bis-hydrazono[1,2,4]thiadiazoles, the obtained CS-CaO nanocomposite could be employed as a potent heterogeneous recyclable catalyst. Better reaction yields, quicker reactions, softer reaction conditions, and green reusable efficient biocatalysts for several uses are just a few advantages of this approach.

Imidazole-thiadiazole hybrids: A multitarget de novo drug design approach, in vitro evaluation, ADME/T, and in silico studies.

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 IC50 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 (IC50 = 14.8 ± 0.01 µM). Compounds 11-13, 16, 20, and 21 exhibited potent activity IC50 = 8.6 ± 0.02 to 34.7 ± 0.03 µM against AChE enzyme, compared to donepezil chloride (IC50 = 39.2 ± 0.05 µM). Compound 21 demonstrated comparable inhibition IC50 = 45.1 ± 0.09 µM against BChE, compared to donepezil chloride (IC50 = 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.

Study on the photo/electrochemical bi-functional properties of a coupling interface of Ru[dcbpy]32+-AMT/Au by SECM imaging-based joint analytical method.

A photo/electrochemical coupling interface of Ru[dcbpy]32+-AMT/Au (AMT; 5-Amino-1,3,4-thiadiazole-2-thiol) was fabricated using a dehydration condensation sulfhydrating method. For the interface functional properties, a combined dual-signal recording (CDSR) method was applied to characterize the response characteristics, and a scanning electrochemical microscopy-electrochemiluminescence (SECM-ECL) imaging was developed to assess the interface distribution uniformity. The interface biosensing compatibility was validated by constructing a simple DNA sensor. The research results show that the interaction between the two functional parameters follows a synergistic effect mechanism in the coupling conditions and an interference effect mechanism in the detection condition. Under optimized conditions, the saturation dual-signal response values are 156.0 and 86.8 µA, respectively. The statistics and imaging comparison analysis validate good interface distribution uniformity and stability performance. The DNA sensor's dual-signal detection limits to the signal probe (SP) are ∼30 fM and 0.3 pM with linear ranges of 100.0 fM âˆ¼ 1.0 nM and 1.0 pM âˆ¼ 10.0 nM, respectively. The fabricated interface exhibits an effective bi-functional response performance compatible with biosensing. The proposed imaging method has a high technical fit for studying photo/electrochemical coupling interfaces and can also provide a reference for other similar coupling interface analyses.

Identification of novel benzothiazole-thiadiazole-based thiazolidinone derivative: in vitro and in silico approaches to develop promising anti-Alzheimer's agents.

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 (1H NMR, 13C 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.

[Box: see text].

Thiadiazole/Thiadiazine Derivatives as Insecticidal Agent: Design, Synthesis, and Biological Assessment of 1,3,4-(Thiadiazine/Thiadiazole)-Benzenesulfonamide Derivatives as IGRs Analogues against Spodoptera littoralis.

In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.

Semiconducting Polymers Based on Asymmetric Thiadiazoloquinoxaline for Augmented In Vivo NIR-II Photoacoustic Imaging.

A photoacoustic (PA) imaging technique using the second near-infrared (NIR-II) window has attracted more and more attention because of its merits of deeper penetration depth and higher signal-to-noise (S/N) ratio than that using the first near-infrared (NIR-I) one. However, the design and development of high-performance PA imaging contrast agents in the NIR-II window is still a challenge. A semiconducting polymer, constructed by asymmetric units, exhibits regiorandom characteristics that effectively increase the distortion of the backbone. This increase in the degree of twist can regulate the twisted intramolecular charge transfer (TICT) effect, resulting in an enhancement of the PA signal. In this paper, an asymmetric structural acceptor strategy is developed to improve the PA signals of the resulting semiconducting polymer (PATQ-MP) in the NIR-II window with improved brightness, higher S/N ratio, and better photothermal conversion efficiency compared to polymers with the same main-chain structure containing a symmetric acceptor. DFT analysis showed that PATQ-MP containing an asymmetric acceptor monomer had a larger dihedral angle, which effectively improved the PA signal intensity by enhancing the TICT effect. The PEG-encapsulated PATQ-MP nanoparticles exhibit promising performance in the PA imaging of mouse tumors in vivo, demonstrating the clear identification of microvessels as small as 100 µm along with rapid metabolism within a span of 5 h. Therefore, this work provides a unique molecular design strategy for improving the signal intensity of PA imaging in the NIR-II window.

Synthesis and Antifungal Activity of Chalcone Derivatives Containing 1,3,4-Thiadiazole.

24 chalcone derivatives containing 1,3,4-thiadiazole were synthesized. The results of bioactivity tests indicated that some of the target compounds exhibited superior antifungal activities in vitro. Notably, the EC50 value of D4 was 14.4 µg/mL against Phomopsis sp, which was significantly better than that of azoxystrobin (32.2 µg/mL) and fluopyram (54.2 µg/mL). The in vivo protective activity of D4 against Phomopsis sp on kiwifruit (71.2 %) was significantly superior to azoxystrobin (62.8 %) at 200 µg/mL. The in vivo protective activities of D4 were 74.4 and 57.6 % against Rhizoctonia solani on rice leaf sheaths and rice leaves, respectively, which were slightly better than those of azoxystrobin (72.1 and 49.2 %) at 200 µg/mL. Scanning electron microscopy (SEM) results showed that the mycelial surface collapsed, contracted and grew abnormally after D4 treatment. Finally, the results were further verified by in vivo antifungal assay, fluorescence microscopy (FM) observation, determination of relative conductivity, membrane lipid peroxidation degree assay, and determination of cytoplasmic content leakage. Molecular docking results suggested that D4 could be a potential SDHI.