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Pathogenic microorganisms are causative agents for different types of serious and even lethal infectious diseases. Despite advancements in medication, bacterial and fungal infections continue to be a growing problem in health care. As more and more bacteria become resistant to antibiotics used in therapy and an increasing number of invasive fungal species become resistant to current antifungal medications, there is considerable interest in the development of new compounds with antimicrobial activity. The compounds containing a heterocyclic ring play an important role among organic compounds with biological activity used as drugs in human and veterinary medicine or as insecticides and pesticides in agriculture. Thiadiazoles belong to the classes of nitrogen-sulfur heterocycles with extensive application as structural units of biologically active molecules and as useful intermediates in medicinal chemistry. The potency of the thiadiazole nucleus is demonstrated by the drugs currently used. 1,3,4-Thiadiazoles and some of their derivatives are extensively studied because of their broad spectrum of pharmacological activities. The aim of this review was to highlight the main antimicrobial properties exhibited by derivatives possessing 2-amino-1,3,4-thiadiazole moiety. Many of the reported 2-amino-1,3,4-thiadiazole derivatives can be considered as lead compounds for drug synthesis, and several of them have demonstrated higher antimicrobial activity in comparison to standard drugs. Furthermore, taking into account the reactivity of the amine group in the derivatization process, 2-amino-1,3,4-thiadiazole moiety may be a good scaffold for future pharmacologically active 1,3,4-thiadiazole derivatives.

Background: Imidazo[2,1-b]thiazole scaffolds were reported to possess various pharmaceutical activities. Results: The novel compound named methyl-2-(1-(3-methyl-6-(p-tolyl)imidazo[2,1-b]thiazol-2-yl)ethylidene)hydrazine-1-carbodithioate 3 acted as a predecessor molecule for the synthesis of new thiadiazole derivatives incorporating imidazo[2,1-b]thiazole moiety. The reaction of 3 with the appropriate hydrazonoyl halide derivatives 4a–j and 7–9 had produced the respective 1,3,4-thiadiazole derivatives 6a–j and 10–12. The chemical composition of all the newly synthesized derivatives were confirmed by their microanalytical and spectral data (FT-IR, mass spectrometry, 1H-NMR and 13C-NMR). All the produced novel compounds were screened for their anti-proliferative efficacy on hepatic cancer cell lines (HepG2). In addition, a computational molecular docking study was carried out to determine the ability of the synthesized thiadiazole molecules to interact with active site of the target Glypican-3 protein (GPC-3). Moreover, the physiochemical properties of the synthesized compounds were derived to determine the viability of the compounds as drug candidates for hepatic cancer. Conclusion: All the tested compounds had exhibited good anti-proliferative efficacy against hepatic cancer cell lines. In addition, the molecular docking results showed strong binding interactions of the synthesized compounds with the target GPC-3 protein with lower energy scores. Thus, such novel compounds may act as promising candidates as drugs against hepatocellular carcinoma.

Voltage-gated sodium (Nav) channels propagate electrical signals in muscle cells and neurons. In humans, Nav1.7 plays a key role in pain perception. It is challenging to target a particular Nav isoform; however, arylsulfonamide antagonists selective for Nav1.7 have been reported recently. Ahuja et al. characterized the binding of these small molecules to human Nav channels. To further investigate the mechanism, they engineered a bacterial Nav channel to contain features of the Nav1.7 voltage-sensing domain that is targeted by the antagonist and determined the crystal structure of the chimera bound to an inhibitor. The structure gives insight into the mechanism of voltage sensing and will enable the design of more-selective Nav channel antagonists. Science , this issue p. 10.1126/science.aac5464 Structural studies give insight into how a human sodium channel involved in pain perception can be selectively inhibited. Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists. GX-936 and related inhibitors bind to the activated state of voltage-sensor domain IV (VSD4), where their anionic aryl sulfonamide warhead engages the fourth arginine gating charge on the S4 helix. By opposing VSD4 deactivation, these compounds inhibit Nav1.7 through a voltage-sensor trapping mechanism, likely by stabilizing inactivated states of the channel. Residues from the S2 and S3 helices are key determinants of isoform selectivity, and bound phospholipids implicate the membrane as a modulator of channel function and pharmacology. Our results help to elucidate the molecular basis of voltage sensing and establish structural blueprints to design selective Nav channel antagonists.

Fluorescent imaging of biological systems in the second near-infrared window (NIR-II) can probe tissue at centimetre depths and achieve micrometre-scale resolution at depths of millimetres. Unfortunately, all current NIR-II fluorophores are excreted slowly and are largely retained within the reticuloendothelial system, making clinical translation nearly impossible. Here, we report a rapidly excreted NIR-II fluorophore (∼90% excreted through the kidneys within 24 h) based on a synthetic 970-Da organic molecule (CH1055). The fluorophore outperformed indocyanine green (ICG)—a clinically approved NIR-I dye—in resolving mouse lymphatic vasculature and sentinel lymphatic mapping near a tumour. High levels of uptake of PEGylated-CH1055 dye were observed in brain tumours in mice, suggesting that the dye was detected at a depth of ∼4 mm. The CH1055 dye also allowed targeted molecular imaging of tumours in vivo when conjugated with anti-EGFR Affibody. Moreover, a superior tumour-to-background signal ratio allowed precise image-guided tumour-removal surgery. A renally cleared, water-soluble dye emitting in the near-infrared-imaging (NIR)-II window outperforms a clinically approved NIR-I dye in the in vivo imaging of tumours and their nearby blood and lymphatic vasculatures.

A novel sulfamoylphenyl-dihydro-thiadiazole derivative (compound 14 ) has been designed and synthesized as a dual inhibitor targeting EGFR and human carbonic anhydrases (hCA_IX and hCA_XII). Computational studies, including density functional theory (DFT), molecular docking, and molecular dynamics simulations, confirmed its stability, favorable binding interactions, and reactivity profiles. Compound 14 showed potent inhibition of EGFR (IC₅₀ = 10.12 ± 0.29 nM), hCA_IX and hCA_XII (IC₅₀ = 79 ± 1.2 nM and 58 ± 0.9 nM, respectively). Cytotoxicity assays demonstrated selective activity against cancer cells, with IC₅₀ values of 16.13 µM in MDA-MB-231 and 22.57 µM in MCF-7 cells, compared to 148.32 µM in non-cancerous Vero cells. Compared to acetazolamide, compound 14 exhibited improved selectivity for cancer cells. Apoptosis studies revealed significant cell death in MDA-MB-231 cells, with early and late apoptosis rates of 22.50% and 58.27%, respectively, alongside a marked G1-phase cell cycle arrest (49.10% in treated cells vs. 44.98% in controls). In silico toxicological evaluations indicated a favorable safety profile, with low irritancy and acceptable rat oral LD₅₀ (15.81 mg/kg) and carcinogenic potency (TD₅₀ = 36.95). Compound 14 ’s potent dual inhibition and selective cytotoxicity make it a promising candidate for further optimization and in vivo studies.

Mechanosensitive Piezo1 and Piezo2 channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes in vertebrate organisms. Besides mechanical forces, Piezo1 is selectively activated by micromolar concentrations of the small molecule Yoda1 through an unknown mechanism. Here, using a combination of all-atom molecular dynamics simulations, calcium imaging and electrophysiology, we identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain, approximately 40 Å away from the central pore. Our simulations further indicate that the presence of the agonist correlates with increased tension-induced motions of the Yoda1-bound subunit. Our results suggest a model wherein Yoda1 acts as a molecular wedge, facilitating force-induced conformational changes, effectively lowering the channel’s mechanical threshold for activation. The identification of an allosteric agonist binding site in Piezo1 channels will pave the way for the rational design of future Piezo modulators with clinical value. Besides mechanical forces, the mechanosensitive channel Piezo1 is activated by the small molecule Yoda1 through an unknown mechanism. Here, using molecular dynamics simulations, calcium imaging and electrophysiology, the authors identify an allosteric Yoda1 binding pocket located in the putative mechanosensory domain.

Significance Antiinfectives, drugs that inhibit virulence strategies of microbial pathogens without affecting bacterial growth, may prevent hospital-acquired infections caused by antibiotic-resistant Staphylococcus aureus . We used virtual screening and synthetic optimization to identify 3,6-disubstituted triazolothiadiazole compounds as inhibitors of sortase, an enzyme that incorporates surface proteins into the staphylococcal envelope. Other Gram-positive bacteria also use sortase for protein assembly in the envelope and disease pathogenesis, suggesting that sortase inhibitors could protect high-risk patients against infection with many nosocomial pathogens.

The medication is the first in decades to have a different mode of action from those of current drugs, achieving better symptom relief with fewer side effects. The medication is the first in decades to have a different mode of action than do current drugs, achieving better symptom relief with fewer side effects. A computer illustration showing activity in the human brain in blue and gold on a black background

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

The dependency of cancer cells on glutamine may be exploited therapeutically as a new strategy for treating cancers that lack druggable driver genes. Here we found that human liver cancer was dependent on extracellular glutamine. However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells. Using a chemical library, we identified V-9302, a novel inhibitor of glutamine transporter ASCT2, as sensitizing glutamine dependent (GD) cells to CB-839 treatment. Mechanically, a combination of CB-839 and V-9302 depleted glutathione and induced reactive oxygen species (ROS), resulting in apoptosis of GD cells. Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.