Search Results (220)

This investigation focused on isoniazid (INH)—saccharin (SAC) salts. One hydrate and one anhydrous INH-SAC salt form were synthesized and characterized spectroscopically by Raman and infrared spectroscopy. Solvent (methanol, acetone, acetonitrile)-assisted synthesis in the presence of water, or in water, resulted in production of the monohydrated form of the salt (MH: (INH+H)⁺/(SAC–H)⁻.H₂O). The anhydrous form (A: (INH+H)⁺/(SAC–H)⁻) was obtained using the same synthesis method but in the absence of water or, together with the hydrate, in the presence of traces of water. Differential scanning calorimetry studies revealed that the hydrate can be converted into the anhydrous form of the salt upon heating, with the latter melting at a T_m (onset) of 131.7 ± 0.5 °C. Melting was followed by a reaction between isoniazid and saccharin leading to saccharin ring opening and formation of a new covalent hydrazide–amide derivative, via nucleophilic acyl substitution at the saccharin carbonyl. The newly formed adduct, 2-[2-(pyridine-4-carbonyl)hydrazine-1-carbonyl] benzene-1-sulfonamide, melts at T_m (onset) = 204.4 ± 0.5 °C. The crystal structures of the hydrate and of the anhydrous form were determined by single-crystal X-ray diffraction, and the dominant intermolecular interactions in the crystalline INH-SAC salts were evaluated using Hirshfeld surface analysis. To complement the experimental results, density functional theory (DFT) calculations were performed both on relevant isolated structural units and on the two salts, employing fully periodic DFT methods. Full article

The angiotensin II type 1 (AT₁) receptor is a key component of the renin–angiotensin system (RAS) and a validated target for cardiovascular and renal disorders. Developing small molecules with defined AT₁ versus AT₂ binding profiles remains important for both therapeutic and mechanistic studies. Here, a series of novel imidazole-based compounds was synthesized and evaluated for their binding affinities toward angiotensin II type 1 (AT₁) and type 2 (AT₂) receptors. Binding studies were conducted by measuring the displacement of radiolabeled [³H]-angiotensin II ([³H]-AII) in PLC-PRF-5 human hepatoma cells for AT₁ receptors and calf cerebellum membranes for AT₂ receptors. Structure–activity relationship (SAR) analysis revealed that sulfonamide substitution significantly enhanced AT₁ receptor affinity, whereas sterically hindered derivatives and ester-containing compounds were less active. Molecular docking studies using the AT₁ receptor crystal structure (PDB: 8TH4) rationalized the observed activity trends. The most active compound showed high AT₁ affinity (Ki = 5 nM), comparable to losartan, and all compounds displayed preferential binding for AT₁ over AT₂ receptors. Full article

Background/Objectives: Klebsiella (K.) pneumoniae is a significant pathogen in both humans and animals. However, data on its occurrence in animals in Germany remain limited. This study aimed to investigate the antimicrobial resistance (AMR) phenotypes, AMR genes, and virulence traits of animal-derived K. pneumoniae isolates from Germany. Methods: A total of 59 K. pneumoniae isolates obtained in 2023 from dogs, cats, horses, cattle, and chickens across 11 German federal states were analysed. Phenotypic antimicrobial susceptibility testing (AST) was performed, and whole-genome sequencing (WGS) was used for genomic characterisation, including detection of AMR genes, virulence-associated genes, sequence types (STs), and plasmid replicons. Results: Most isolates (78%) were susceptible to all tested antibiotics, while three isolates were classified as multidrug-resistant (MDR). Resistance was most frequently observed for piperacillin (n = 8) and trimethoprim/sulfamethoxazole (n = 4). Carbapenem resistance was detected in two isolates (one from a dog and one from a cat), and phenotypic colistin resistance in one dog isolate. WGS identified 96 AMR genes across isolates, with 20–42 AMR determinants per isolate, conferring resistance to β-lactams, aminoglycosides, fluoroquinolones, sulfonamides, tetracyclines, trimethoprim, and fosfomycin. Ten extended-spectrum β-lactamase (ESBL)-producing isolates carried genes including bla_CTX-M-15, bla_SHV-2, bla_SHV-27, bla_SHV-42, bla_SHV-106, and bla_TEM-158. Although fosA was detected in all isolates, only three exhibited phenotypic resistance to fosfomycin. A total of 52 STs were identified, including high-risk clones. One hypervirulent isolate (ST60) carrying hypervirulence-associated genes rmpA and iroB was detected. Plasmid replicons were present in 70% of isolates, while plasmid-associated AMR genes were identified in nine isolates. Conclusions: This study demonstrates the genomic diversity of K. pneumoniae identified in companion animals and highlights the presence of AMR and virulence determinants relevant to a One Health context. Full article

Voltage-gated ion channels are central regulators of cardiac, neuronal, and skeletal muscle excitability, and their dysfunction underlies a wide spectrum of channelopathies, including arrhythmias and neuromuscular disorders. While conventional ion channel therapeutics typically target a single pore-binding site, emerging evidence supports the therapeutic potential of polypharmacological compounds capable of modulating multiple channel subtypes. ARumenamides represent a novel class of sulfonamide-based ligands originally identified as fenestration-targeting sodium channel modulators; however, their cross-family binding mechanisms and multitarget potential remain incompletely defined. Here, we employed an integrated structure-based computational workflow combining molecular docking, in silico ADMET profiling, and long-timescale (250 ns) molecular dynamics simulations to systematically evaluate 20 ARumenamide derivatives across 15 voltage-gated sodium, calcium, and potassium channel structures. Docking analyses revealed broad multitarget binding profiles, with several compounds exhibiting high predicted affinity across cardiac, neuronal, and skeletal muscle channel isoforms. ADMET predictions demonstrated favorable intestinal absorption and metabolic safety for most candidates, although solubility and mutagenicity liabilities were identified for select derivatives. Detailed molecular dynamics simulations of prioritized compounds (AR-310, AR-769, and AR-946) uncovered site-specific binding behaviors and conformational effects. AR-769 exhibited exceptional stability at both fenestration and central pore sites of Cav1.2, associated with persistent hydrogen-bond networks, reduced protein flexibility, and a well-defined free energy minimum. In contrast, AR-310 and AR-946 displayed selective stability within Nav1.4 fenestrations and the Kv4.3 central pore, respectively, highlighting how subtle chemical features bias binding site preference and dynamic retention. Collectively, these findings establish a structure–dynamics framework for rational design of ARumenamide-based multitarget ion channel modulators. Our results demonstrate that fenestration-focused binding can support sustained ligand engagement without obligatory pore occlusion, offering a mechanistically distinct strategy for developing next-generation polypharmacological therapeutics for cardiac and neuromuscular disorders. Full article

As a devastating disease worldwide, rice bacterial leaf blight—caused by Xanthomonas oryzae pv. oryzae (Xoo)—leads to substantial reductions in grain yield. The increasing resistance to conventional bactericides necessitates the development of novel and sustainable control agents. This study evaluated 58 novel alkyl sulfonamide compounds against Xoo. In the turbidimetric assay at 100 mg/L, several compounds showed potent antibacterial activity. Among them, SYAUP-116 and SYAUP-212 exhibited in vitro inhibition comparable to that of streptomycin sulfate at the same concentration. Furthermore, in EC₅₀ determination assays, both compounds yielded lower EC₅₀ values than zinc thiazole. Among the 58 compounds tested, SYAUP-491 exhibited an in vitro EC₅₀ of 6.96 mg/L and achieved 74.1% in vivo therapeutic efficacy at 200 mg/L, representing the most promising lead for further characterization. Molecular docking, based on prior proteomic data, indicates potential stable binding to ribosomal proteins (50S L33/L34 and 30S S5), with the strongest interaction observed for L33 (binding free energy: −5.73 kcal/mol). This suggests a putative mechanism involving ribosome targeting and protein synthesis inhibition, which may be facilitated by hydrophobic interactions and halogen bonds derived from its trifluoromethyl and sulfonamide groups. SYAUP-491 demonstrates significant potential as a novel bactericide for rice bacterial leaf blight, warranting further research on structure-activity optimization, target validation, and field performance. Full article

Thiazolyl-benzene/camphor sulfonamide derivatives (series 4a–k, 5a–j and 6a–i) were synthesized by reaction of various aryl sulfonyl chlorides and camphor sulfonyl chlorides with 2-amino-4-phenylthiazole. The compounds were evaluated for antibacterial, antioxidant, and α-glucosidase/α-amylase inhibitory activities. Biological screening showed that 4h, 5g and 5i displayed significant activity against most Gram-positive bacteria (MICs 4.68–18.75 µg/mL), while 4b and 5i were active against most Gram-negative bacteria with similar MIC ranges. In the DPPH assay, 4e, 4f, 4g and 4h exhibited slightly stronger radical-scavenging activity than ascorbic acid (IC₅₀ ≈ 3.5–3.8 µM vs. 4.14 µM); 5f emerged as the best dual carbohydrate-digesting enzyme inhibitor, and 5b and 5e demonstrated selectivity toward α-amylase. Full article

Antimicrobial resistance (AMR) in Escherichia coli (E. coli) from food-producing animals constitutes a substantial public health concern. This study characterized antimicrobial resistance profiles, phylogenetic diversity, virulence-gene distribution, and plasmid-borne extended-spectrum β-lactamase (ESBL) determinants of E. coli isolates recovered from water buffaloes with subclinical mastitis. Among the 54 ESBL-producing E. coli isolates, all were resistant to ampicillin and cefotaxime. High resistance rates were also observed for cephalothin (75.9%), trimethoprim–sulfamethoxazole (74.0%), ceftiofur (70.4%), florfenicol (68.5%), and cefazolin (63.0%). Lower resistance was recorded for colistin sulfate (40.7%), enrofloxacin (33.3%), and gentamicin (25.9%). Phylogenetic analysis of ESBL producers identified phylogroup B1 (42.6%) as predominant, followed by groups A (29.6%) and D (25.9%). Multilocus sequence typing (MLST) revealed that ST50 (20.4%) was the most common sequence type, and serogroup O150 was dominant (70.4%). Virulence genes, such as iss (81.5%), astA (59.3%), and espP (38.9%), were frequently detected among ESBL isolates. ESBL genes were predominantly bla_CTX-M-1 (27.8%) in all isolates, while the narrow-spectrum β-lactamase genes bla_TEM-1 (55.6%) and bla_OXA-10 (14.8%) were also commonly co-detected. Bioinformatic analysis predicted that all ESBL genes were associated with plasmid-derived contigs, with the predicted plasmid size ranging from approximately 32 to 187 kb and belonging to IncFIB, IncFIA, IncI1, IncFIA + I1, and IncFII replicon types. Conjugation frequencies ranged from 4.8 × 10⁻⁷ to 4.1 × 10⁻², and plasmids were predicted to carry additional resistance genes mediating resistance to chloramphenicol (floR), sulfonamides (sul1, sul3), tetracyclines (tet(A) and tet(B)), and trimethoprim (dfrA1, dfrA12). The co-carriage of ESBL genes with additional antimicrobial resistance and virulence determinants suggests the potential role of water buffaloes as reservoirs of clinically relevant resistance traits that may disseminate through horizontal gene transfer. Full article

Chronic oxidative stress and lipid imbalance drive metabolic disorders such as obesity and non-alcoholic fatty liver disease, yet few therapies target the upstream redox imbalance in key tissues. Human carbonic anhydrase III (hCA III), a redox-associated enzyme enriched in liver and adipose tissue, has long remained pharmacologically elusive due to its low catalytic activity and lack of modulators. Here, we identify fragment-like nicotinic acid derivatives as non-sulfonamide hCA III modulators and evaluate their associated cellular effects. Using an esterase activity assay, we screened 25 analogues and identified two fragment-like hits, compound 17 (2-thioethyl) and compound 22 (6-morpholino), with IC₅₀ values of 487 and 361 µM, respectively. Orthogonal thermal shift analysis supported compound-protein interaction, and selected hits were subsequently evaluated in HepG2 cells. Both compounds were associated with reduced CA3 mRNA expression after treatment at 1 µM, while their cellular phenotypes diverged, with compound 22 increasing ROS under oxidative stress conditions and compound 17 affecting mitochondrial membrane potential. Taken together, these findings identify tractable nicotinic acid-derived fragment hits and associated cellular phenotypes that warrant further mechanistic investigation. These fragment-like hits provide a practical starting point for studying the redox-linked biology of hCA III. Full article

Background/Objectives: Worldwide, diabetes is a 21st century disease with continuously increasing prevalence. Current medications often have long-term adverse effects, which is why new substances are needed to help combat these disadvantages. Methods: In this respect, the present study develops a series of compounds with potential antidiabetic activity, including synthesis, physicochemical–spectral characterization and in vitro–in silico evaluation. Results: The sulfonamide derivatives were obtained by condensation reactions of para-toluenesulfonamide (p-TSA) with two different isocyanates, directly or after the condensation reaction with urea. The spectroscopic methods, IR, ¹H-NMR, ¹³C-NMR, were used for the structural elucidation of the compounds to confirm the presence of the functional groups responsible for the antihyperglycemic action, namely amide, azomethine and sulfonyl groups. Cytotoxicity screening on NCTC fibroblasts confirmed the excellent safety profile of the most synthesized derivatives across the tested range (100–1500 μg/mL). In contrast, the p-TSA-c-d derivative showed a clear transition from a biocompatible profile at 100 μg/mL to a more cytotoxic phenotype at concentrations exceeding 750–1500 μg/mL. The synthesized derivatives, particularly p-TSA-c-d, exhibited remarkable antidiabetic potential by effectively inhibiting α-amylase and α-glucosidase, with IC₅₀ values as low as 46.54 μM, outperforming the standard reference acarbose. The molecular docking tests revealed different mechanisms for the inhibitory activity exerted by the p-TSA derivatives on the two targeted enzymes. Conclusions: Although these developed compounds can be considered promising antidiabetic agents, studies can be further deepened in the future by performing in vivo tests. Full article

Prior molecular docking and dynamics studies indicated a pyrazolopyridine–sulfonamide derivative (L87/PPS2, or simply PPS2) as a potential interactant with SARS-CoV-2 protein targets. The in vitro anti-SARS-CoV-2 activity and cytotoxicity profile of PPS2 were screened alongside a series of pyrazolopyrimidine (PZP) and triazolopyrimidine (TZP) derivatives. PPS2 demonstrated only partial inhibition of SARS-CoV-2 growth in Vero E6 cells at 100 µM. Crucially, however, four out of five PZPs and eight out of fourteen TZPs exhibited potent in vitro inhibitory activity against SARS-CoV-2 at 100 µM, with none of the tested compounds displaying cytotoxicity against Vero E6 cells at this concentration. Further characterization of one compound, PZP25, revealed an inhibitory concentration (IC50) of 8.2 µM, combined with low cytotoxicity (CC50 > 800 µM), yielding a selectivity index greater than 100. Time of addition assays indicated that PZP25’s antiviral effects were most pronounced when administered post-infection. While cellular pre-treatment provided a partial reduction in virus growth, modest virucidal activity was also observed at warmer temperatures (20 °C and 37 °C). Collectively, our findings demonstrate that PZP and TZP derivatives possess potent inhibitory activity of SARS-CoV-2 replication in vitro and highlight such compounds as promising chemical scaffolds for the development of novel antiviral agents targeting coronaviruses. Full article

The essential reaction of CO₂ hydration, fundamental to all living organisms, is facilitated by the enzyme carbonic anhydrase (CA, EC 4.2.1.1). This enzyme plays a crucial role in regulating various physiological and pathological processes. A series of heterocyclic benzenesulfonamide derivatives (19 compounds) were evaluated as possible inhibitors of human CAs. Their inhibitory properties were tested against several isoforms such as the cytosolic hCA I and hCA II, as well as the transmembrane isoforms hCA IV, hCA IX and hCA XII. The tested molecules demonstrated notable inhibitory potential, particularly toward hCA II and hCA IV, where five and four compounds, respectively, exhibited greater potency than the reference inhibitor, acetazolamide. Molecular docking simulations were further performed to elucidate the binding interactions of the most active compounds with the human CA II, IV IX and XII isoforms Full article

Topological graph theory provides a quantitative approach to understanding the structural complexities of sulfonamide compounds, which are prominent for their therapeutic importance in cancer treatment. A new computational scheme to predict the physicochemical and biological functions of sulfonamide derivatives, based on connection numbers and connection-based topological indices as alternatives to the theoretically overt degree-based index, is proposed. A set of structurally diverse sulfonamide compounds as chemical graphs is considered, and the relevant graph descriptors are computed using different connection numbers. Due to the complexity of the calculations involved in connectivity and other such indices, algorithms were developed in Python 3.12.12 to automate the extraction and calculation of these indices. QSPR analysis, with the help of supervised machine learning models like linear regression, among others, and various statistical techniques, was employed to obtain insight into the relationships existing between the structural properties and the molecular properties measured, such as melting point, molecular weight, etc. These results demonstrate the great predictive capability of connection-based indices in assessing pharmacologic efficacy or molecular behavior. The holistic setting thus links topological modeling to data-driven prediction and provides a window into the rational design and optimization of sulfonamide-based cancer therapeutics. Full article

The protein kinase N family belongs to the AGC kinase group and contains three isozymes: PKN1, PKN2, and PKN3. Catalytic domains of PKNs share high sequence similarity, yet the proteins differ in tissue distribution, functions, and involvement in pathological processes. In particular, PKN3 has been implicated in tumor growth and metastatic progression, highlighting the need for isozyme-selective inhibitors as both research tools and therapeutic leads. Here, we report the rational design of selective PKN3 inhibitors based on distinctive structural features of this kinase. Two strategies were applied. First, the smaller threonine gatekeeper residue unique to PKN3 within the AGC group was exploited by derivatization of N-(2-aminoethyl)isoquinoline-5-sulfonamide (H-9) at position C8. Among the resulting compounds, a phenylamino-substituted derivative displayed the highest affinity, with a dissociation constant (K_D) of 23 nM and more than 1000-fold selectivity over protein kinase A. Second, bisubstrate-analog design was employed to enhance binding to basophilic AGC kinases through covalent attachment of a (d-Arg)₃-containing chain to H-9 derivatives. This approach yielded ARC-2603, which bound PKN3 with a K_D value of 0.2 nM and showed 5500-fold selectivity over PKAcα. The selectivity of ARC-2603 was further evaluated in a commercial panel of 397 protein kinases, which supported its utility as a highly selective PKN3 inhibitor. Full article

The ongoing emergence of antiviral drug resistance underscores the critical need for new broad-spectrum antiviral agents. Sulfonamides and their derivatives have emerged as promising candidates for the development of new antiviral therapeutics. In this study, a series of camphor-10-sulfonamide derivatives was synthesized through a feasible and sustainable synthetic approach starting from naturally available precursors and evaluated for antiviral properties. Their activity was examined against three structurally distinct viruses—herpes simplex virus type 1 (HSV-1), human coronavirus (HCoV-OC43), and feline calicivirus (FCV)—representing both DNA and RNA, enveloped and non-enveloped types. The compounds were examined for their effects on viral replication, the stage of viral adsorption to the cell, and extracellular virions. The weakest cytotoxicity and the most pronounced activity of all the tested substances was demonstrated by the tryptophan derivative 7a. A time-dependent inhibition of the stage of adsorption of HCoV-OC43 (Δlg = 2.0 at 120 min) and FCV (Δlg = 1.75 at 60 min) to susceptible cells was established, as well as virucidal activity on the three types of virions tested, with the most pronounced effect at 120 min—for HSV-1 (Δlg = 2.75) and Δlg = 2.0 for HCoV-OC43 and FCV. Molecular docking studies performed using Glide (Schrödinger) provided insights into the active conformations of the most effective ligands and predicted possible interactions with relevant viral targets, supporting their potential as lead structures for further therapeutic development. Full article

The indiscriminate and excessive use of antimicrobial agents in livestock production is a major driver of antimicrobial resistance (AMR), thereby posing a grave threat to global public health. Although several surveillance studies have documented antimicrobial resistance patterns of swine-derived E. coli in different regions of China, comprehensive investigations integrating multilocus sequence typing (MLST), resistance determinants, and virulence gene profiles have remained scarce for central China, particularly Hubei province, since 2018. This study investigated the prevalence of antibiotic resistance, and molecular epidemiology of E. coli isolated from swine farms in Hubei province, China, while simultaneously analyzing their clonal and genetic diversity. A total of 148 E. coli isolates were collected from porcine sources in central China, revealing distinct regional variations in genetic diversity. Multilocus sequence typing (MLST) analysis identified 38 sequence types (STs) distributed across 7 clonal complexes (CCs) and several unassigned clones. ST46 emerged as the predominant sequence type (19.6% prevalence), followed by ST23 and ST10. Antimicrobial susceptibility testing demonstrated 100% resistance to lincosamides and sulfonamides, with all isolates exhibiting multidrug resistance (MDR) to antimicrobial classes. Genetic characterization detected 16 resistance determinants, with individual isolates carrying 5–7 resistance genes on average. The resistance profile included seven β-lactamase genes: blaTEM (61.5%), blaCTX-M-1G (57.4%), blaDHA (46.6%), blaSHV (39.2%), blaCTX-M-9G (24.3%), blaOXA (13.5%), and blaCMY-2 (1.4%); and eight aminoglycoside-modifying enzyme genes, including polymyxin resistance gene mcr-1 (7.4%). Virulence factor screening through PCR detected nine associated genes, with EAST1, fyuA, STa, K88, STb, Irp2, and LT-1 present in 95.3% of isolates, while K99 and 987P were absent in all specimens. This investigation documents alarmingly high antimicrobial resistance rates in swine-derived E. coli populations while elucidating their genetic diversity. The findings suggest that intensive antibiotic use in porcine production systems has driven the evolution of extensively drug-resistant bacterial isolates. These results emphasize the urgent need to implement antimicrobial stewardship programs in livestock management to mitigate AMR proliferation. Full article