Search Results (41)

Background: Alcohol use disorder is a common condition with high morbidity and mortality and no highly effective treatments. Achieving and maintaining abstinence is necessary or desired for many persons with AUD, but is difficult due to the nature of the condition. Pharmacologic inhibition of the enzyme ALDH2, which increases levels of the substrate acetaldehyde when alcohol is imbibed, can serve as a powerful enforcer of efforts to remain abstinent. Disulfiram is an approved ALDH2 inhibitor via its active metabolite DETC-MeSO, but has many limitations, including numerous adverse effects, hepatotoxicity, oral administration, and unpredictable mechanistic activity. Methods: SOPH-110S, an analog of DETC-MeSO, was evaluated in a series of experiments to assess mechanism, pharmacokinetics in male beagle dogs, cardiovascular safety in telemeterized male beagle dogs, selectivity, off-target activity, CYP inhibition, and proof of mechanism in a rat model that included dosing and alcohol challenge followed by analysis of liver ALDH2 inhibition. Results: SOPH-110S showed high potency with a comparable IC₅₀ vs. positive controls and no physiologically relevant off-target binding in an 84-target panel. It did not inhibit or induce any major CYP enzymes or meaningfully inhibit the hERG channel. After 10 days’ dosing in rats, followed by administration of alcohol, SOPH-110S was a highly potent, dose-dependent inhibitor of ALDH2, comparable to DETC-MeSO. No cardiovascular safety concerns were found at multiples above expected clinical doses. Conclusions: The preclinical data support further clinical study of SOPH-110S as a potential ALDH2 inhibitor treatment for AUD. The FDA approved the IND to conduct a first-in-man phase 1 study in September 2025. Full article

Fritillaria pallidiflora Schrenk ex Fisch. & C.A.Mey. (Yi Beimu) is a culturally significant Beimu drug in Northwest China, officially listed in the Chinese Pharmacopoeia and traditionally used to clear heat, moisten the lung, resolve phlegm, and relieve cough and wheeze. This narrative, critical review synthesizes current evidence on ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics/toxicology, and conservation of F. pallidiflora to support sustainable, evidence-based development. Literature was retrieved from major English and Chinese databases and screened for studies that unambiguously involved Yi Beimu or its key constituents. Ethnomedicinal records consistently support antitussive, expectorant, and anti-asthmatic use in Xinjiang and the Ili River Valley. Chemically, F. pallidiflora is rich in cevanine-type steroidal alkaloids (e.g., imperialine, peimine, yibeinones), steroidal saponins (pallidiflosides), polysaccharides, and minor phenolics. Preclinical data show that alkaloids relax airway smooth muscle, suppress inflammatory mediators, and contribute to antitussive and anti-asthmatic effects, while polysaccharides and total alkaloid extracts exhibit antioxidant and cytoprotective activity in cell and animal models of airway injury. Additional studies report cytotoxic saponins and seed-derived antimicrobial peptides. Pharmacokinetic work highlights low to moderate and variable oral bioavailability, shaped by P-glycoprotein efflux and CYP-mediated metabolism, and reveals potential hERG channel inhibition for peimine as a cardiac safety concern. Overharvesting and habitat loss have reduced wild resources, underscoring the need for conservation, cultivation, and marker-guided quality control. Overall, Yi Beimu shows credible ethnopharmacological rationale and promising multi-target pharmacology for respiratory disorders, but translation will require bioactivity-guided isolation coupled with PK–PD-guided in vivo studies, rigorous safety evaluation, and conservation-aware cultivation to move from traditional remedy toward validated therapeutic resource. Full article

Introduction: Acinetobacter baumannii is a multidrug-resistant pathogen from the ESKAPE group, associated with nosocomial infections. Its resistance to multiple antibiotics poses a global threat. The QACE protein, an efflux pump, has been identified as a key resistance mechanism, making it a promising target for the development of new antibacterial agents. Objective: Our aim is to identify low-molecular-weight compounds derived from natural products with potential inhibitory activity against the QACE protein, using virtual screening and molecular docking studies. Materials and Methods: The three-dimensional structure of QACE was retrieved from AlphaFold, followed by energy minimization and assignment of Kollman-type charges. Ligand screening was performed using the BioMX database through structural similarity analysis (Tanimoto coefficient ≥ 0.85), using ciprofloxacin as the reference compound. Selected molecules were evaluated using SwissADME to predict their pharmacokinetic properties, and three candidates with favorable profiles were chosen. Molecular docking studies were then performed using AutoDock 4 to estimate binding affinities. Results: Voacangine was the compound with the highest structural similarity, strongest binding affinity to QACE (ΔG = −6.2 kcal/mol; ki = 28.51 μM), and stable molecular interactions including hydrogen bonds and π-stacking. It showed favorable tissue distribution, low potential for CYP3A4 inhibition, and minimal predicted cardiotoxicity (hERG channel blockade). Conclusion: Voacangine emerges as a promising candidate for inhibiting the QACE efflux pump in Acinetobacter baumannii. This study highlights the value of computer-aided drug design as an effective strategy in the search for new treatments against multidrug-resistant bacteria. Full article

Curcumin (CUR), atractylodin (ATD), α-mangostin (αMG), ethyl-p-methoxycinnamate (EPMC), ligustilide (LIG), and β-eudesmol (BEU) are commonly used in Thai traditional medicine formulations. This study evaluated the cytotoxic effects of these compounds in HepG2 liver cancer cells and ReNcell VM neural progenitor cells using the resazurin assay, as well as their potential for hERG inhibition in hERG-overexpressing HEK293 cells, utilizing the automated patch-clamp technique. αMG and CUR significantly reduced HepG2 cell viability (IC₅₀ = 5.5 and 21 µM, respectively). In undifferentiated ReNcell VM cells, αMG was the most potent inhibitor of cell viability (IC₅₀ = 2.1 µM), followed by CUR (IC₅₀ = 21.1 µM), while in differentiated ReNcell VM cells, only αMG exhibited significant neurotoxicity (IC₅₀ = 6.0 µM). Other compounds showed no significant effects on these cells. ATD, BEU, LIG, and EPMC demonstrated low inhibition of hERG channels (IC₅₀ = 26.4, 33.4, 37.3, and 53 µM, respectively), while CUR and αMG displayed weak inhibitory effects (IC50 > 100 µM). αMG may have cytotoxic effects on hepatocytes and neurons at concentrations much higher than when used as medicine or food supplements. At regular clinical doses, αMG, ATD, BEU, EPMC, LIG, and CUR are unlikely to cause significant side effects. However, if these compounds are considered for drug development, their potential effects on hERG channels should be carefully assessed to avoid possible cardiotoxicity. Pharmacokinetics, both preclinical and clinical studies, are necessary to understand the relationship between the plasma concentration profile of EPMC and its potential risks for hepatotoxicity, neurotoxicity, cardiotoxicity, and drug interactions. Full article

This study reports the rational design and systematic evaluation of a novel series of 2-substituted aniline pyrimidine derivatives as dual Mer/c-Met inhibitors. Among the synthesized compounds, 17c demonstrated potent dual kinase inhibition, with IC₅₀ values of 6.4 ± 1.8 nM (Mer) and 26.1 ± 7.7 nM (c-Met). The compound exhibited significant antiproliferative activity across multiple cancer cell lines (HepG2, MDA-MB-231, and HCT116), while showing minimal hERG channel inhibition (IC₅₀ > 40 μM), indicating favorable cardiac safety. Pharmacokinetic profiling revealed high metabolic stability in human liver microsomes (t_1/2 = 53.1 min) and moderate oral bioavailability (F: 45.3%), with strong plasma protein-binding affinity (>95%). Mechanistic studies further demonstrated that 17c dose-dependently suppressed HCT116 cell migration and induced apoptosis. These integrated pharmacological properties position 17c as a promising therapeutic candidate for dual Mer/c-Met drive malignancies. Full article

Background/Objectives: Silybum marianum extract, obtained via microwave-enhanced extraction, was evaluated for its antioxidant, antidiabetic, and antimicrobial activities to explore its therapeutic potential. Methods: The extraction was performed using microwave-enhanced techniques, and LC-MS/MS was employed to profile the metabolites in the extract. Total phenolic and flavonoid contents were quantified using spectrophotometric methods. Antioxidant activity was assessed using DPPH, ABTS, CUPRAC, Phenanthroline, and FRAP assays. Enzyme inhibition assays were conducted to evaluate antidiabetic activity against α-glucosidase and α-amylase. Antimicrobial activity was determined using the disc diffusion method, and in silico ADMET and drug-likeness analyses were performed for key metabolites. Results: The extract contained 251.2 ± 1.2 mg GAE/g of total phenolics and 125.1 ± 1.6 mg QE/g of total flavonoids, with 33 metabolites identified, including phenolic acids, tannins, flavonoids, and flavolignans. Strong antioxidant activity was observed, with IC₅₀ values of 19.2 ± 2.3 μg/mL (DPPH), 7.2 ± 1.7 μg/mL (ABTS), 22.2 ± 1.2 μg/mL (CUPRAC), 35.2 ± 1.8 μg/mL (Phenanthroline), and 24.1 ± 1.2 μg/mL (FRAP). Antidiabetic effects were significant, with IC₅₀ values of 18.1 ± 1.7 μg/mL (α-glucosidase) and 26.5 ± 1.3 μg/mL (α-amylase). Antimicrobial activity demonstrated inhibition zones of 8.9 ± 1.1 mm (Bacillus subtilis), 12.6 ± 1.6 mm (Escherichia coli), 8.2 ± 1.2 mm (Fusarium oxysporum), and 9.2 ± 1.1 mm (Aspergillus niger). In silico analyses showed high absorption, favorable metabolism and excretion, and minimal toxicity, with no hERG channel inhibition or hepatotoxicity. Conclusions: The comprehensive results highlight the significant antioxidant, antidiabetic, and antimicrobial activities of S. marianum extract, suggesting its potential for therapeutic and preventive applications. Full article

Cenobamate is a novel third-generation antiepileptic drug used for the treatment of focal onset seizures and particularly for multi-drug-resistant epilepsy; it acts on multiple targets: GABA_A receptors (EC₅₀ 42–194 µM) and persistent neuronal Na⁺ currents (IC₅₀ 59 µM). Side effects include QT_c interval shortening with >20 ms, but not <300 ms. Our in vitro cardiac safety pharmacology study was performed via whole-cell patch-clamp on HEK293T cells with persistent/inducible expression of human cardiac ion channel isoforms hNav1.5 (I_Na), hCav1.2 (α1c + β2 + α2δ1) (I_CaL), hKv7.1 + minK (I_Ks), and hKv11.1 (hERG) (I_Kr). We found IC50 of 87.6 µM (peak I_Na), 46.5 µM (late I_Na), and 509.75 µM (I_CaL). In experiments on Ncyte^® ventricular cardiomyocytes, APD90 was reduced with 28.6 ± 13.5% (mean ± SD) by cenobamate 200 µM. Cenobamate’s marked inhibition of I_Na raises the theoretical possibility of cardiac arrhythmia induction at therapeutic concentrations in the context of preexisting myocardial pathology, in the presence of action potential conduction and repolarization heterogeneity. This hypothetical mechanism is consistent with the known effects of class Ib antiarrhythmics. In simulations with a linear strand of 50 cardiomyocytes with variable inter-myocyte conductance based on a modified O’Hara–Rudy model, we found a negligible cenobamate-induced conduction delay in normal tissue, but a marked delay and also a block when gap junction conduction was already depressed. Full article

Multidrug-resistant tuberculosis (MDR-TB) patients are treated with a standardised, short World Health Organization (WHO) regimen which includes clofazimine (CFZ) and bedaquiline (BDQ) antibiotics. These two antibiotics lead to the development of QT prolongation in patients, inhibiting potassium (K⁺) uptake by targeting the voltage-gated K⁺ (Kv)11.1 (hERG) channel of the cardiomyocytes (CMs). However, the involvement of these antibiotics to regulate other K⁺ transporters of the CMs, as potential mechanisms of QT prolongation, has not been explored. This study determined the effects of CFZ and BDQ on sodium, potassium–adenosine triphosphatase (Na⁺,K⁺-ATPase) activity of CMs using rat cardiomyocytes (RCMs). These cells were treated with varying concentrations of CFZ and BDQ individually and in combination (1.25–5 mg/L). Thereafter, Na⁺,K⁺-ATPase activity was determined, followed by intracellular adenosine triphosphate (ATP) quantification and cellular viability determination. Furthermore, molecular docking of antibiotics with Na⁺,K⁺-ATPase was determined. Both antibiotics demonstrated dose–response inhibition of Na⁺,K⁺-ATPase activity of the RCMs. The greatest inhibition was demonstrated by combinations of CFZ and BDQ, followed by BDQ alone and, lastly, CFZ. Neither antibiotic, either individually or in combination, demonstrated cytotoxicity. Molecular docking revealed an interaction of both antibiotics with Na⁺,K⁺-ATPase, with BDQ showing higher protein-binding affinity than CFZ. The inhibitory effects of CFZ and BDQ, individually and in combination, on the activity of Na⁺,K⁺-ATPase pump of the RCMs highlight the existence of additional mechanisms of QT prolongation by these antibiotics. Full article

In a landmark study, oleocanthal (OLC), a major phenolic in extra virgin olive oil (EVOO), was found to possess anti-inflammatory activity similar to ibuprofen, involving inhibition of cyclooxygenase (COX) enzymes. EVOO is a rich source of bioactive compounds including fatty acids and phenolics; however, the biological activities of only a small subset of compounds associated with Olea europaea have been explored. Here, the OliveNet^TM library (consisting of over 600 compounds) was utilized to investigate olive-derived compounds as potential modulators of the arachidonic acid pathway. Our first aim was to perform enzymatic assays to evaluate the inhibitory activity of a selection of phenolic compounds and fatty acids against COX isoforms (COX-1 and COX-2) and 15-lipoxygenase (15-LOX). Olive compounds were found to inhibit COX isoforms, with minimal activity against 15-LOX. Subsequent molecular docking indicated that the olive compounds possess strong binding affinities for the active site of COX isoforms, and molecular dynamics (MD) simulations confirmed the stability of binding. Moreover, olive compounds were predicted to have favorable pharmacokinetic properties, including a readiness to cross biological membranes as highlighted by steered MD simulations and umbrella sampling. Importantly, olive compounds including OLC were identified as non-inhibitors of the human ether-à-go-go-related gene (hERG) channel based on patch clamp assays. Overall, this study extends our understanding of the bioactivity of Olea-europaea-derived compounds, many of which are now known to be, at least in part, accountable for the beneficial health effects of the Mediterranean diet. Full article

This study reports the first application of in silico methods to assess the toxicity of 4-chloromethcathinone (4-CMC), a novel psychoactive substance (NPS). Employing advanced toxicology in silico tools, it was possible to predict crucial aspects of the toxicological profile of 4-CMC, including acute toxicity (LD₅₀), genotoxicity, cardiotoxicity, and its potential for endocrine disruption. The obtained results indicate significant acute toxicity with species-specific variability, moderate genotoxic potential suggesting the risk of DNA damage, and a notable cardiotoxicity risk associated with hERG channel inhibition. Endocrine disruption assessment revealed a low probability of 4-CMC interacting with estrogen receptor alpha (ER-α), suggesting minimal estrogenic activity. These insights, derived from in silico studies, are critical in advancing the understanding of 4-CMC properties in forensic and clinical toxicology. These initial toxicological findings provide a foundation for future research and aid in the formulation of risk assessment and management strategies in the context of the use and abuse of NPSs. Full article

Gain-of-function mutations in the KCNT1 gene, which encodes the sodium-activated potassium channel known as SLACK, are associated with the rare but devastating developmental and epileptic encephalopathy known as epilepsy of infancy with migrating focal seizures (EIMFS). The design of small molecule inhibitors of SLACK channels represents a potential therapeutic approach to the treatment of EIMFS, other childhood epilepsies, and developmental disorders. Herein, we describe a hit optimization effort centered on a xanthine SLACK inhibitor (8) discovered via a high-throughput screen. Across three distinct regions of the chemotype, we synthesized 58 new analogs and tested each one in a whole-cell automated patch-clamp assay to develop structure–activity relationships for inhibition of SLACK channels. We further evaluated selected analogs for their selectivity versus a variety of other ion channels and for their activity versus clinically relevant SLACK mutants. Selectivity within the series was quite good, including versus hERG. Analog 80 (VU0948578) was a potent inhibitor of WT, A934T, and G288S SLACK, with IC₅₀ values between 0.59 and 0.71 µM across these variants. VU0948578 represents a useful in vitro tool compound from a chemotype that is distinct from previously reported small molecule inhibitors of SLACK channels. Full article

Loperamide has been a safe and effective treatment for diarrhea for many years. However, many cases of cardiotoxicity with intentional abuse of loperamide ingestion have recently been reported. We evaluated loperamide in in vitro and in vivo cardiac safety models to understand the mechanisms for this cardiotoxicity. Loperamide slowed conduction (QRS-duration) starting at 0.3 µM [~1200-fold (×) its human Free Therapeutic Plasma Concentration; FTPC] and reduced the QT-interval and caused cardiac arrhythmias starting at 3 µM (~12,000× FTPC) in an isolated rabbit ventricular-wedge model. Loperamide also slowed conduction and elicited Type II/III A-V block in anesthetized guinea pigs at overdose exposures of 879× and 3802× FTPC. In ion-channel studies, loperamide inhibited hERG (I_Kr)_, I_Na, and I_Ca currents with IC₅₀ values of 0.390 µM, 0.526 µM, and 4.091 µM, respectively (i.e., >1560× FTPC). Additionally, in silico trials in human ventricular action potential models based on these IC50s confirmed that loperamide has large safety margins at therapeutic exposures (≤600× FTPC) and confirmed repolarization abnormalities in the case of extreme doses of loperamide. The studies confirmed the large safety margin for the therapeutic use of loperamide but revealed that at the extreme exposure levels observed in human overdose, loperamide can cause a combination of conduction slowing and alterations in repolarization time, resulting in cardiac proarrhythmia. Loperamide’s inhibition of the I_Na channel and hERG-mediated IKr are the most likely basis for this cardiac electrophysiological toxicity at overdose exposures. The cardiac toxic effects of loperamide at the overdoses could be aggravated by co-medication with other drug(s) causing ion channel inhibition. Full article

hERG (human Ether-à-go-go Related Gene)-encoded potassium channels underlie the cardiac rapid delayed rectifier (I_Kr) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is a high potency hERG channel inhibitor from the methanesulphonanilide drug family. This study utilized a methanesulphonate-lacking E-4031 analogue, “E-4031-17”, to evaluate the role of the methanesulphonamide group in E-4031 inhibition of hERG. Whole-cell patch-clamp measurements of the hERG current (I_hERG) were made at physiological temperature from HEK 293 cells expressing wild-type (WT) and mutant hERG constructs. For E-4031, WT I_hERG was inhibited by a half-maximal inhibitory concentration (IC₅₀) of 15.8 nM, whilst the comparable value for E-4031-17 was 40.3 nM. Both compounds exhibited voltage- and time-dependent inhibition, but they differed in their response to successive applications of a long (10 s) depolarisation protocol, consistent with greater dissociation of E-4031-17 than the parent compound between applied commands. Voltage-dependent inactivation was left-ward voltage shifted for E-4031 but not for E-4031-17; however, inhibition by both compounds was strongly reduced by attenuated-inactivation mutations. Mutations of S6 and S5 aromatic residues (F656V, Y652A, F557L) greatly attenuated actions of both drugs. The S624A mutation also reduced I_hERG inhibition by both molecules. Overall, these results demonstrate that the lack of a methanesulphonate in E-4031-17 is not an impediment to high potency inhibition of I_hERG. Full article

Erythromycin is one of the few compounds that remarkably increase ether-a-go-go-related gene (hERG) inhibition from room temperature (RT) to physiological temperature (PT). Understanding how erythromycin inhibits the hERG could help us to decide which compounds are needed for further studies. The whole-cell patch clamp technique was used to investigate the effects of erythromycin on hERG channels at different temperatures. While erythromycin caused a concentration-dependent inhibition of cardiac hERG channels, it also shifted the steady-state activation and steady-state inactivation of the channel to the left and significantly accelerated the onset of inactivation at both temperatures, although temperature itself caused a profound change in the dynamics of hERG channels. Our data also suggest that the binding pattern to S6 of the channels changes at PT. In contrast, cisapride, a well-known hERG blocker whose inhibition is not affected by temperature, does not change its critical binding sites after the temperature is raised to PT. Our data suggest that erythromycin is unique and that the shift in hERG inhibition may not apply to other compounds. Full article

GABA mediates inhibitory actions through various GABA_A receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of α2/3 GABAARs can treat mood and anxiety, while α5 GABAA-Rs can treat anxiety, depression, and cognitive performance. GL-II-73 and MP-III-022, α5-positive allosteric modulators have shown promising results in animal models of chronic stress, aging, and cognitive disorders, including MDD, schizophrenia, autism, and Alzheimer’s disease. Described in this article is how small changes in the structure of imidazodiazepine substituents can greatly impact the subtype selectivity of benzodiazepine GABAAR. To investigate alternate and potentially more effective therapeutic compounds, modifications were made to the structure of imidazodiazepine 1 to synthesize different amide analogs. The novel ligands were screened at the NIMH PDSP against a panel of 47 receptors, ion channels, including hERG, and transporters to identify on- and off-target interactions. Any ligands with significant inhibition in primary binding were subjected to secondary binding assays to determine their K_i values. The newly synthesized imidazodiazepines were found to have variable affinities for the benzodiazepine site and negligible or no binding to any off-target profile receptors that could cause other physiological problems. Full article