Multi-Task ADME/PK prediction at industrial scale: leveraging large and diverse experimentaldatasets.

ADME (Absorption, Distribution, Metabolism, Excretion) properties are key parameters to judge whether a drug candidate exhibits a desired pharmacokinetic (PK) profile. In this study, we tested multi-task machine learning (ML) models to predict ADME and animal PK endpoints trained on in-house data generated at Boehringer Ingelheim. Models were evaluated both at the design stage of a compound (i. e., no experimental data of test compounds available) and at testing stage when a particular assay would be conducted (i. e., experimental data of earlier conducted assays may be available). Using realistic time-splits, we found a clear benefit in performance of multi-task graph-based neural network models over single-task model, which was even stronger when experimental data of earlier assays is available. In an attempt to explain the success of multi-task models, we found that especially endpoints with the largest numbers of data points (physicochemical endpoints, clearance in microsomes) are responsible for increased predictivity in more complex ADME and PK endpoints. In summary, our study provides insight into how data for multiple ADME/PK endpoints in a pharmaceutical company can be best leveraged to optimize predictivity of ML models.

Inhibition of the Janus kinase protein (JAK1) by the A. Pyrethrum Root Extract for the treatment of Vitiligo pathology. Design, Molecular Docking, ADME-Tox, MD Simulation, and in-silico investigation.

This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo.

Discovery of pyridoquinoxaline-based new P-gp inhibitors as coadjutant against Multi Drug Resistance in cancer.

Multi-drug resistance (MDR) is a serious challenge in contemporary clinical practice and is mostly responsible for the failure of cancer medication therapies. Several experimental evidence links MDR to the overexpression of the drug efflux transporter P-gp, therefore, the discovery of novel P-glycoprotein inhibitors is required to treat or prevent MDR and to improve the absorption of chemotherapy drugs via the gastrointestinal system. In this work, we explored a series of novel pyridoquinoxaline-based derivatives designed from parental compounds, previously proved active in enhancing anticancer drugs in MDR nasopharyngeal carcinoma (KB). Among them, derivative 10d showed the most potent and selective inhibition of fluorescent dye efflux, if compared to reference compounds (MK-571, Novobiocin, Verapamil), and the highest MDR reversal activity when co-administered with the chemotherapeutic agents Vincristine and Etoposide, at non-cytotoxic concentrations. Molecular modelling predicted the two compound 10d binding mode in a ratio of 2:1 with the target protein. No cytotoxicity was observed in healthy microglia cells and off-target investigations showed the absence of CaV1.2 channel blockade. In summary, our findings indicated that 10d could potentially be a novel therapeutic coadjutant by inhibiting P-gp transport function in vitro, thereby reversing cancer multidrug resistance.

Preclinical evaluation of [18F]FP-CIT, the radiotracer targeting dopamine transporter for diagnosing Parkinson's disease: pharmacokinetic and efficacy analysis.

BACKGROUND: N-(3-fluoropropyl)-2ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising biomarker, as it reflects the severity of Parkinson's disease (PD). 123I- and 18F-labeled FP-CIT has been used for PD diagnosis. However, preclinical studies evaluating [18F]FP-CIT as a potential diagnostic biomarker are scarce. Among translational research advancements from bench to bedside, translating preclinical findings into clinical practice is one-directional. The aim of this study is to employ a circular approach, beginning back from the preclinical stage, progressing to the supplementation of [18F]FP-CIT, and subsequently returning to clinical application. We investigated the pharmacokinetic properties of [18F]FP-CIT and its efficacy for PD diagnosis using murine models. RESULTS: Biodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [18F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [18F]FP-CIT injection. [18F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [18F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [18F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011). CONCLUSIONS: This study fills the gap regarding insufficient preclinical studies on [18F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [18F]FP-CIT excretion, provide complementary evidence that [18F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics.

The mitochondrial TSPO ligand Atriol mitigates metabolic-associated steatohepatitis by downregulating CXCL1.

BACKGROUND AND AIMS: The mitochondrial translocator protein (TSPO, 18 kDa) is pivotal in binding cholesterol and facilitating its transfer from the outer to the inner mitochondrial membrane. Atriol is a TSPO ligand disrupting cholesterol binding by targeting the cholesterol-recognition amino acid consensus domain. Prior research has shown that TSPO deficiency improved metabolic-associated steatohepatitis (MASH). We hypothesized that Atriol may have the potential to alleviate MASH. METHODS AND RESULTS: In vitro cell culture studies revealed that Atriol treatment effectively mitigated MASH by restoring mitochondrial function, inhibiting the NF-κB signaling pathway, and reducing hepatic stellate cell (HSC) activation. SD male rats were fed a GAN diet for 10 months to induce MASH. During the final two weeks of feeding, rats received intraperitoneal Atriol administration daily. Atriol treatment significantly ameliorated MASH by reducing lipid accumulation, diminishing hepatic lobular inflammation and fibrosis, decreasing cell death, and inhibiting excessive bile acid synthesis. Moreover, Atriol restored mitochondrial function in primary hepatocytes isolated from MASH rats. In search of the mechanism(s) governing these effects, we found that Atriol downregulated the proinflammatory chemokine CXCL1 through the NF-κB signaling pathway or via myeloperoxidase (MPO) in HSCs and Kupffer cells. Additionally, in vitro, studies further suggested that CXCL1 treatment induced dysfunctional mitochondria, inflammation, HSCs activation, and macrophage migration, whereas Atriol countered these effects. Finally, the mitigating effects of Atriol on MASH were reproduced by pharmacological inhibition of NF-κB or MPO and neutralization of CXCL1. CONCLUSION: Atriol ameliorates MASH both in vitro and in vivo, demonstrating its potential therapeutic benefits in managing MASH.

Combating the causative agent of amoebic keratitis, Acanthamoeba castellanii, using Padina pavonica alcoholic extract: toxicokinetic and molecular docking approaches.

Natural products play a significant role in providing the current demand as antiparasitic agents, which offer an attractive approach for the discovery of novel drugs. The present study aimed to evaluate in vitro the potential impact of seaweed Padina pavonica (P. pavonica) extract in combating Acanthamoeba castellanii (A. castellanii). The phytochemical constituents of the extract were characterized by Gas chromatography-mass spectrometry. Six concentrations of the algal extract were used to evaluate its antiprotozoal activity at various incubation periods. Our results showed that the extract has significant inhibition against trophozoites and cysts viability, with complete inhibition at the high concentrations. The IC50 of P. pavonica extract was 4.56 and 4.89 µg/mL for trophozoites and cysts, respectively, at 24 h. Morphological alterations of A. castellanii trophozoites/cysts treated with the extract were assessed using inverted and scanning electron microscopes and showed severe damage features upon treatment with the extract at different concentrations. Molecular Docking of extracted compounds against Acanthamoeba cytochrome P450 monooxygenase (AcCYP51) was performed using Autodock vina1.5.6. A pharmacokinetic study using SwissADME was also conducted to investigate the potentiality of the identified bioactive compounds from Padina extract to be orally active drug candidates. In conclusion, this study highlights the in vitro amoebicidal activity of P. pavonica extract against A. castellanii adults and cysts and suggests potential AcCYP51 inhibition.

Spasmolytic, Antimicrobial, and Antioxidant Activities of Spray-Dried Extracts of Gentiana asclepiadea L. with In Silico Pharmacokinetic Analysis.

This study aimed to evaluate the spasmolytic activity of an underground parts extract of Gentiana asclepiadea L. (Gentianaceae), assess its antioxidant and antimicrobial activities, and explore the impact of extract encapsulation on the aforementioned bioactivities. An extract encapsulated by spray drying with whey protein, pure extract, and pure whey protein were comparatively tested. The main compounds identified via HPLC-DAD analysis underwent in silico ADME assessment. The spasmolytic effect was tested on a model of spontaneous rat ileum contractions, and the mechanism of action was further evaluated on acetylcholine-, KCl-, CaCl2-, BaCl2-, histamine-, N(ω)-nitro-L-arginine methyl ester-, and glibenclamide-modified contractions. The most abundant compounds were secoiridoids (dominantly gentiopicroside), followed by C-glycosylated flavonoids and xanthones. Both pure and encapsulated extracts achieved significant spasmolytic effects, despite the spasmogenic activity of pure whey protein. The extract may exert its spasmolytic effect through multiple pathways, predominantly by antagonizing the Ca2+ channel and opening the K+ channel, while the nitric oxide pathway appears not to be involved. The antimicrobial and antioxidant activities of the pure extract were moderate. The extract stabilized by encapsulation retained all of the tested bioactivities of the unencapsulated extract. The obtained results suggest that G. asclepiadea has potential for use in the treatment of some gastrointestinal complaints and that the encapsulated extract could be a valuable functional ingredient in pharmaceutical and food products.

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.

Identification of Novel Inhibitors for ERα Target of Breast Cancer By In Silico Approach.

BACKGROUND: Estrogen alpha has been recognized as a perilous factor in breast cancer cell proliferation and has been proficiently treated in breast cancer chemotherapy with the development of selective estrogen receptor modulators (SERMs). OBJECTIVES: The major aim of this study was to identify the potential inhibitors against the most influential target ERα receptor by in silico studies of 115 phytochemicals from 17 medicinal plants using in silico molecular docking studies. METHODS: The molecular docking investigation was carried out by a genetic algorithm using the Auto Dock Vina program, and the validation of docking was also performed using molecular dynamic (MD) simulation by the Desmond tool of Schrödinger molecular modeling. The ADME( T) studies were performed by SWISS ADME and ProTox-II. RESULTS: The top ten highest binding energy phytochemicals identified were amyrin acetate (- 10.7 kcal/mol), uscharine (-10.5 kcal/mol), voruscharin (-10.0 kcal/mol), cyclitols (-10.0 kcal/mol), taraxeryl acetate (-9.9 kcal/mol), amyrin (-9.9 kcal/mol), barringtogenol C (-9.9 kcal/mol), calactin (-9.9 kcal/mol), 3-beta taraxerol (-9.8 kcal/mol), and calotoxin (-9.8 kcal/mol). A molecular docking study revealed that these phytochemical constituents showed higher binding affinity compared to the reference standard tamoxifen (-6.6 kcal/mol) towards the target protein ERα. The results of MD studies showed that all four tested compounds possess comparatively stable ligand-protein complexes with ERα target as compared to the tamoxifen- ERα complex. CONCLUSION: Among the ten compounds, phytochemical amyrin acetate (triterpenoids) formed a more stable complex as well as exhibited greater binding affinity than standard tamoxifen. ADMET studies for the top ten phytochemicals showed a good safety profile. Additionally, these compounds are being reported for the first time in this study as possible inhibitors of ERα for the treatment of breast cancer by adopting the concept of drug repurposing. Hence, these phytochemicals can be further studied and can be used as a parent core molecule to develop novel lead molecules for breast cancer therapy.

N-Benzyl piperidine Fragment in Drug Discovery.

The N-benzyl piperidine (N-BP) structural motif is commonly employed in drug discovery due to its structural flexibility and three-dimensional nature. Medicinal chemists frequently utilize the N-BP motif as a versatile tool to fine-tune both efficacy and physicochemical properties in drug development. It provides crucial cation-π interactions with the target protein and also serves as a platform for optimizing stereochemical aspects of potency and toxicity. This motif is found in numerous approved drugs and clinical/preclinical candidates. This review focuses on the applications of the N-BP motif in drug discovery campaigns, emphasizing its role in imparting medicinally relevant properties. We provide an overview of approved drugs, the clinical and preclinical pipeline, and discuss its utility for specific therapeutic targets and indications, along with potential challenges.

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.

Cadmium Exposure: Mechanisms and Pathways of Toxicity and Implications for Human Health.

Cadmium (Cd), a prevalent environmental contaminant, exerts widespread toxic effects on human health through various biochemical and molecular mechanisms. This review encapsulates the primary pathways through which Cd inflicts damage, including oxidative stress induction, disruption of Ca2+ signaling, interference with cellular signaling pathways, and epigenetic modifications. By detailing the absorption, distribution, metabolism, and excretion (ADME) of Cd, alongside its interactions with cellular components such as mitochondria and DNA, this paper highlights the extensive damage caused by Cd2+ at the cellular and tissue levels. The role of Cd in inducing oxidative stress-a pivotal mechanism behind its toxicity-is discussed with emphasis on how it disrupts the balance between oxidants and antioxidants, leading to cellular damage and apoptosis. Additionally, the review covers Cd's impact on signaling pathways like Mitogen-Activated Protein Kinase (MAPK), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Tumor Protein 53 (p53) pathways, illustrating how its interference with these pathways contributes to pathological conditions and carcinogenesis. The epigenetic effects of Cd, including DNA methylation and histone modifications, are also explored to explain its long-term impact on gene expression and disease manifestation. This comprehensive analysis not only elucidates the mechanisms of Cd toxicity but also underscores the critical need for enhanced strategies to mitigate its public health implications.

Prospects for Prostate Cancer Chemotherapy: Cytotoxic Evaluation and Mechanistic Insights of Quinolinequinones with ADME/PK Profile.

The evaluation of in vitro biological activity of several previously reported quinolinequinones (AQQ1-5) against 60 human cancer cell lines (NCI-60) used by the National Cancer Institute's Developmental Therapeutics Program (DTP) contributed to our earlier research on possible anticancer and/or antibacterial agents. Of interest, NCI-60 screening revealed that two quinolinequinones (AQQ1 and AQQ2) significantly reduced the proliferation of several cancer genotypes. Following the administration of a single dose and five additional doses, all quinolinequinones demonstrated a significant inhibitory effect on the growth of leukemia and other cancer cell lines. Hence, a series of subsequent in vitro biological assessments were performed to further understand the mechanistic impact of the compounds. In MTT assays, it was found that AQQ1 and AQQ2 exhibited higher efficacy against DU-145 cells (IC50 4.18 µM and 4.17 µM, respectively) compared to MDA-MB-231 (IC50 8.27 and 13.33 µM, respectively) and HCT-116 cells (IC50 5.83 and 9.18 µM, respectively). Additionally, AQQ1 demonstrated greater activity in this context. Further investigations revealed that AQQ1 inhibited DU-145 cell growth and migration dose-dependently. Remarkably, arrest of the DU-145 cell cycle at G0/G1 phase and ROS elevation were observed. Pharmacokinetic (PK) studies revealed that AQQ1 has better PK parameters than AQQ2 with %F of 9.83 in rat. Considering the data obtained with human liver microsomal stability studies, AQQ1 should have a better PK profile in human subjects. In silico studies (molecular dynamics) with three kinases (CDK2, CDK4, and MAPK) leading to cell cycle arrest at G0/G1 identified MAPK as a probable target for AQQ1. Taken together, our results showed that AQQ1 could be a potential chemotherapeutic lead molecule for prostate cancer.

Synthesis and structural investigation of salts of 2-amino-3-methylpyridine with carboxylic acid derivatives: an experimental and theoretical study.

The salts bis(2-amino-3-methylpyridinium) fumarate dihydrate, 2C6H9N2+·C4H2O22-·2H2O (I), and 2-amino-3-methylpyridinium 5-chlorosalicylate, C6H9N2+·C7H4ClO3- (II), were synthesized from 2-amino-3-methylpyridine with fumaric acid and 5-chlorosalicylic acid, respectively. The crystal structures of these salts were characterized by single-crystal X-ray diffraction, revealing protonation in I and II by the transfer of a H atom from the acid to the pyridine base. In the crystals of both I and II, N-H...O interactions form an R22(8) ring motif. Hirshfeld surface analysis distinguishes the interactions present in the crystal structures of I and II, and the two-dimensional (2D) fingerprint plot analysis shows the percentage contribution of each type of interaction in the crystal packing. The volumes of the crystal voids of I (39.65 Å3) and II (118.10 Å3) have been calculated and reveal that the crystal of I is more mechanically stable than II. Frontier molecular orbital (FMO) analysis predicts that the band gap energy of II (2.6577 eV) is lower compared to I (4.0035 eV). The Quantum Theory of Atoms In Molecules (QTAIM) analysis shows that the pyridinium-carboxylate N-H...O interaction present in I is stronger than the other interactions, whereas in II, the hydroxy-carboxylate O-H...O interaction is stronger than the pyridinium-carboxylate N-H...O interaction; the bond dissociation energies also confirm these results. The positive Laplacian [∇2ρ(r) > 0] of these interactions shows that the interactions are of the closed shell type. An in-silico ADME (Absorption, Distribution, Metabolism and Excretion) study predicts that both salts will exhibit good pharmacokinetic properties and druglikeness.

In vitro antibacterial and antioxidant activity of flavonoids from the roots of Tephrosia vogelii: a combined experimental and computational study.

Tephrosia vogelii is a traditional medicinal plant used to treat hypertension, diarrhea and urinary disorders. Silica gel chromatographic separation of CH2Cl2/MeOH (1:1) roots extract of T. vogelii afforded seven compounds namely; ß-sitosterol (1a), stigmasterol (1b), 6a, 12a-dehydro-deguelin (2), tephrosin (3), maackiain (4), obovatin (5) and 6-oxo, 6a, 12a-dehydro-deguelin (6). GC-MS analysis of essential oils from the root of T. vogelii displayed a total of 17 compounds of which cis-nerolidol (41.7 %) and cadinol (19.7 %) were the major constituents. CH2Cl2/MeOH (1:1) extract, MeOH extract, maackiain (4) and obovatin (5) showed moderate inhibitory activity against Pseudomonas aeruginosa with MIC value of 0.5, 0.66, 0.83 and 0.83 mg/mL, respectively, compared to ciprofloxacin (MIC of 0.078 µg/mL). 6a, 12a-dihydro-deguelin (2), and 6-oxo, 6a, 12a-dehydro-deguelin (6) displayed significant activity against S. epidermis with MIC values of 0.66 mg/mL. Tephrosin (3) and maackiain (4) also showed moderate antibacterial activity against Staphylococcus aureus and Proteus mirabilis with MIC values of 0.83 and 0.5 mg/mL, respectively, compared to ciprofloxacin (0.312 µg/mL). The radical scavenging activity results indicated that tephrosin (3), obovatin (5) and 6-oxo, 6a, 12a-dehydro-deguelin (6) showed potent DPPH scavenging activity with IC50 values of 10.97, 10.43 and 10.73 µg/mL, respectively, compared to ascorbic acid (IC50 of 5.83 µg/mL). The docking prediction results revealed that 6a, 12a-dehydro-deguelin (2) displayed the best binding energy of -8.1 kcal/mol towards pyruvate kinase of S. aureus (PDB ID: 3T07) and -7.9 kcal/mol towards P. mirabilis urease (PDB ID: 1E9Y) and DNA gyrase B of Escherichia coli (PDB: 4F86) receptors compared to ciprofloxacin (-7.2 to -8.0 kcal/mol). Maackiain (4) and obovatin (5) displayed the minimum binding energy of -7.9 and -8.2 kcal/mol towards the LasR protein of P. aeruginosa (PDB: ID 2UV) and S. epidermidis FtsZ (PDB: ID 4M8I), respectively. The SwissADME drug-likeness and Pro Tox II toxicity prediction results indicated that compounds (2-6) obeyed Lipinski's rule of five with 0 violations and none of them were found to be hepatotoxic, mutagenic, and cytotoxic, respectively. The in vitro assessment results supported by the in silico analysis revealed that crude extracts and isolated compounds showed promising antibacterial and antioxidant activity, which proves the therapeutic potential of the roots of T. vogelii.

Novel acyl hydrazide derivatives of polyhydroquinoline as potent anti-diabetic and anti-glycating agents: Synthesis, in vitro α-amylase, α-glucosidase inhibition and anti-glycating activity with molecular docking insights.

In this study, eleven novel acyl hydrazides derivative of polyhydroquinoline were synthesized, characterized and screened for their in vitro anti-diabetic and anti-glycating activities. Seven compounds 2a, 2d, 2i, 2 h, 2j, 2f, and 2 g exhibited notable α-amylase inhibitory activity having IC50 values from 3.51 ± 2.13 to 11.92 ± 2.30 µM. Similarly, six compounds 2d, 2f, 2 h, 2i, 2j, and 2 g displayed potent α-glucosidase inhibitory activity compared to the standard acarbose. Moreover, eight derivatives 2d, 2 g, 2f, 2j, 2a, 2i, 2 g, and 2e showed excellent anti-glycating activity with IC50 values from 6.91 ± 2.66 to 15.80 ± 1.87 µM when compared them with the standard rutin (IC50 = 22.5 ± 0.90 µM). Molecular docking was carried out to predict the binding modes of all the compounds with α-amylase and α-glucosidase. The docking analysis revealed that most of the compounds established strong interactions with α-amylase and α-glucosidase. All compounds fitted well into the binding pockets of α-amylase and α-glucosidase. Among all compounds 2a and 2f were most potent based on docking score -8.2515 and -7.3949 against α-amylase and α-glucosidase respectively. These results hold promise for the development of novel candidates targeted at controlling postprandial glucose levels in individuals with diabetes.

Pyrazoles as Anti-inflammatory and Analgesic Agents: In-vivo and In-silico Studies.

BACKGROUND: Pyrazole is a well-known nucleus in the pharmacy field with a wide range of other activities in addition to anti-inflammatory and analgesic, i.e., anticonvulsant, antiviral, and anticancer activities. There are well-known marketed drugs having pyrazole moiety as celecoxib, and lonazolac as COX-II inhibitors. AIMS: We aim to synthesize better anti-inflammatory than existing ones. Thiophene is also known for its analgesic and anti-inflammatory action. Thus, the fusion of both gives better anti-inflammatory agents. In the present studies, derivatives from two series of pyrazole were prepared by reacting substituted chalcone (3a-3f) derivatives prepared from 2-acetyl thiophene. They substituted aromatic aldehydes with phenyl hydrazine to form (5a-5f) and with 2, 4-dinitro phenyl hydrazine giving compounds (6a-6f) separately. METHODS: Purified and characterized pyrazoles have been analyzed for in-vivo analgesic and anti-inflammatory activities by using standard methods. Compounds 5e, 5f, and 6d were proved to be potent analgesics and series (5a-5f) was found to have anti-inflammatory action, which was further validated using docking and ADME studies. RESULTS: The ADME profile of synthesized compounds was found to be satisfactory. CONCLUSION: The synthesized compounds can serve as lead for further drug designing.

Overview of preclinical and clinical studies investigating pharmacokinetics and drug-drug interactions of padsevonil.

BACKGROUND: Padsevonil is an antiseizure medication candidate intended to benefit patients with drug-resistant epilepsy. Our investigations aimed at characterizing pharmacokinetics and drug-drug interaction (DDI) profile of padsevonil. RESEARCH DESIGN AND METHODS: An overview of preclinical and clinical pharmacology studies conducted during padsevonil development is provided. RESULTS: In preclinical studies, cytochrome (CYP) 3A4 was identified as the main P450 isoform involved in padsevonil metabolism, with potential minor contribution from CYP2C19. Padsevonil was shown to be a time-dependent CYP2C19-inhibitor, weak CYP3A4-inducer, weak inhibitor of P-gp/OCT1/MATE2-K, and potent OCT2-inhibitor. Initial clinical pharmacology studies in healthy participants showed that padsevonil had (i) good absorption, (ii) clearance mediated mainly by metabolism, and (iii) time-dependent kinetics. A study in genotyped participants confirmed the role of CYP2C19 in clearance and time-dependent kinetics; the major contribution of CYP3A4 was confirmed in DDI studies with CYP3A4-inducers (carbamazepine, oxcarbazepine) and -inhibitor (erythromycin). Padsevonil did not affect pharmacokinetics of valproate/lamotrigine/levetiracetam/oxcarbazepine or oral contraceptives. In a cocktail clinical study, padsevonil showed moderate CYP2C19 inhibition (omeprazole) and weak CYP3A4 induction (oral midazolam). No specific effects on CYP1A2 (caffeine), CYP2C9 (S-warfarin), and CYP2D6 (dextromethorphan) were observed. CONCLUSIONS: The studies presented helped in understanding padsevonil disposition and risks of DDIs, which would inform dosing and prescribing. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov identifiers are NCT04131517, NCT03480243, NCT03695094, NCT04075409.

[Screening of Highly Hazardous Pollutants in Groundwater of Beijing].

Groundwater contaminants pose a great threat to water safety and human health. Therefore, in this study, the traditional hazard assessment method was improved and a comprehensive system covering hazard assessment, screening, and characterization by combining the toxicological priority index (Tox Pi) framework; absorption, distribution, metabolism, and excretory (ADME) analysis; and bipartite network analysis was constructed. Then, the system was applied to hazard assessment and toxic pollutants screening from the 234 hydrophobic organic contaminants (HOCs) identified in the groundwater of Beijing. First, the top 20 pollutants with hazard potential were screened out using the Tox Pi method. Subsequently, 17 high-priority HOCs were further identified based on the ADME property analysis. Then, the molecular targets of these 17 high-priority HOCs were characterized through systematic bipartite network analysis. Finally, ten HOCs with high hazard were screened through correlation and weighted average analysis, and it was revealed that their toxic effects were mainly concentrated in the endocrine-disrupting effect, carcinogenic effect, and genetic toxicity. This study provides technical support for the prevention of regional groundwater contaminants.