Moderate Inhibition Research Articles

In vitro α-amylase and α-glucosidase inhibitory effects and antioxidant potential of new dihydrochalcones from Baphia massaiensis Taub

Two previously undescribed dihydrochalcones, 4,2′-dihydroxy- [2″, 2″-dimethylpyrano (3″, 4″: 4′, 5′]) dihydrochalcone (1) and 4, 2′, 4′, 2″-tetrahydroxy-5′-(3″-methylbut-3″-enyl) dihydrochalcone (2), along with six known compounds (3-8) were isolated from chloroform-methanol (1:1) extract of Baphia Massaiensis twigs. Their chemical structures were determined using NMR analysis, mass spectrometry, electronic circular dichroism (ECD), density functional theory (DFT) calculations, and a thorough comparison with reported data from the literature. All the isolated compounds (1−8) were assessed for their antioxidant activities, α-amylase and α-glucosidase inhibition effects. Dihydrochalcone 1 showed significant antioxidant activity with IC50 value of 118.8 ± 2.95 µM, and a more potent antioxidant activity was exhibited by compounds 3 and 6 with IC50 values of 84.3 ± 0.07 µM and 62.1 ± 1.59 µM, respectively, compared to the positive control, gallic acid with IC50 value of 92.9 µM. Dihydrochalcone 2 showed moderate inhibition against α-amylase and α-glucosidase with IC50 values of 44.0 ± 4.83 µM and 51.7 ± 9.72 µM compared to the standard acarbose with IC50 values of 22.9 ± 0.92 µM and 31.5 ± 0.63 µM, respectively. Molecular docking studies of the new dihydrochalcones 1 and 2, revealed the active binding sites which support the observed α-amylase and α-glucosidase inhibitory effects.

Preliminary Study on Potential Bacterial Species Introducing Antibacterial Agent from Sponge in Unggeh Island Central Tapanuli, Indonesia

Sponges have the potential to symbiont with bacteria that produce antibacterial compounds. This study was conducted to isolate and test the antibacterial activity of sponge symbiont bacteria. Bacterial isolates obtained were tested for antibacterial activity against Staphylococcus aureus, Bacillus subtilis and Escherichia coli using the Kirby-Bauer method. The identification results of both sponges have similarities with Clathria sp. and Hyrtios sp. symbiont bacteria obtained from both sponges as many as 16 isolates. Antibacterial activity testing had a weak inhibitory effect on isolates Sp1A, Sp2C, Sp2D and Sp2F, while Sp2J showed moderate inhibition against gram-negative and positive bacteria. The antibacterial activity of the whole supernatant of symbiont bacteria obtained the diameter of the inhibition zone with weak, medium and strong categories. Sp1A isolate supernatant was obtained, potentially able to fight Escherichia coli bacteria with a strong category as a representation of gram-negative bacteria and against gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus) classified into the medium category. In conclusion, 16 symbiont bacterial supernatants have antibacterial activity mostly active against gram-negative bacteria Escherichia coli and gram-positive bacteria Bacillus subtilis. There are 6 isolates (Sp1A, Sp1B, Sp1E, Sp1F, Sp2D, Sp2F) active as antibacterial against Staphylococcus aureus with weak and moderate categories.

Chloroquine Downregulation of Intestinal Autophagy Changed Intestinal Microbial Community Compositions and Metabolite Profiles in Piglets.

Our previous study demonstrated that moderate inhibition of intestinal autophagy was beneficial to alleviate early weaning stress in piglets, but the detailed mechanism behind this was unclear. Microbiota-mediated enterocyte autophagy helps maintain intestinal homeostasis. This study investigated the effects of inhibition or activation of autophagy in intestinal microbial community compositions and metabolite profiles in piglets. Eighteen 24-day-old weaned piglets were divided into three groups (each treatment of six piglets) and treated daily with rapamycin (RAPA), chloroquine (CQ) or a control volume of normal saline (CON group). Before the formal trial, the piglets were allowed to acclimatize for 3 days, and then the trial period was 14 days. Collected samples from the ileum and colon underwent 16S rRNA gene sequencing and metabolite analysis. Significant differences in microbial composition were observed in both the ileum and colon of the RAPA and CQ groups compared to the CON group (p < 0.05). In addition, the relative levels of abundance of Peptostreptococcus, Fusobacterium, Dialister, Selenomonas and Oceanobacillus in the ileum and Porphyromonas, Bacteroides, unidentified_Lachnospiraceae, Akkermansia, Sharpea, Peptococcus, Pseudoalteromonas, Peptoclostridium and unidentified_Acidobacteria in the colon were improved in piglets fed the RAPA diet, whereas the relative levels of abundance of Turicibacter, Rickettsiella and Sarcina in the ileum and Roseburia and Kroppenstedtia in the colon were enhanced in the CQ group (p < 0.05). Meanwhile, metabolomic analysis showed that there were significant differences in metabolites among all groups (p < 0.05), and KEGG enrichment analysis revealed that differential metabolites were mainly enriched in the ABC transporters and biosynthesis of amino acids pathways. Furthermore, these metabolites were closely related to differential microorganisms (p < 0.05). Overall, autophagy inhibition regulates the composition of intestinal microorganisms and their metabolites, and these differential metabolites are significantly correlated with differential intestinal microorganisms, which may in turn affect the production performance of weaned piglets.

Synthesis and Biological Properties of Ferrocenyl and Organic Methotrexate Derivatives.

Synthesis and biological activity of two series of modified side chain methotrexate (MTX) derivatives are presented, one with a ferrocenyl moiety inserted between the pteroyl and glutamate portions of the molecule and the other with glutamate substituted for short chain amino acids. Ferrocenyl derivatives of MTX turned out to be rather moderate inhibitors of dihydrofolate reductase (DHFR) although molecular modeling suggested more effective interactions between these compounds and the target enzyme. More interestingly, ferrocene-decorated MTX derivatives were able to impede the proliferation of four murine and human cell lines as well as their methotrexate-resistant counterparts, overcoming the multidrug resistance (MDR) barrier. They were also able to directly interact with Abcc1, an MDR protein. Of the amino acid pteroyl conjugates, the γ-aminobutyric acid derivative was an efficient inhibitor of DHFR but had no effect on cell proliferation in the concentration range studied while a taurine conjugate was a poor DHFR inhibitor but able to affect cell viability. We postulate that modification of the methotrexate side chain may be an efficient strategy to overcome efflux-dependent methotrexate resistance.

Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation.

Butyrylcholinesterase (BChE) is considered a promising therapeutic target for treating Alzheimer's disease due to the increase in the levels and activity of BChE in the late stage of the disease. In this study, a series of novel 1,2,4-triazole derivatives bearing the naphthalene moiety linked to the benzothiazole, thiazole, and phenyl scaffolds via amid chain were designed and synthesized as potential and selective BChE inhibitors. The results of the inhibitory activity studies revealed that most of these compounds exhibited significant inhibitor potency on BChE. Compounds 35a (0.025 ± 0.01 μM) and 37a (0.035 ± 0.01 μM) displayed the most potent inhibitory activity, with excellent selectivity against BChE over acetylcholinesterase (SIBChE, 23,686 and 16,936, respectively) among the target compounds. The kinetics studies revealed that these compounds behaved with noncompetitive BChE inhibitors. Molecular docking studies indicated that 35a and 37a fit well into the active side of BChE. In addition, 35a and 37a also had the lowest cytotoxicity for human neuroblastoma cells (SH-SY5Y), potential antioxidant capacity, moderate inhibition potency on amyloid-β1-42 aggregation, and significant neuroprotective effect against SH-SY5Y cellinjury induced by H2O2 and amyloid-β1-42. All results suggest that these compounds might be considered as promising new lead compounds in the drug discovery process for the treatment of late-stage Alzheimer's disease.

Adpressins A-G: Oligophenalenone Dimers from Talaromyces adpressus.

Nine new oligophenalenone dimers, adpressins A-G (1-9), together with nine known compounds (10-18), were isolated from the fungus Talaromyces adpressus. Their chemical structures were determined on the basis of spectroscopic and mass spectral analyses. Their relative and absolute configurations were identified by 1H and 13C NMR calculations followed by DP4+ analyses, electronic circular dichroism (ECD) calculations, and ECD spectra comparison with related compounds. Compound 1 is the first example of a duclauxin derivative featuring an unusual 6/6/6/5/6/6/6 ring system, while compounds 6 and 7 contained a novel pyrrolidine ring. Compounds 5, 9, and 18 exhibited moderate inhibition against LPS-induced B lymphocyte proliferation with IC50 values ranging from 1.6 to 8.6 μM. Additionally, compounds 9 and 18 exhibited moderate inhibition against Con A-induced T lymphocyte proliferation with IC50 values of 9.3 and 2.6 μM, respectively.

PBPK Modeling of Entrectinib and Its Active Metabolite to Derive Dose Adjustments in Pediatric Populations Co-Administered with CYP3A4 Inhibitors.

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady-state systemic exposure on co-administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5-12.5 mg/kg and fluconazole at 3-12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co-administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0-t) was increased by approximately sevenfold and five to threefold by strong and high-moderate and low-moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies.

Exploring essential oil-based bio-composites: molecular docking and in vitro analysis for oral bacterial biofilm inhibition.

Oral bacterial biofilms are the main reason for the progression of resistance to antimicrobial agents that may lead to severe conditions, including periodontitis and gingivitis. Essential oil-based nanocomposites can be a promising treatment option. We investigated cardamom, cinnamon, and clove essential oils for their potential in the treatment of oral bacterial infections using in vitro and computational tools. A detailed analysis of the drug-likeness and physicochemical properties of all constituents was performed. Molecular docking studies revealed that the binding free energy of a Carbopol 940 and eugenol complex was -2.0kcal/mol, of a Carbopol 940-anisaldehyde complex was -1.9kcal/mol, and a Carbapol 940-eugenol-anisaldehyde complex was -3.4kcal/mol. Molecular docking was performed against transcriptional regulator genes 2XCT, 1JIJ, 2Q0P, 4M81, and 3QPI. Eugenol cinnamaldehyde and cineol presented strong interaction with targets. The essential oils were analyzed against Staphylococcus aureus and Staphylococcus epidermidis isolated from the oral cavity of diabetic patients. The cinnamon and clove essential oil combination presented significant minimum inhibitory concentrations (MICs) (0.0625/0.0312mg/mL) against S. epidermidis and S. aureus (0.0156/0.0078mg/mL). In the anti-quorum sensing activity, the cinnamon and clove oil combination presented moderate inhibition (8mm) against Chromobacterium voilaceum with substantial violacein inhibition (58% ± 1.2%). Likewise, a significant biofilm inhibition was recorded in the case of S. aureus (82.1% ± 0.21%) and S. epidermidis (84.2% ± 1.3%) in combination. It was concluded that a clove and cinnamon essential oil-based formulation could be employed to prepare a stable nanocomposite, and Carbapol 940 could be used as a compatible biopolymer.

Naturally Derived Terpenoids Targeting the 3Dpol of Foot-and-Mouth Disease Virus: An Integrated In Silico and In Vitro Investigation.

Foot-and-mouth disease virus (FMDV) belongs to the Picornaviridae family and is an important pathogen affecting cloven-hoof livestock. However, neither effective vaccines covering all serotypes nor specific antivirals against FMDV infections are currently available. In this study, we employed virtual screening to screen for secondary metabolite terpenoids targeting the RNA-dependent RNA polymerase (RdRp), or 3Dpol, of FMDV. Subsequently, we identified the potential antiviral activity of the 32 top-ranked terpenoids, revealing that continentalic acid, dehydroabietic acid (abietic diterpenoids), brusatol, bruceine D, and bruceine E (tetracyclic triterpenoids) significantly reduced cytopathic effects and viral infection in the terpenoid-treated, FMDV-infected BHK-21 cells in a dose-dependent manner, with nanomolar to low micromolar levels. The FMDV minigenome assay demonstrated that brusatol and bruceine D, in particular, effectively blocked FMDV 3Dpol activity, exhibiting IC50 values in the range of 0.37-0.39 µM and surpassing the efficacy of the antiviral drug control, ribavirin. Continentalic acid and bruceine E exhibited moderate inhibition of FMDV 3Dpol. The predicted protein-ligand interaction confirmed that these potential terpenoids interacted with the main catalytic and bystander residues of FMDV 3Dpol. Additionally, brusatol and bruceine D exhibited additive effects when combined with ribavirin. In conclusion, terpenoids from natural resources show promise for the development of anti-FMD agents.

Overview of preclinical and clinical studies investigating pharmacokinetics and drug–drug interactions of padsevonil

ABSTRACT 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.

Investigation of in vitro biological activity of young Hordeum vulgare leaf in correlation with its bioactive compounds.

Young shoots of cereals are widely regarded as superfoods with health benefits attributed to their potential antioxidant activity and antioxidant-related effects (e.g. anticancer). The current study aimed to examine the chemical characteristics of Hordeum vulgare methanolic and aqueous extracts and assess their antioxidant activity using the DDPH and ORAC. Furthermore, the inhibitory effect of xanthine oxidase was screened. TLC bioautography was employed to determine the polarity of the compounds present in the extracts that exhibited the most potent free radical scavenging activity. Total flavonoid content of the methanolic and aqueous extracts was 0.14mgQE/g and 0.012mgQE/g, respectively. The antioxidant activity of the methanolic extract was found to be more potent, with a value of 0.97 ± 0.13mmolTE/g than the aqueous extract which had no activity. This study presents novel findings on the xanthine inhibitory activity of H. vulgare. The methanolic extract demonstrated moderate inhibition of xanthine oxidase with a value of 23.24%. The results of our study were compared with the phytochemical and pharmacological analysis of Triticum aestivum, and further comparison was made with the data reported in the literature. Inconsistencies were observed in the chemical and pharmacological properties of H. vulgare, which could be a result of using herbal material harvested in different vegetative phases and various methods used for extraction. The findings of our study indicate that the timing of the harvest and extraction method may play crucial role in attaining the optimal phytochemical composition of H. vulgare, hence enhancing its pharmacological activity.

Mauritone A, a new polyketide from a fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532

A new polyketide, mauritone A (1) with six known polyketides curvulone B (2), curvularin (3), 12-oxocurvularin (4), (10E,15S)-10,11-dehydrocurvularin (5), (11R,15S)-11-hydroxycurvularin (6), and (11S,15S)-11-hydroxycurvularin (7) were isolated from the fungal-bacterial symbiont Aspergillus spelaeus GXIMD 04541/Sphingomonas echinoides GXIMD 04532 derived from Mauritia arabica. Their structures were elucidated by extensive spectral analysis. All compounds (1-7) were evaluated for their anti-inflammatory effects. The inhibitory effects of 4, 5, and 7 on nitric oxide (NO) production were found to be significant, with IC50 values of 5.5 ± 0.26, 2.0 ± 0.31, and 8.3 ± 0.62 μM, respectively, surpassing that of the positive control quercetin (10.6 ± 0.64 μM). Compounds 3 and 6 exhibited moderate inhibition of NO, with IC50 values of 18.6 ± 0.53 and 12.7 ± 0.45 μM, respectively.

Mango peel extracts and mangiferin chromatographic Fourier-transform infrared correlation with antioxidant, antidiabetic, and advanced glycation end product inhibitory potentials using in silico modeling and in vitro assays.

Mangifera indica peels are a rich source of diverse flavonoids and xanthonoids; however, generally these are discarded. Computational studies revealed that mangiferin significantly interacts with amino acid residues of transcriptional regulators 1IK3, 3TOP, and 4f5S. The methanolic extract of Langra variety of mangoes contained the least phenol concentrations (22.6 ± 0.32 mg/gGAE [gallic acid equivalent]) compared to the chloroform (214.8 ± 0.12 mg/gGAE) and ethyl acetate fractions (195.6 ± 0.14 mg/gGAE). Similarly, the methanolic extract of Sindhri variety contained lower phenol concentrations (42.3 ± 0.13 mg/gRUE [relative utilization efficiency]) compared with the chloroform (85.6 ± 0.15 mg/gGAE) and ethyl acetate (76.1 ± 0.32 mg/gGAE) fractions. Langra extract exhibited significant α-glucosidase inhibition (IC50 0.06 mg/mL), whereas the ethyl acetate fraction was highly active (IC50 0.12 mg/mL) in Sindhri variety. Mangiferin exhibited significant inhibition (IC50 0.026 mg/mL). A moderate inhibition of 15-LOX was observed in all samples, whereas mangiferin was least active. In advanced glycation end product inhibition assay, the chloroform fraction of Langra variety exhibited significant inhibition in nonoxidative (IC50 64.4μg/mL) and oxidative modes (IC50 54.7μg/mL). It was concluded that both Langra and Sindhri peel extracts and fractions possess significant antidiabetic activities. The results suggest the potential use of peel waste in the management and complications of diabetes.

Synthesis and biological evaluation of cyclohexanpyridin-2(1H)-one analogues as novel HIV-1 NNRTIs

In the search and development of new non-nucleoside reverse transcriptase inhibitor (NNRTI) compounds that are more effective against HIV-1, eight C-4 alkylated cyclohexanpyridinone derivatives of the alkyloxy and alkylamino type were synthesized. Compounds were characterized by spectroscopic and spectrometric techniques. In addition, their inhibitory effect against reverse transcriptase (RT), inhibition of HIV in vitro and cytotoxicity in JLTRG cells was evaluated. Compound 8e showed reasonable cellular antiviral activity (EC50 = 28.78 μM), moderate inhibition against RT (IC50 = 69.8 μM), and was not cytotoxic at the concentrations evaluated. Docking and molecular dynamics studies corroborate favorable binding to the HIV IT allosteric site with 8e, providing a basis for the design of more potent analogues.

Phytochemical Analysis and Antibacterial Activity of Tribulus terrestris from Cholistan Desert

Tribulus terrestris (Puncture vine) is a medicinal herb found all around the world and also in the desert of Cholistan. Its therapeutic efficacy as eastern medicines have been known since ancient times. The present studies investigated the presence of phytochemicals and its antibacterial potential of Tribulus terrestris collected from desert of Cholistan, Punjab, Pakistan. Qualitative tests indicated the presence of alkaloids flavonoids, saponins terpenoids, tannins, carbs, proteins, amino acids and glycosides. Moreover, antibacterial potential of methanolic extracts of (seeds, leaves, stem and roots) was assessed using diffusion methods against different bacterial strains Staphylococcus aureus, Escherichia coli, Proteus vulgaris, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Results shown that leaf and fruit extracts had (0 mm) activity against Pseudomonas aeruginosa. While, methanolic extracts of leaves had the highest inhibitory activity (12 mm) against Klebsiella pneumoniae, whereas other bacteria, such as Escherichia coli, had the lowest inhibition region (2.2mm). Furthermore, methanolic extract of leaves showed a quite moderate inhibition zone (10mm) against Staphylococcus aureus, compared to Tribulus terrestris extract of fruits, which had a (7mm) inhibition zone. The present study indicated that the phytochemicals extracted from Tribulus terrestris are valuable for the development of pharmacological formulations to treat different diseases.

DESIGN, SYNTHESIS, AND BIOLOGICAL ASSESSMENT OF NOVEL N'-(BENZYLIDENE)PROPANEHYDRAZIDES AS MTDL FOR ALZHEIMER’S DISEASE

Objective: In this study, following the multi-target directed ligands (MTDLs) strategy and drawing inspiration from the neuroprotective structure of ferulic acid, eight novel N'-(benzylidene)propanehydrazide derivatives were designed, synthesized, and tested to evaluate their cholinesterase inhibitory and antioxidant capacities. Material and Method: To obtain the final compounds, first, corresponding key intermediates, 3-(substitutedamino)propanehydrazides, were prepared by the hydrolysis with hydrazine hydrate of methyl 3-(substitutedamino)propanoate intermediates. These intermediates had been prepared from the Michael addition of methyl acrylate and commercially available tertiary amine derivatives. Subsequently, the final compounds were synthesized from the reaction of the starting compounds 4-hydroxybenzaldehyde or 4-methoxybenzaldehyde and the corresponding key intermediates. Structural analysis of the synthesized and purified compounds was carried out using 1H-NMR, 13C-NMR, and HRMS. Then, all the final compounds were examined for their cholinesterase inhibitory effect using the modified Ellman method, their antioxidant effect using the DPPH and ORAC methods, and their metal chelator effect using UV-spectroscopy analysis. Moreover, physicochemical parameters were calculated using QikProp Schrödinger Suite 2023 to predict the druggability of all compounds. Result and Discussion: Seven of the eight final compounds exhibited moderate cholinesterase inhibition at varying rates. Compounds 2a (IC50 = 12.83 µM) and 2d (IC50 = 16.02 µM) were identified as the most potent inhibitors for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), respectively. Moreover, all the final compounds exhibited antioxidant activity in the ORAC assay. Chelator effects of all compounds were also observed for Cu(II), Fe(II), and Zn(II) ions at varying rates. Additionally, the final compounds demonstrated acceptable lead-like properties according to in-silico predictions.

Identification of potent indolizine derivatives against Mycobacterial tuberculosis: In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies

In the current study, two sets of compounds: (E)-1-(2-(4-substitutedphenyl)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium derivatives (3a-3e); and (E)-3-(substitutedbenzoyl)-7-((hydroxyimino)methyl)-2-substitutedindolizine-1-carboxylate derivatives (5a-5j), were synthesized and biologically evaluated against two strains of Mycobacterial tuberculosis (ATCC 25177) and multi-drug resistant (MDR) strains. Further, they were also tested in vitro against the mycobacterial InhA enzyme. The in vitro results showed excellent inhibitory activities against both MTB strains and compounds 5a-5j were found to be more potent, and their MIC values ranged from 5 to 16 μg/mL and 16–64 μg/mL against the M. tuberculosis (ATCC 25177) and MDR-TB strains, respectively. Compound 5h with phenyl and 4-fluorobenzoyl groups attached to the 2- and 3-position of the indolizine core was found to be the most active against both strains with MIC values of 5 μg/mL and 16 μg/mL, respectively. On the other hand, the two sets of compounds showed weak to moderate inhibition of InhA enzyme activity that ranged from 5 to 17 % and 10–52 %, respectively, with compound 5f containing 4-fluoro benzoyl group attached to the 3-position of the indolizine core being the most active (52 % inhibition of InhA). Unfortunately, there was no clear correlation between the InhA inhibitory activity and MIC values of the tested compounds, indicating the probability that they might have different modes of action other than InhA inhibition.Therefore, a computational investigation was conducted by employing molecular docking to identify their putative drug target(s) and, consequently, understand their mechanism of action. A panel of 20 essential mycobacterial enzymes was investigated, of which β-ketoacyl acyl carrier protein synthase I (KasA) and pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzymes were revealed as putative targets for compounds 3a-3e and 5a-5j, respectively. Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.

Identification of the human Cytochrome P450 enzymes (P450s) responsible for metabolizing infigratinib to its pharmacologically active Metabolites, BHS697, and CQM157, and assessment of their in vitro inhibition of P450s and UDP-glucuronosyltransferases (UGTs)

Infigratinib, an oral FGFR inhibitor for advanced cholangiocarcinoma, yielded two active metabolites, BHS697 and CQM157, with similar receptor affinity. Our study characterized P450s that are responsible for the metabolism of infigratinib to its two major active metabolites, BHS697 and CQM157. In vitro inhibition of P450s and UGTs by infigratinib, BHS697 or CQM157 was further investigated. The unbound apparent Km values for metabolism of infigratinib to BHS697 by HLM, human recombinant CYP2C8, CYP2C19, CYP2D6 and CYP3A4 enzymes are 4.47, 0.65, 2.50, 30.6 and 2.08 μM, while Vmax values are 90.0 pmol/min/mg protein, 0.13, 0.027, 0.81, and 0.56 pmol/min/pmol protein, respectively. The unbound apparent Km value for metabolism of infigratinib to CQM157 by HLM is 0.049 μM, while the Vmax value is 0.32 pmol/min/mg protein respectively. In HLM, infigratinib displayed moderate inhibition of CYP3A4 and CYP2C19 and weak or negligible inhibition of other P450 isoforms. BHS697 exhibited weak inhibition of CYP2B6, CYP2C9, CYP2C19 and CYP3A4, and no inhibition of CYP2C8 and CYP2D6. CQM157 moderately inhibited CYP2C9 and CYP3A4, and weakly or negligibly inhibited other P450 isoforms. Regarding UGTs, infigratinib moderately inhibited UGT1A4 and weakly inhibited UGT1A1, respectively. BHS697 weakly inhibited UGT1A1. In contrast, CQM157 moderately inhibited both UGT1A1 and UGT1A4. Our findings provide novel insights into the metabolism of and potential DDIs implicating infigratinib.

Does Erodium trifolium (Cav.) Guitt exhibit medicinal properties? Response elements from phytochemical profiling, enzyme-inhibiting, and antioxidant and antimicrobial activities

Abstract Geraniaceae are typically used as diuretic, anti-diarrhoeal, stomachic, and anti-hemorrhagic drugs. This study examined the phytochemicals and bioactivities in methanolic extract (ME) and petroleum ether extract (PEE) of the Erodium trifolium aerial part. Inductively coupled plasma mass spectrometry was used to assess the mineral profiles, high-performance liquid chromatography coupled with mass spectrometry (HPLC-MS) and high-performance liquid chromatography with diode-array detection (HPLC-DAD) were used to assess the phenolic content of ME, and gas chromatography-mass spectrometry (GC-MS) was used to assess the fatty acid and volatile composition of the PEEs. In addition, the bioactivities of extracts were evaluated by using the 1,1-diphenyl-2-picrylhydrazyl, ABTS, and cupric reducing antioxidant capacity assays, including enzyme inhibition against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), α-amylase, α-glucosidase activities, and antibacterial properties. HPLC-MS identified eight compounds in ME: rutin, catechin, and caffeine were the major phenolic compounds detected. HPLC-DAD analysis showed that 11 compounds detected among epicatechin, catechin, chlorogenic acid, and gallic acid were predominant. GC-MS analysis revealed 30 fatty acids in PEE, with palmitic acid and oleic acid being predominant. The mineral content showed that Fe was the abundant microelement, and Ca and K were the abundant macroelements. The ME exhibited the highest activity compared to the PEE in all tests regarding antioxidant and antibacterial activities. Furthermore, all the extracts showed moderate inhibition against AChE, BChE, α-amylase, and α-glucosidase. In conclusion, E. trifolium may be employed to separate novel bioactive metabolites with potential pharmaceutical activities.

The Potential of Hemp Extracts to Modify the Course of Oxidative-Stress Related Conditions.

The leaves of industrial hemp, which have long been considered as a waste product, have been proven to contain numerous compounds that possess potential biological activity. One of the most interesting groups of compounds present are polyphenolic compounds, which, due to their specific structure, have a pronounced antioxidant and antihyperglycemic potential. This study aimed to detect biological activity, including antioxidant and antihyperglycemic potential, of water and water-alcoholic extracts of five commercially available hemp teas, followed by phytochemical profiling. Hemp aqueous and ethanolic extracts demonstrate potent antioxidant properties. Ethanol extracts are better scavengers of DPPH• and OH•, while aqueous extracts neutralize NO• better. Both types of extracts exhibit antioxidant potential in the catalase test and moderate XOD inhibition. Furthermore, aqueous extracts are potent α-amylase inhibitors, while ethanolic extracts demonstrate stronger anti-α-glucosidase activity, suggesting therapeutic potential for chronic diseases like insulin resistance or diabetes. Further detailed chemical characterization and in vivo studies are needed to validate these findings.