Synthesis, Antimicrobial Evaluation, DFT, in Silico-Docking, and ADMET Investigations of Novel Chromene-based 2,4-Thiazolidinediones.

Three series of thiazolidinedione (TZD) derivatives (5a-f, 7a-f, and 9a-f) were prepared efficiently. Afterward, the synthesized candidates' antibacterial efficacy against both gram-positive and gram-negative bacteria was assessed. Compounds 7c, 7d, and 7f had values comparable to that of ampicillin, a reference antibiotic, whereas compounds 5c, 5d, and 7e exhibited the greatest values (23.0 ± 1.0, 27.7 ± 0.6, and 20.0 ± 1.0, respectively) against gram-positive bacteria (Staphylococcus aureus). The optimal structure of the produced molecules was determined by DFT computing. To assess the binding energy and elucidate the interaction between the potential candidates and different proteins, silico-docking is employed. ADMET analysis to assess the synthesized compounds' toxicity, metabolism, excretion, distribution, and absorption.

Kiwi (Actinidia deliciosa) juice as a natural inhibitor of the enzymatic activity of sugarcane juice, insights from experimental assessment and molecular docking analysis.

The present work evaluated kiwi juice addition alongside pasteurization (at 85 °C for 5 min) or microwave treatment (for 3 min) on the quality improvement of sugarcane juice. The juice was treated in the presence of kiwi juice (0-8%), and its physicochemical properties and microbial load were compared with raw juice. The study also highlighted the key enzymes causing sugarcane juice discoloration, peroxidase (POD) and polyphenol oxidase (PPO), by quantifying kiwi juice constituents using GC-MS and monitoring their effects by molecular docking. Kiwi addition considerably raised (p < 0.05) acidity, ascorbic acid (54.28%), and phenolic compounds (32%), and decreased the POD and PPO activity of raw cane juice. Pasteurization in the presence of kiwi, rather than microwave treatment, has significantly (p < 0.05) increased the phenolic compounds and reduced POD and PPO activities until barley was detected. Molecular docking revealed that heptacosane, oleic acid, and melezitose are the primary kiwi components responsible for enzyme inactivation.

Discovery of Protease-activated receptor 2 antagonists derived from phenylalanine for the treatment of breast cancer.

Protease-activated receptor 2 (PAR2) has garnered attention as a potential therapeutic target in breast cancer. PAR2 is implicated in the activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) via G protein and beta-arrestin pathways, contributing to the proliferation and metastasis of breast cancer cells. Despite the recognized role of PAR2 in breast cancer progression, clinically effective PAR2 antagonists remain elusive. To address this unmet clinical need, we synthesized and evaluated a series of novel compounds that target the orthosteric site of PAR2. Using in silico docking simulations, we identified compound 9a, an optimized derivative of compound 1a ((S)-N-(1-(benzylamino)-1-oxo-3-phenylpropan-2-yl)benzamide), which exhibited enhanced PAR2 antagonistic activity. Subsequent molecular dynamics simulations comparing 9a with the partial agonist 9d revealed that variations in ligand-induced conformational changes and interactions dictated whether the compound acted as an antagonist or agonist of PAR2. The results of this study suggest that further development of 9a could contribute to the advancement of PAR2 antagonists as potential therapeutic agents for breast cancer.

Comparative analyses of anti-inflammatory effects of Resveratrol, Pterostilbene and Curcumin: in-silico and in-vitro evidences.

Inflammation is an adaptive response that involves activation, and recruitment of cells of innate and adaptive immune cells for restoring homeostasis. To safeguard the host from the threat of inflammatory agents, microbial invasion, or damage, the immune system activates the transcription factor NF-κB and produces cytokines such as TNF-α, IL- 6, IL-1ß, and α. Sirtuin 1 (SIRT1) controls the increased amounts of proinflammatory cytokines, which in turn controls inflammation. Three phytoconstituents resveratrol (RES), pterostilbene (PTE), and curcumin (CUR) which are SIRT1- activators and that have marked anti-inflammatory effects (in-vivo), were chosen for the current study. These compounds were compared for their anti-inflammatory potential by in-silico docking studies for IL-6, TNF-α, NF-κB, and SIRT1 and in-vitro THP-1 cell line studies for IL-6, TNF-α. PTE was found to be more effective than RES and CUR in lowering the concentrations of IL-6 and TNF-α in THP-1 cell line studies, and it also showed a favorable docking profile with cytokines and SIRT1. Thus, PTE appears to be a better choice for further research and development as a drug or functional food supplement with the ability to reduce inflammation in metabolic disorders. Graphical abstract: Schematic representation of in-silico and in-vitro analysis of Resveratrol, Pterostilbene, and Curcumin.

In Vitro and In Vivo Evaluation of the Effects of Drug 2c and Derivatives on Ovarian Cancer Cells.

BACKGROUND: The identification of novel therapeutic strategies for ovarian cancer (OC), the most lethal gynecological neoplasm, is of utmost urgency. Here, we have tested the effectiveness of the compound 2c (4-hydroxy-2,6-bis(4-nitrobenzylidene)cyclohexanone 2). 2c interferes with the cysteine-dependent deubiquitinating enzyme (DUB) UCHL5, thus affecting the ubiquitin-proteasome-dependent degradation of proteins. METHODS: 2c phenotypic/molecular effects were studied in two OC 2D/3D culture models and in a mouse xenograft model. Furthermore, we propose an in silico model of 2c interaction with DUB-UCHL5. Finally, we have tested the effect of 2c conjugated to several linkers to generate 2c/derivatives usable for improved drug delivery. RESULTS: 2c effectively impairs the OC cell line and primary tumor cell viability in both 2D and 3D conditions. The effectiveness is confirmed in a xenograft mouse model of OC. We show that 2c impairs proteasome activity and triggers apoptosis, most likely by interacting with DUB-UCHL5. We also propose a mechanism for the interaction with DUB-UCHL5 via an in silico evaluation of the enzyme-inhibitor complex. 2c also reduces cell growth by down-regulating the level of the transcription factor E2F1. Eventually, 2c activity is often retained after the conjugation with linkers. CONCLUSION: Our data strongly support the potential therapeutic value of 2c/derivatives in OC.

Encapsulation of Apium graveolens essential oil into chitosan nanobiopolymer for protection of stored rice against Fusarium verticillioides and fumonisins contamination.

The present investigation entails the encapsulation of Apium graveolens essential oil into chitosan nanobiopolymer (AGEO-Ne) and assessment of its efficacy against Fusarium verticillioides contamination and fumonisins biosynthesis in stored rice (Oryza sativa L.) samples. The AGEO was encapsulated through ionic gelation process and characterized by scanning electron microscopy (SEM), Dynamic light scattering (DLS), X-ray diffractometry (XRD), and Fourier transform infrared spectroscopy (FTIR) analyses. The AGEO exhibited bi-phasic delivery pattern from chitosan matrix. The AGEO caused complete inhibition of F. verticillioides growth at 1.2 µL/mL, while fumonisin B1 (FB1) and B2 (FB2) biosynthesis at 1.2 and 1.0 µL/mL, respectively. On the other hand, nanoencapsulated AGEO (AGEO-Ne) exhibited improved efficacy, caused complete inhibition of fungal growth at 0.8 µL/mL, and FB1 and FB2 production at 0.8 and 0.6 µL/mL, respectively. AGEO-Ne caused 100 % inhibition of ergosterol synthesis at 0.8 µL/mL and exhibited greater efflux of Ca2+, Mg2+, K+ ions (18.99, 21.63, and 25.38 mg/L) as well as 260 and 280 nm absorbing materials from exposed fungal cells. The in silico interaction of granyl acetate and linalyl acetate with FUM 21 protein validated the molecular mechanism for inhibition of FB1 and FB2 biosynthesis. Further, improvement in antioxidant activity of AGEO-Ne was observed after encapsulation with IC50 values of 12.08 and 6.40 µL/mL against DPPH and ABTS radicals, respectively. During in situ investigation, AGEO caused 82.09 and 86.32 % protection of rice against F. verticillioides contamination in inoculated and uninoculated rice samples, respectively, while AGEO-Ne exhibited 100 % protection of fumigated rice samples against F. verticillioides proliferation as well as FB1 and FB2 contamination. The AGEO-Ne also caused better retardation of lipid peroxidation (41.35 and 37.52 µM/g FW malondialdehyde in inoculated and uninoculated treatment) and acceptable organoleptic properties in rice samples, which strengthen its application as plant based novel preservative in food and agricultural industries.

Oxyresveratrol-ß-cyclodextrin mitigates streptozotocin-induced Alzheimer's model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies.

Alzheimer's disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-ß-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD.

Exploring ligand interactions with human phosphomannomutases using recombinant bacterial thermal shift assay and biochemical validation.

PMM2-CDG, a disease caused by mutations in phosphomannomutase-2, is the most common congenital disorder of glycosylation. Yet, it still lacks a cure. Targeting phosphomannomutase-2 with pharmacological chaperones or inhibiting the phosphatase activity of phosphomannomutase-1 to enhance intracellular glucose-1,6-bisphosphate have been proposed as therapeutical approaches. We used Recombinant Bacterial Thermal Shift Assay to assess the binding of a substrate analog to phosphomannomutase-2 and the specific binding to phosphomannomutase-1 of an FDA-approved drug - clodronate. We also deepened the clodronate binding by enzyme activity assays and in silico docking. Our results confirmed the selective binding of clodronate to phosphomannomutase-1 and shed light on such binding.

Exploring the Therapeutic Potential of Ammodaucus leucotrichus Seed Extracts: A Multi-Faceted Analysis of Phytochemical Composition, Anti-Inflammatory Efficacy, Predictive Anti-Arthritic Properties, and Molecular Docking Insights.

Ammodaucus leucotrichus exhibits promising pharmacological activity, hinting at anti-inflammatory and anti-arthritic effects. This study investigated seed extracts from Ammodaucus leucotrichus using methanol and n-hexane, focusing on anti-inflammatory and anti-arthritic properties. The methanol extract outperformed the n-hexane extract and diclofenac, a reference anti-inflammatory drug, in trypsin inhibition (85% vs. 30% and 64.67% at 125 µg/mL). For trypsin inhibition, the IC50 values were 82.97 µg/mL (methanol), 202.70 µg/mL (n-hexane), and 97.04 µg/mL (diclofenac). Additionally, the n-hexane extract surpassed the methanol extract and diclofenac in BSA (bovine serum albumin) denaturation inhibition (90.4% vs. 22.0% and 51.4% at 62.5 µg/mL). The BSA denaturation IC50 values were 14.30 µg/mL (n-hexane), 5408 µg/mL (methanol), and 42.30 µg/mL (diclofenac). Gas chromatography-mass spectrometry (GC-MS) revealed 59 and 58 secondary metabolites in the methanol and n-hexane extracts, respectively. The higher therapeutic activity of the methanol extract was attributed to hydroxyacetic acid hydrazide, absent in the n-hexane extract. In silico docking studies identified 28 compounds with negative binding energies, indicating potential trypsin inhibition. The 2-hydroxyacetohydrazide displayed superior inhibitory effects compared to diclofenac. Further mechanistic studies are crucial to validate 2-hydroxyacetohydrazide as a potential drug candidate for rheumatoid arthritis treatment.

In vitro and in silico studies reveal antidiabetic properties of arylbenzofurans from the root bark of Morus mesozygia Stapf.

Diabetes remains an important disease worldwide with about 500 million patients globally. In tropical Africa, Morus mesozygia is traditionally used in the treatment of diabetes. Biological and phytochemical investigation of the root bark extracts of the plant led to the isolation of a new prenylated arylbenzofuran named 7-(3-hydroxy-3-methylbutyl)moracin M (1) and two congeners, moracins P (2) and M (3). When compared to acarbose (IC50 = 486 µM), all the isolated compounds are better inhibitors of α-glucosidase with in vitro IC50 values of 16.9, 16.6, and 40.9 µM, respectively. However, they were not active against α-amylase. The compounds also demonstrated moderate inhibition of dipeptidyl peptidase-4 (DPP4). Based on in silico docking studies, all isolates (1, 2, and 3) exhibit binding affinities of -8.7, -9.5, and -8.5 kcal/mol, respectively against α-glucosidase enzyme (PDB: 3AJ7). They are stabilized within the α-glucosidase active site through hydrogen bonds, pi interactions, and hydrophobic interactions. This study provides scientific support for the traditional use of Morus mesozygia in the treatment of diabetes as well as adding to the repository of α-glucosidase inhibitory agents.

Design, Synthesis and In vitro Antitubercular Effect of New Chalcone Derivatives Coupled with 1,2,3-Triazoles: A Computational Docking Techniques.

A very interesting foundation for this study is the creation of new methods for modifying compounds with a 1,2,3-triazole and chalcone scaffolds, as these compounds are significant in organic synthesis, particularly in the synthesis of bioactive organic compounds. To contribute to the development of an efficient method for the conversion of antimicrobial and antituberculosis heterocyclics, a novel series of cyclohepta pyridinone fused 1,2,3-triazolyl chalcones were designed and synthesized. All the newly prepared scaffolds were characterized by FT-IR, NMR (1H & 13C) and mass spectrometry. Among the tested compounds, hybrids 8b, 8d, and 8f exhibited exceptional antibacterial susceptibilities with zone of inhibition 27.84±0.04, 32.27±0.02, and 38.26±0.01 mm against the tested E. faecalis bacteria, whereas 8d had better antitubercular potency against M. tuberculosis H37Rv strain with MIC value 5.25 µg/mL, compared to Streptomycin [MIC=5.01 µg/mL]. All the synthesized compounds were initially assessed in silico against the targeted protein i. e., DprE1 that indicated compound 8d, 8f and 8h along with several other 1,2,3-triazole compounds as possible inhibitors. Based on docking results, 8d showed that the amino acids His74(A), Lys76(A), Cys332(A), Asp331(A), Val307(A), Tyr357(A), Met226(A), Gln276(A), Gly75(A), Peo58(A), Leu259(A), and Lys309(A) exhibited highly stable binding to DprE1 receptor of Mycobacterium tuberculosis (PDB: 4G3 U). Moreover, these scaffolds physicochemical characteristics, filtration molecular properties, assessment of toxicity, and bioactivity scores were assessed in relation to ADME (absorption, distribution, metabolism, and excretion).

Phytocompounds as potential inhibitors of mycobacterial multidrug efflux pump Rv1258c: an in silico approach.

The number of infections and deaths caused by multidrug resistant (MDR) tuberculosis is increasing globally. One of the efflux pumps, that makes Mycobacterium tuberculosis resistant to a number of antibiotics and results in unfavourable treatment results is Tap or Rv1258c. In our study, we tried to utilize a rational drug design technique using in silico approach to look for an efficient and secure efflux pump inhibitor (EPI) against Rv1258c. The structure of Rv1258c was built using the homology modeling tool MODELLER 9.24. 210 phytocompounds were used for blind and site-specific ligand docking against the modelled structure of Rv1258c using AutoDock Vina software. The best docked plant compounds were further analysed for druglikeness and toxicity. In addition to having excellent docking scores, two plant compounds-ellagic acid and baicalein-also exhibited highly desirable drug-like qualities. These substances outperform more well-known EPIs like piperine and verapamil in terms of effectiveness. This data shows that these two compounds might be further investigated for their potential as Rv1258c inhibitors.

Structure-activity relationship and target investigation of 2-aryl quinolines with nematocidal activity.

Within the context of our anthelmintic discovery program, we recently identified and evaluated a quinoline derivative, called ABX464 or obefazimod, as a nematocidal candidate; synthesised a series of analogues which were assessed for activity against the free-living nematode Caenorhabditis elegans; and predicted compound-target relationships by thermal proteome profiling (TPP) and in silico docking. Here, we logically extended this work and critically evaluated the anthelmintic activity of ABX464 analogues on Haemonchus contortus (barber's pole worm) - a highly pathogenic nematode of ruminant livestock. First, we tested a series of 44 analogues on H. contortus (larvae and adults) to investigate the nematocidal pharmacophore of ABX464, and identified one compound with greater potency than the parent compound and showed moderate activity against a select number of other parasitic nematodes (including Ancylostoma, Heligmosomoides and Strongyloides species). Using TPP and in silico modelling studies, we predicted protein HCON_00074590 (a predicted aldo-keto reductase) as a target candidate for ABX464 in H. contortus. Future work aims to optimise this compound as a nematocidal candidate and investigate its pharmacokinetic properties. Overall, this study presents a first step toward the development of a new nematocide.

Investigating the anti-cancer potential of pyrimethamine analogues through a modern chemical biology lens.

Pharmacological inhibition of dihydrofolate reductase (DHFR) is an established approach for treating a variety of human diseases, including foreign infections and cancer. However, treatment with classic DHFR inhibitors, such as methotrexate (MTX), are associated with negative side-effects and resistance mechanisms that have prompted the search for alternatives. The DHFR inhibitor pyrimethamine (Pyr) has compelling anti-cancer activity in in vivo models, but lacks potency compared to MTX, thereby requiring higher concentrations to induce therapeutic responses. The purpose of this work was to investigate structural analogues of Pyr to improve its in vitro and cellular activity. A series of 36 Pyr analogues were synthesized and tested in a sequence of in vitro and cell-based assays to monitor their DHFR inhibitory activity, cellular target engagement, and impact on breast cancer cell viability. Ten top compounds were identified, two of which stood out as potential lead candidates, 32 and 34. These functionalized Pyr analogues potently engaged DHFR in cells, at concentrations as low as 1 nM and represent promising DHFR inhibitors that could be further explored as potential anti-cancer agents.

HPLC/ESI-MS Characterization of Phenolic Compounds from Cnicus benedictus L. Roots: A Study of Antioxidant, Antibacterial, Anti-Inflammatory, and Anti-Alzheimer's Activity.

The phenolic composition of Cnicus benedictus roots from four Algerian regions was investigated. Extractions were performed in both hydro-methanolic (30 : 70, v/v) and hydro-ethanolic (30 : 70, v/v) solvents. Their efficiency was determined in terms of the qualitative and quantitative composition in phenolic compounds by HPLC-LC/MS of the different extracts isolated from C. Benedictus roots. Cnicus benedictus roots extract have been characterized by high content of phenolic compounds, where the trans chalcone, 2,3-dihydro flavone, 3-hydroxy flavone and cinnamic acid constitute the major components, in addition to fourteen minor acidic compounds and flavonoids as rutin. The hydro-methanolic extract was the richest in phenolic compounds yield from C benedictus. On the other hand, hydro methanolic (30 : 70, v/v) and hydro ethanolic (30 : 70, v/v) extracts exhibited a high anti-inflammatory activity by in vitro 5-lipoxygenase inhibitory activity (IC50 : 6.05±94.16 µg/mL) as well as by in silico docking according two methods. Likewise, anti-Alzheimer activity of extracts was confirmed by this last technique taking into account the major compounds identified. Antibacterial tests revealed interesting results compared to amoxicillin for the different regions studied with a high content in trans chalcone and 3-hydroxy Flavone.

Possible cerebroprotective effect of citronellal: molecular docking, MD simulation and in vivo investigations.

This study focused on molecular docking, dynamic simulation, and in vivo approaches to examine the molecular interactions between citronellal (CT) and neurotoxic proteins. In silico studies of CT were performed using proteins involved in the pathophysiology of stroke, such as interleukin-6 (IL-6), interleukin-12 (IL-12), TNF-α, and nitric oxide synthase (NOS), to determine the binding affinity based on their interactions. The docking results of CT revealed that, among the targets, NOS had a better binding energy of -6.4 Kcal/mol. NOS showed good hydrophobic interactions: TYR A, 347; VAL A, 352; PRO A, 350; TYR A, 373 amino acids. Interactions with IL-6, TNF-α, and IL-12 resulted in lower binding affinities of -3.7, -3.9 and -3.1 Kcal/mol. Based on molecular dynamics simulations of 100 ns, the binding affinity of CT (-66.782 ± 7.309 kJ/mol) was well complemented, and NOS stability at the docked site was confirmed. In in vivo studies, cerebral stroke was induced by occlusion of the bilateral common carotid arteries for 30 min and reperfusion for 4 h. CT treatment protected the brain by decreasing cerebral infarction size, increasing GSH(p < 0.001***), decreasing MPO (p < 0.001***), MDA (p < 0.001***), NO production (p < 0.01**), and AChE (p < 0.001***) compared to stroke rats. Histopathological examination revealed that CT treatment reduced the severity of cerebral damage. The investigation concluded that CT strongly binds to NOS, as observed in molecular docking and dynamic simulation studies, which are involved in nitric oxide production, leading to cerebral damage, and CT treatment reduces NO production and oxidative stress parameters, and increases antioxidants via inhibition of NOS function.Communicated by Ramaswamy H. Sarma.

Synthesis of novel 5-[3-(4-chlorophenyl)-substituted-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives as potential anti-diabetic and anticancer agents.

In this work, we developed a series of novel 5-[3-(4-chlorophenyl)-substituted-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione derivatives 4(a-e) via a one-pot multicomponent reaction. The structures of the compounds were confirmed using analytical and spectroscopic techniques. Also, the synthesized compounds were screened for their anti-diabetic activity, cytotoxicity and in silico studies. The activity results suggested that the compound 4e exhibited least IC50 values of 0.055 ± 0.002 µM, 0.050 ± 0.002 µM and 0.009 ± 0.001 µM for α-amylase, α-glucosidase and cytotoxicity respectively. Further, in silico molecular docking results revealed that all the obtained compounds effectively interacted with exo-ß-D-glucosaminidase and P38 MAP kinase proteins with good binding energies. In that, 4e compound established the least binding energy of -9.6 and -9.1 kcal/mol, respectively. Moreover, our synthesized compounds were subjected to ADME studies, which suggested that all the synthesized compounds obeyed all five rules with good bioavailability and were suitable as drug leads against anti-diabetic and anticancer treatment.

Synthesis and Structural Activity Relationship Study of Ursolic Acid Derivatives as Antitubercular Agent.

OBJECTIVE: The chemical transformation of ursolic acid (UA) into novel C-3 aryl ester derivatives and in vitro and silico assessment of their antitubercular potential. BACKGROUND: UA is a natural pentacyclic triterpenoid with many pharmacological properties. Semisynthetic UA analogs have demonstrated enhanced anticancer, antimalarial, and antifilarial properties in our previous studies. METHOD: The C-30 carboxylic group of previously isolated UA was protected, and various C-3 aryl ester derivatives were semi-synthesized. The agar dilution method was used to evaluate the in vitro antitubercular efficacy of Mycobacterium tuberculosis (Mtb) H37Ra. In silico docking studies of the active derivative were carried out against Mtb targets, catalase peroxidase (PDB: 1SJ2), dihydrofolate reductase (PDB: 4M2X), enoyl-ACP reductase (PDB: 4TRO), and cytochrome bc1 oxidase (PDB: 7E1V). RESULTS: The derivative 3-O-(2-amino,3-methyl benzoic acid)-ethyl ursolate (UA-1H) was the most active among the eight derivatives (MIC1 2.5 µg/mL) against Mtb H37Ra. Also, UA-1H demonstrated significant binding affinity in the range of 10.8-11.4 kcal/mol against the antiTb target proteins, which was far better than the positive control Isoniazid, Ethambutol, and co-crystallized ligand (HEM). Moreover, the predicted hit UA-1H showed no inhibition of Cytochrome P450 2D6 (CYP2D6), suggesting its potential for favorable metabolism in Phase I clinical studies. CONCLUSION: The ursolic acid derivative UA-1H possesses significant in vitro antitubercular potential with favorable in silico pharmacokinetics. Hence, further in vivo assessments are suggested for UA-1H for its possible development into a secure and efficient antitubercular drug.

Phytochemical characterization of Typha domingensis and the assessment of therapeutic potential using in vitro and in vivo biological activities and in silico studies.

Typha domingensis, a medicinal plant with significant traditional importance for curing various human diseases, has potentially bioactive compounds but was less explored previously. Therefore, this study aims to investigate the therapeutic potential of T. domingensis by evaluating the phytochemical profile through high-performance liquid chromatography (HPLC) techniques and its biological activities (in vitro and in vivo) from the methanolic extract derived from the entire plant (TDME). The secondary metabolite profile of TDME regulated by reverse phase ultra-high-performance liquid chromatography-mass spectrometry (RP-UHPLC-MS) revealed some bioactive compounds by -ve and +ve modes of ionization. The HPLC quantification study showed the precise quantity of polyphenols (p-coumaric acid, 207.47; gallic acid, 96.25; and kaempferol, 95.78 µg/g extract). The enzyme inhibition assays revealed the IC50 of TDME as 44.75 ± 0.51, 52.71 ± 0.01, and 67.19 ± 0.68 µgmL-1, which were significant compared to their respective standards (indomethacin, 18.03 ± 0.12; quercetin, 4.11 ± 0.01; and thiourea, 8.97 ± 0.11) for lipoxygenase, α-glucosidase, and urease, respectively. Safety was assessed by in vitro hemolysis (4.25% ± 0.16% compared to triton × 100, 93.51% ± 0.36%), which was further confirmed (up to 10 g/kg) by an in vivo model of rats. TDME demonstrated significant (p < 0.05) potential in analgesic activity by hot plate and tail immersion tests and anti-inflammatory activity by the carrageenan-induced hind paw edema model. Pain latency decreased significantly, and the anti-inflammatory effect increased in a dose-dependent way. Additionally, in silico molecular docking revealed that 1,3,4,5-tetracaffeoylquinic acid and formononetin 7-O-glucoside-6″-O-malonate possibly contribute to enzyme inhibitory activities due to their higher binding affinities compared to standard inhibitors. An in silico absorption, distribution, metabolism, excretion, and toxicological study also predicted the pharmacokinetics and safety of the chosen compounds identified from TDME. To sum up, it was shown that TDME contains bioactive chemicals and has strong biological activities. The current investigations on T. domingensis could be extended to explore its potential applications in nutraceutical industries and encourage the isolation of novel molecules with anti-inflammatory and analgesic effects.

Combating planktonic and biofilm growth of Serratia marcescens by repurposing ebselen / Combatir el crecimiento planctónico y de biopelículas de Serratia marcescens mediante la reutilización de ebselen

Aim of the study: The rising instances of multidrug-resistant pathogens are rapidly evolving into a global healthcare crisis. Identifying new ways of synthesis of antibiotics is both time-consuming and expensive. Repurposing existing drugs for the treatment of such antimicrobial-resistant pathogens has also been explored. Methods and results: In the current study, ebselen was screened for antibacterial and antibiofilm activity against Serratia marcescens. Various antibacterial studies such as minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), time-kill curves, intracellular reactive oxygen species (ROS) quantification, and colony-forming unit assays were performed. The antibiofilm potential was assayed by biofilm inhibition, cell surface hydrophobicity assay, eradication, quantification of extracellular DNA (eDNA), and extracellular polymeric substance (EPS) layer and scanning electron microscopy (SEM) analysis were performed. Anti-quorum sensing assay was validated by quantifying the virulence factors production. Further molecular docking of ebselen with two quorum sensing (QS) specific proteins was also carried out. Antibacterial susceptibility tests showed potent antimicrobial activity of ebselen against S. marcescens with MIC50 of 14 μg/mL. Ebselen’s ability to disturb the redox environment by inducing significant ROS generation led to bacterial death. It also showed concentration-dependent bactericidal activity as indicated by reduced bacterial growth and colony-forming unit propagation. Ebselen was also found to prevent biofilm attachment by altering the cell surface hydrophobicity while also being effective against preformed biofilms as validated by scanning electron microscopy (SEM) analysis. Additionally, ebselen showed reduced virulence factors like urease enzyme activity and prodigiosin pigment production indicating its promising anti-quorum sensing potential...(AU)