Absorption, Distribution, Metabolism And Excretion Research Articles

Virtual Screening, Synthesis and Biological Evaluation of Streptococcus mutans Mediated Biofilm Inhibitors.

Dental caries, a global oral health concern, is a biofilm-mediated disease. Streptococcus mutans, the most prevalent oral microbiota, produces extracellular enzymes, including glycosyltransferases responsible for sucrose polymerization. In bacterial communities, the biofilm matrix confers resistance to host immune responses and antibiotics. Thus, in cases of chronic dental caries, inhibiting bacterial biofilm assembly should prevent demineralization of tooth enamel, thereby preventing tooth decay. A high throughput screening was performed in the present study to identify small molecule inhibitors of S. mutans glycosyltransferases. Multiple pharmacophore models were developed, validated with multiple datasets, and used for virtual screening against large chemical databases. Over 3000 drug-like hits were obtained that were analyzed to explore their binding mode. Finally, six compounds that showed good binding affinities were further analyzed for ADME (absorption, distribution, metabolism, and excretion) properties. The obtained in silico hits were evaluated for in vitro biofilm formation. The compounds displayed excellent antibiofilm activities with minimum inhibitory concentration (MIC) values of 15.26–250 µg/mL.

In silico drug-like properties prediction and in vivo antifungal potentials of Citrullus lanatus seed oil against Candida albicans

Citrullus lanatus seed is an important but neglected seed rich in essential fatty acids. The study sought to investigate in silico and in vivo antifungal activity of some bioactive compounds of Citrullus lanatus (watermelon) seed oil (CLSO) on oral candidiasis induced by Candida albicans in immunosuppressed female albino rats and to predict the Absorption, Distribution, Metabolism and Excretion (ADME) properties of isolated natural compound. Docking studies was performed using standard procedure, standard microbiological and histopathological techniques was employed for study of in vivo antifungal activity of the oil; as well as renal function tests at days 7 and 14 post-infection treatments. Treated groups were compared with that of the control groups. In vitro studies showed varied zone of inhibitions at different concentrations. Ligand-protein interaction showed better binding activity between Palmitic acid and SAP-5 as well as CYP51 when compared with fluconazole (reference drug). Treatment with CLSO showed that there was a significant reduction in the kidney fungal burden (cfu/ml/g) of rats treated with CLSO after 14 days post-infection treatment, compared to group 2 (untreated control) rats. Histomorphology of group 2 showed multifocal aggregation and widespread distribution of fungal blastospores when compared with CLSO-treated groups, which had minimal fungal blastospores in the renal tissues. Thus, in silico and histological data agreed with the findings in microbiology. Furthermore, within the CLSO treated group, a significant increase in the serum concentrations of creatinine was observed, while no significant difference in blood urea values was recorded after day 14 post-infection study. Linoleic and palmitic acid could be considered as a potential antifungal drug candidate with palmitic acid playing a significant role.

Antibacterial and anticancer profiling of new benzocaine derivatives: Design, synthesis, and molecular mechanism of action

The need for new chemotherapeutics to overcome development of resistance merits research to discover new agents. Benzocaine derivatives are essential compounds in medicinal chemistry due to their various biological activities including antibacterial and anticancer activities. Therefore, this study focuses on the synthesis of new benzocaine derivatives 3a-e, 6, 7a and 7b, 8, 10-14, and 16a-d and their in vitro evaluation as antibacterial agents against gram +ve and -ve strains and as anticancer agents against HepG-2, HCT-116, and MCF-7 human cancer cell lines. The obtained results demonstrated that thiazolidines 6 and 7b showed higher antibacterial and anticancer activity in comparison with the reference drugs. In addition, 6 and 7b showed high potency as inhibitors toward their biological targets, that is DNA gyrase and human topoisomerase IIα, as compared to the reference standard drugs novobiocin and etoposide, respectively. Molecular docking demonstrated that both compounds could identify the active site of their target enzymes and develop effective binding interactions. Absorption, distribution, metabolism and elimination (ADME) and drug-likeness predictions of both compounds showed that they both have good ADME profiles and no structural alerts that might cause toxicity. Based on this, 6 and 7b could serve as lead compounds for the design of more potent antibacterial and anticancer agents.

Alpha-glucosidase activity of phytochemicals from Phyllanthus amarus leaves via in-silico approaches

Diabetes mellitus is a metabolic disease that poses a serious global health challenge. The provision of alternative and complementary medicine to combat the disease has attracted the attention of numerous scientists. In this study, anti- α-glucosidase activities of selected seven compounds obtained from Phyllanthus amarus leaves were explored using computational chemistry approach. The absorption, distribution, metabolism and excretion (ADME) properties of the compound with the best binding affinity and metformin were examined. The descriptors obtained from the optimized compounds accurately describe anti- α-glucosidase activities of the studied compounds. The results showed that Compound 1[(1S,19R,21S,22R,23R)-6,7,8,11,12,13,22,23-octahydroxy-3,16-dioxo-2,17,20-trioxatetracyclo[17.3.1.04,9.010,15] tricosa-4,6,8,10,12,14-hexaen-21-yl] 3,4,5-trihydroxybenzoate possesses greater capacity to inhibit α-glucosidase than other studied compounds selected from Phyllanthus amarus leaves as well as Metformin.

Synthesis, Hirshfeld surface analysis, spectral investigations, DFT calculations, ADME studies and molecular docking of Hexahydropyrimidines derivative against dimeric Apolipoprotein A-IV

On Ethyl 6-(4-chlorophenyl)-4-hydroxy-2-oxo-4-(trifluoromethyl)hexahydropyrimidine-5-carboxylate (ECHFPC), X-ray crystallographic, FT-IR, DFT, MEP, UV-Vis, Molecular docking studies and ADME properties are conducted. From X-ray diffraction studies it shows that the structure belongs to a monoclinic system with space group P21/c. The molecular surface and hydrogen bonding interactions in the ECHFPC crystal structure were found and studied using a 2D fingerprint plot and Hirshfeld Surfaces. The calculated optimized geometry of the ECHFPC molecule is determined using DFT–B3LYP calculations with the 6-31++G (d, p) basis set and the experimental bond length and bond angles are compared. Molecular Electrostatic Potential (MEP) aids in the optimization of protein-ligand electrostatic interactions. The measured vibrational frequencies of the FT-IR spectrum are compared with experimental values and it shows good agreement. The small molecule (ECHFPC) docking experiments with the target protein revealed that it is a good molecule that docks well with dimeric Apolipoprotein A-IV protein. The comparison of ECHFPC with Statin drugs available in the market with dimeric Apolipoprotein A-IV (PDB ID: 3S84) was also discussed. The online server preADMET was used to measure the absorption, distribution, metabolism and excretion (ADME) properties.

Synthesis and evaluation of 2-aryl-1H-benzo[d]imidazole derivatives as potential microtubule targeting agents.

Microtubule targeting agents (MTAs) are the potential drug candidates for anticancer drug discovery. Disrupting the microtubule formation or inhibiting the de-polymerization process by a synthetic molecule can lead to an excellent anticancer drug candidate. Here, we present the 2,5-substituted-1H-benzo[d]imidazole derivatives as potential colchicine, nocodazole binding site targeting agents. About 20 benzimidazole derivatives were synthesized with 82.0%-94.0% yield using mild reaction conditions. The synthesized compounds showed moderate to excellent anticancer activity established in three cell lines, including Hela cells, A549 cells, MRC-5 cells. The compounds B15, B16, B19, and B20 are the potential candidates with the IC50 values <15 μM in the three different cell lines. In MTT assay, compounds B15, B16, B19, and B20 showed excellent antiproliferation activity indicated by IC50 values in the range of 5.3 ± 0.21 to 18.1 ± 0.32 μM using HeLa and A549 cell lines. The predicted absorption, distribution, metabolism and excretion (ADME) properties and drug-likeness properties of B15, B16, B19, and B20 indicate that these compounds can be used as lead compounds for further study to develop excellent MTAs.

In silico profiling of histone deacetylase inhibitory activity of compounds isolated from Cajanus cajan

BackgroundCancer is responsible for high morbidity and mortality globally. Because the overexpression of histone deacetylases (HDACs) is one of the molecular mechanisms associated with the development and progression of some diseases such as cancer, studies are now considering inhibition of HDAC as a strategy for the treatment of cancer. In this study, a receptor-based in silico screening was exploited to identify potential HDAC inhibitors among the compounds isolated from Cajanus cajan, since reports have earlier confirmed the antiproliferative properties of compounds isolated from this plant.ResultsCajanus cajan-derived phytochemicals were docked with selected HDACs, with givinostat as the reference HDAC inhibitor, using AutodockVina and Discovery Studio Visualizer, BIOVIA, 2020. Furthermore, absorption, distribution, metabolism and excretion (ADME) drug-likeness analysis was done using the Swiss online ADME web tool. From the results obtained, 4 compounds; betulinic acid, genistin, orientin and vitexin, were identified as potential inhibitors of the selected HDACs, while only 3 compounds (betulinic acid, genistin and vitexin) passed the filter of drug-likeness. The molecular dynamic result revealed the best level of flexibility on HDAC1 and HDAC3 compared to the wild-type HDACs and moderate flexibility of HDAC7 and HDAC8.ConclusionsThe results of molecular docking, pharmacokinetics and molecular dynamics revealed that betulinic acid might be a suitable HDAC inhibitor worthy of further investigation in order to be used for regulating conditions associated with overexpression of HDACs. This knowledge can be used to guide experimental investigation on Cajanus cajan-derived compounds as potential HDAC inhibitors.

Analysis of the active components and mechanism of Shufeng Jiedu capsule against COVID-19 based on network pharmacology and molecular docking.

This study investigates the active components and mechanism of Shufeng Jiedu Capsules (SFJDC) against novel coronavirus through network pharmacology and molecular docking.The TCMSP, TCMID, and BATMAN-TCM databases were used to retrieve the components of SFJDC. The active components were screened by ADME (absorption, distribution, metabolism, and excretion) parameters, and identified by Pubchem, Chemical Book, and ChemDraw softwares. The molecular docking ligands were constructed. SARS Coronavirus-2 Major Protease (SARS-CoV-2-Mpro) and angiotension converting enzyme 2 (ACE2) were used as molecular docking receptors. AutoDock software was used for molecular docking. Cytoscape 3.7.1 software was used to generate an herbs-active components-targets network. Gene Ontology gene function and Kyoto Encyclopedia of Genes and Genomes signal pathway analysis were performed by DAVID data.A total of 1244 components were identified from SFJDC, and 210 active components were obtained. Among them, 97 active components were used as docking ligands to dock with SARS-CoV-2-Mpro and ACE2. There were 48 components with good binding activity to SARS-CoV-2-Mpro. Ten active components (including 7-Acetoxy-2-methylisoflavone, Kaempferol, Quercetin, Baicalein, Glabrene, Glucobrassicin, Isoglycyrol, Wogonin, Petunidin, and Luteolin) combined with SARS-CoV-2-Mpro and ACE2 simultaneously. Among them, Kaempferol, Wogonin, and Baicalein showed higher binding activity. The herbs-active components-targets network contained 7 herbs, 10 active components, and 225 targets. The 225 target targets were involved in 653 biological processes of Gene Ontology analysis and 130 signal pathways (false discovery rate ≤ 0.01) of Kyoto Encyclopedia of Genes and Genomes analysis.The active components of SFJDC (such as Kaempferol, Wogonin, and Baicalein) may combine with ACE2 and act on multiple signaling pathways and targets to exert therapeutic effect on novel coronavirus.

Perspectives on the evaluation and adoption of complex in vitro models in drug development: Workshop with the FDA and the pharmaceutical industry (IQ MPS Affiliate).

Complex in vitro models (CIVM) offer the potential to improve pharmaceutical clinical drug attrition due to safety and/ or efficacy concerns. For this technology to have an impact, the establishment of robust characterization and qualifi­cation plans constructed around specific contexts of use (COU) is required. This article covers the output from a workshop between the Food and Drug Administration (FDA) and Innovation and Quality Microphysiological Systems (IQ MPS) Affiliate. The intent of the workshop was to understand how CIVM technologies are currently being applied by pharma­ceutical companies during drug development and are being tested at the FDA through various case studies in order to identify hurdles (real or perceived) to the adoption of microphysiological systems (MPS) technologies, and to address evaluation/qualification pathways for these technologies. Output from the workshop includes the alignment on a working definition of MPS, a detailed description of the eleven CIVM case studies presented at the workshop, in-depth analysis, and key take aways from breakout sessions on ADME (absorption, distribution, metabolism, and excretion), pharmacology, and safety that covered topics such as qualification and performance criteria, species differences and concordance, and how industry can overcome barriers to regulatory submission of CIVM data. In conclusion, IQ MPS Affiliate and FDA scientists were able to build a general consensus on the need for animal CIVMs for preclinical species to better determine species concordance. Furthermore, there was acceptance that CIVM technologies for use in ADME, pharmacology and safety assessment will require qualification, which will vary depending on the specific COU.

Targeting mucormycosis polyprotein (RVT_1 region) through antifungal phytochemicals: An in-silico perspective

Mucormycosis has become a global issue due to its potential to infect and destroy organs, as well as its high fatality rate. Co-infecting with Covid 19 or when infecting after Covid 19, it becomes more lethal. Several antifungal medicines have been utilized to treat this illness, but they come with a slew of dangerous side effects. Hence, using various computational tools; the current study was attempted to determine several antifungal plant metabolites that can act as inhibitory agents of Rhizopus oryzae, which is responsible for 70% of mucormycosis cases. In total, 56 antifungal plant metabolites were evaluated against Rhizopus oryzae polyprotein (RVT_1 region). Four metabolites, i.e., emetine, jatrorrhizine, isoboldine, and 6-a-hydroxymedicarpin showed maximum binding affinity with the targeted polyprotein (RVT_1 region) according to the lowest global binding energy and binding energy. The fungal protein's critical binding sites and drug surface hotspots were uncovered. The best candidates were gone through an ADME (absorption, distribution, metabolism, and excretion) analysis to observe their drug profiles. According to the findings, none have any side effects that could interfere with their drug likeness efficiency as well as no significant toxic effects and allergenicity were found. The majority of the target classes for proposed drug candidates were enzyme groups (e.g., oxidoreductase, family a g protein-coupled receptor, enzyme, protease). Furthermore, emetine and jatrorrhizine have been proposed to have inhibitory potency against covid 19 in several studies. Hence, we strongly propose additional in vivo trials in order to experimentally validate our findings, based on the optimistic results.

Novel one-pot synthesis of a library of 2-aryloxy-1,4-naphthoquinone derivatives. Determination of antifungal and antibacterial activity.

The development of new antibiotics and inexpensive antifungals is an important field of research. Based on the privileged pharmacophore of lawsone, a series of phenolic ether derivatives of 1,4-naphthoquinone were synthesized easily in one step in reasonable yields. All the new compounds were characterized and tested as potential antifungal and antibacterial agents against Candida albicans, Escherichia coli and Staphylococcus aureus. Compound 55 has significant antibacterial action (as good as or better than the controls) against E. coli and S. aureus. Against C. albicans, compounds 38, 46, 47 and 60 were the best candidates as antifungals. Using a qualitative structure–activity analysis, a correlation between molar mass and antimicrobial activity was identified, regardless of the substituent group on the phenolic moiety, except for 55 and 63, where electronic effects seem more important. An in silico evaluation of the absorption, distribution, metabolism and excretion (ADME) for 37, 50, 55 and 63 was made, indicating that the classic Lipinski's rule of five applies in all cases.

In Silico Docking of Rhodanine Derivatives and 3D-QSAR Study to Identify Potent Prostate Cancer Inhibitors

The 3VHE protein is considered as a potential target for the treatment of prostate cancer. In order to find new 3VHE inhibitors, pharmacophore models based on the molecular structure of rhodanine derivatives and a three-dimensional quantitative structure-activity relationship model (3D-QSAR) have been developed and validated by different methods. The 3D-QSAR model was evaluated for its predictive performance on a diverse test set containing 18 prostate cancer inhibitors. It presents very interesting internal and external statistical validation parameters (SD = 0.081; R2 = 0.903; Q2 = 0.869; ; F = 247.2). This result suggests that the 3D-QSAR combinatorial model can be used to search for new 3VHE inhibitors and predict their potential activity. Based on the combinatorial pharmacophore model, a virtual screening of the Enamine database was performed. Compounds selected after virtual screening were subjected to molecular docking protocols (HTVS, SP, XP and IFD). Twenty new active compounds have been identified and their absorption, distribution, metabolism and excretion (ADME) property calculated using Schr?dinger’s Qikprop module. These results suggest that these new compounds could constitute new chemical starting points for further structural optimization of 3VHE inhibitors.

Integration of Engineered Delivery with the Pharmacokinetics of Medical Candidates via Physiology-Based Pharmacokinetics.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic computational model that can be used to predict a drug product's ADME (absorption, distribution, metabolism, and excretion) and pharmacokinetics (PK). In recent years, PBPK modeling and simulation has been used increasingly to address many biopharmaceutics and clinical pharmacology questions, such as the effect of formulations, intrinsic factors (age, organ dysfunction, etc.), and extrinsic factors (comedications, food) on the PK of an investigational drug product. In this chapter, we will briefly introduce various PBPK models for ADME prediction and general procedures for PBPK modeling and simulations. The readers are encouraged to read updated literature on new applications of PBPK modeling and simulation which is still an emerging area in pharmaceutical development.

Development and Application of DropletProbe Mass Spectrometry for Examining Biodistribution of Therapeutics.

dropletProbe mass spectrometry is a novel technique for molecular characterization of surfaces. It can be used for rapid ex vivo analysis of therapeutics from thin animal tissue sections and has been shown to improve understanding of a drug's absorption, distribution, metabolism and excretion (ADME) properties. Here, we describe the tissue distribution analysis of diclofenac from a dosed whole-body mouse thin tissue section using a dropletProbe mass spectrometry system.

In Silico Prediction and Bioactivity Evaluation of Chemical Ingredients Against Influenza A Virus From Isatis tinctoria L.

Influenza A virus (IAV) is one of the major causes of seasonal endemic diseases and unpredictable periodic pandemics. Due to the high mutation rate and drug resistance, it poses a persistent threat and challenge to public health. Isatis tinctoria L. (Banlangen, BLG), a traditional herbal medicine widely used in Asian countries, has been reported to possess strong efficacy on respiratory viruses, including IAV. However, its effective anti-IAV components and the mechanism of actions (MOAs) are not yet fully elucidated. In this study, we first summarized the chemical components and corresponding contents in BLG according to current available chemical analysis literature. We then presented a network-based in silico framework for identifying potential drug candidates against IAV from BLG. A total of 269 components in BLG were initially screened by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) evaluation. Thereafter, network predictive models were built via the integration of compound–target networks and influenza virus–host proteins. We highlighted 23 compounds that possessed high potential as anti-influenza virus agents. Through experimental evaluation, six compounds, namely, eupatorin, dinatin, linarin, tryptanthrin, indirubin, and acacetin, exhibited good inhibitory activity against wild-type H1N1 and H3N2. Particularly, they also exerted significant effects on drug-resistant strains. Finally, we explored the anti-IAV MOAs of BLG and showcased the potential biological pathways by systems pharmacology analysis. In conclusion, this work provides important information on BLG regarding its use in the development of anti-IAV drugs, and the network-based prediction framework proposed here also offers a powerfulful strategy for the in silico identification of novel drug candidates from complex components of herbal medicine.

Determination of Chemical Composition, In Vitro and In Silico Evaluation of Essential Oil from Leaves of Apium graveolens Grown in Saudi Arabia.

The aim of this study was to explore the composition and evaluate the in silico and in vitro antioxidants and antimicrobial and anti-inflammatory effects of Apium graveolens var. dulce leaves essential oil (AGO) collected from Al-Kharj (Saudi Arabia). AGO was isolated using the hydro-distillation method, and its composition was studied using gas-chromatography-mass Spectrometry (GC–MS), antimicrobial activities using well diffusion assay, and antioxidant and anti-inflammatory activities using spectrophotometric methods. The pharmacological activities of their major compounds were predicted using PASS (prediction of activity spectra for substances) and drug-likening properties by ADME (absorption, distribution, metabolism, and excretion) through web-based online tools. Isocnidilide (40.1%) was identified as the major constituent of AGO along with β-Selinene, Senkyunolide A, Phytyl acetate, and 3-Butylphthalide. AGO exhibited a superior antibacterial activity, and the strongest activity was detected against Gram-positive bacteria and Candida albicans. Additionally, it exhibited a weaker antioxidant potential and stronger anti-inflammatory effects. PASS prediction supported the pharmacological finding, whereas ADMET revealed the safety of AGO. The molecular docking of isocnidilide was carried out for antibacterial (DNA gyrase), antioxidant (tyrosinase), and anti-inflammatory (cyclooxygenase-2) activities. The docking simulation results were involved hydrophilic interactions and demonstrated high binding affinity of isocnidilide for anti-inflammatory protein (cycloxygenase-2). The presence of isocnidilide makes AGO a potential anti-inflammatory and antimicrobial agent. AGO, and its major metabolite isocnidilide, may be a suitable candidate for the future drug development.

Safety of iron hydroxide adipate tartrate as a novel food pursuant to Regulation (EU) 2015/2283 and as a source of iron in the context of Directive 2002/46/EC.

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on iron hydroxide adipate tartrate as a novel food (NF) pursuant to Regulation (EU) 2015/2283 and as a source of iron in the context of Directive 2002/46/EC. The NF is intended to be used in food supplements up to a maximum dose of 100 mg per day, corresponding to a maximum daily intake of iron of 36 mg. The target population proposed by the applicant is the general population above 3 years of age. The NF which is the subject of the application is an engineered nanomaterial having primary particles, of almost spherical morphology, with a diameter typically smaller than 5 nm. The studies provided for absorption, distribution, metabolism and excretion (ADME) and bioavailability indicate that iron, once taken up into the epithelial cells of the gut, is subject to the same mechanisms of regulation and absorption as that of other forms of iron. Further studies provided in the context of the toxicological assessment indicate that the NF does not lead to iron bioaccumulation in tissues and organs at the doses tested. The Panel notes that the NF contains nickel at concentrations that may increase the risk of flare‐up reactions in nickel‐sensitised young individuals up to 10 years of age. In the 90‐day toxicity study, findings related to haematology, clinical biochemistry and organ weights were observed and the Panel defined a no observed adverse effect level (NOAEL) of 231 mg/kg body weight (bw) per day, that is, the mid‐dose used in the study. The Panel considers that the NF is a source from which iron is bioavailable and it is safe under the proposed conditions of use.

A New Series of Triazolothiadiazines as Potential Anticancer Agents for Targeted Therapy of Non-Small Cell Lung and Colorectal Cancers: Design, Synthesis, In silico and In vitro Studies Providing Mechanistic Insight into Their Anticancer Potencies.

Targeted therapies acting on specific molecular targets in cancer cells with better curative efficacy and lower toxicity have come into prominence for the management of nonsmall cell lung cancer (NSCLC) and colorectal cancer (CRC). COX-2 stands out as a plausible target for anticancer agents due to its pivotal role in tumor initiation, progression and invasion. Due to the importance of triazolothiadiazine scaffold in targeted anticancer drug discovery, the aim of this work is the design of new triazolothiadiazines as potential anticancer agents for the targeted therapy of NSCLC and CRC. New triazolo[3,4-b]-1,3,4-thiadiazines (2a-g) were synthesized via the ring closure reactions of 2-bromo-1-arylethanones with 4-amino-5-((5-methoxy-2-methyl-1H-indol-3-yl)methyl)-2,4- dihydro-3H-1,2,4-triazole-3-thione (1), which was obtained via the solvent-free reaction of 5- methoxy-2-methyl-3-indoleacetic acid with thiocarbohydrazide. MTT assay was performed to determine their cytotoxic effects on A549 human lung adenocarcinoma, Caco-2 human colorectal adenocarcinoma and CCD-19Lu human lung fibroblast cells. The most potent compounds were evaluated for their effects on apoptosis, caspase-3, mitochondrial membrane potential, cell cycle, ultrastructural morphological changes and COX-2 in A549 and Caco-2 cells. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger's Maestro molecular modeling package. 6-(4-Chlorophenyl)-3-[(5-methoxy-2-methyl-1H-indol-3-yl)methyl]-7H-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazine (2e) was the most potent and selective anticancer agent in this series against A549 and Caco-2 cell lines. Compound 2e induced early apoptosis, caused mitochondrial membrane depolarization and arrested cell cycle at G0/G1 phase in A549 cells. On the other hand, compound 2e triggered intrinsic apoptotic pathway involving caspase-3 activation in Caco-2 cells. Compound 2e caused apoptotic morphological changes in both cancer cell lines. The cytotoxic and apoptotic effects of this compound on CRC were found to be related to its selective COX-2 inhibitory activity. According to molecular docking studies, compound 2e showed good affinity to the active site of COX-2 (PDB code: 4COX). Based on in silico ADME studies, the compound is predicted to possess a favorable ADME profile. According to in vitro and in silico studies, compound 2e was identified as a potential orally bioavailable anticancer agent for COX-2-targeted therapy of CRC.

Glutamine conjugated organotin(IV) Schiff base compounds: Synthesis, structure, and anticancer properties

AbstractHerein, glutamine conjugated organotin(IV) Schiff base compounds, [(SBGlu‐Naph)Sn (Me)2] (1), [(SBGlu‐Naph)Sn(n‐Bu)2] (2), [(SBGlu‐Sali)Sn (Me)2] (3), [(SBGlu‐Sali)Sn(n‐Bu)2] (4) and [(SBGlu‐Sali)Sn (Ph)2] (5), were synthesized by one‐pot reaction with an aldehyde (2‐hydroxy‐1‐naphthaldehyde) for 1 and 2, and 5‐methyl‐2‐hydroxybenzaldehyde (for 3–5) and respective diorganotin oxide. The compounds were characterized using elemental micro‐analyses, spectroscopic techniques (FT‐IR, 1H NMR, 13C NMR, and 119Sn NMR), mass spectrometry, and single‐crystal X‐ray diffraction analyses. Based on in‐silico ADME (absorption, distribution, metabolism, and excretion) and drug‐likeness properties, compounds 1, 3, and 4 were selected to investigate their DNA/Protein binding properties with calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA) using spectrophotometry and spectrofluorimetry. The intercalative mode of binding with CT‐DNA was supported by molecular docking simulations. The emission spectral data of compounds with CT‐DNA showed 1 as a groove binder, and 3 and 4 as an intercalator which was confirmed by competitive displacement assays. Similarly, static and dynamic mode of interaction between the compounds and BSA was found. Furthermore, these compounds were screened for their cytotoxic activity against two human cancer cell lines; PC‐3 (Prostate) and Mg‐63 (Osteosarcoma) at different concentrations. Quantitative structure–activity relationship (QSAR)‐based regression models were developed and implemented on compounds 1, 3, and 4 that inferred compound 3 to be the most potential candidate for further in vivo studies.

In Silico Analysis of Cissus rotundifolia Constituents as Human Neutrophil Elastase (HNE), Matrix Metalloproteinases (MMP 2 and MMP 9), and Tyrosinase Inhibitors.

Cissus rotundifolia has been reported to possess various biological activities such as anti-diabetic, anti-fertility, anti-hyperlipidemic, anti-malarial, anti-osteoporotic, and anti-parasitic activities. Therefore in the present study, eleven selected constituents of Cissus rotundifolia which includes aconitic acid, astragalin, acteoside, aliospiroside A, beta amyrin, bergenin, formononetin, gallic acid, isovitexin, isoorientin, and isoquercitrin were studied on the docking behavior of human neutrophil elastase (HNE), matrix metalloproteinases (MMP 2 and MMP 9), and tyrosinase by using PatchDock method. Furthermore, molecular physicochemical, bioactivity score/drug-likeness, ADME (absorption, distribution, metabolism, and excretion), and toxicity analyses were also carried out using Molinspiration, Swiss ADME, and ProTox-II methods, respectively. The molecular physicochemical investigation showed that three ligands such as acteoside, aliospiroside A, and isoorientin have three violations for Lipinski’s rule of five. Similarly, ADME analysis one ligand (formononetin) predicated to have high blood-brain barrier (BBB) permeability effect. The docking studies showed that isovitexin exhibited the highest atomic contact energy (−341.61 kcal/mol) for human neutrophil elastase (HNE), more over alliospiroside A has shown maximum atomic contact energy for both matrix metalloproteinases (MMP 2 [−618.00 kcal/mol] and MMP 9 [−634.73 kcal/mol]). Furthermore, isoquercitrin has exhibited the highest atomic contact energy (−145.70 kcal/mol) for tyrosinase. Thus, the present investigation outcome provides new knowledge in understanding eleven Cissus rotundifolia constituents as possible novel inhibitors against HNE, MMP 2, MMP 9, and tyrosinase.