Synthesis, spectroscopic characterization, DFT calculations, in silico-ADMET and molecular docking analysis of novel quinoline-substituted 5H-chromeno [2,3-b] pyridine derivatives as antibacterial agents.

A convenient, straightforward, and effective one-step reaction for the synthesis of a three-component compound of biologically relevant novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno[2,3-b] pyridine-3-carbonitrile derivatives was designed and synthesized. The synthesis was developed by the reaction between salicylaldehyde 1, 8-hydroxyquinoline 2, 2-aminopropene-1,1,3-tricarbonitrile 3, and the catalytic amount of triethylamine in ethanol at 78 °C. This methodology has many beneficial features, including the use of inexpensive and non-hazardous starting materials, single-flask reactions, optimized reaction conditions, the termination of intermediate isolation, easy workup, reducing organic waste products, being chromatography-free, and decreasing the reaction time along with quantitative yields with high functional group tolerance. A proposed mechanism with supporting experimental data is presented, including 1H NMR, 13C NMR, 2D NMR (HMBC, COSY, HSQC), mass, and IR spectroscopy, which are used to characterize the complete derivatives. All synthesized compounds were evaluated in vitro for their antibacterial activities against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa bacterial strains via the agar-well diffusion method compared with the reference drug gentamicin. The data indicated that compounds 4A, 4F, 4G, 4 J, and 4K consistently demonstrated strong antimicrobial activity against Gram-positive and Gram-negative bacteria. Furthermore, a molecular docking investigation was carried out to gain insight into the binding mode of the most promising compounds via the crystal structure of the S. aureus DNA gyrase complex with ciprofloxacin (PDB ID: 2XCT). Density functional theory (DFT) calculations were performed to determine the various molecular properties of the synthesized novel 2,4-diamino-5-(8-hydroxyquinolin-7-yl)-5H-chromeno [2,3-b] pyridine-3-carbonitrile derivatives (4A-4 M). On the basis of the reactive sites explored by the molecular electrostatic potential maps, the antibacterial activities of the compounds were screened.

Novel copper complex inhibits the proteasome in skin squamous cell carcinoma induced by DMBA in mice.

The proteasomal system is becoming a target for the treatment of several diseases, especially in cancer therapy. The present study aims to develop a novel copper complex that inhibits the proteasome in skin squamous cell carcinoma. New molecules based on the copper complex were synthesized for the first time to assess their potential as proteasome inhibitors, specifically targeting squamous cell carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in mouse models. Fourier Transform Infrared (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), nuclear magnetic resonance (NMR), and energy dispersive X-ray analysis (EDX) were carried out to characterize this new copper complex. Notably, the presence of a papilloma (skin tumor) was confirmed by histopathological analysis. Subsequent investigation included the quantification of proteasome levels using a sandwich ELISA test, and the catalytic activity of the 20S proteasome was determined by measuring the fluorescence emitted after the cleavage of 7-amino-4-methylcoumarin (AMC). Hence, X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration and biological activity of copper Schiff base complex, which exhibits high proteasome inhibitory activities with particular selectivity of ß5 subunit. The pharmacokinetic properties (ADMET) of the copper complex named Cu(L1) showed encouraging results with very low toxicity, distribution, and absorption. Structure-activity relationship (SAR) information obtained from Cu(L1) demonstrated its selectivity and potent inhibition for ß5 subunit. In this regard, this copper complex has emerged as a novel therapy for skin cancer.

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates.

Objective: Biological studies have elucidated that phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the serine synthesis pathway in humans that is abnormally expressed in numerous cancers. Inhibition of the PHGDH activity is thought to be an attractive approach for novel anti-cancer therapy. The development of structurally diverse novel PHGDH inhibitors with high efficiency and low toxicity is a promising drug discovery strategy. Methods: A ligand-based 3D-QSAR pharmacophore model was developed using the HypoGen algorithm methodology of Discovery Studio. The selected pharmacophore model was further validated by test set validation, cost analysis, and Fischer randomization validation and was then used as a 3D query to screen compound libraries with various chemical scaffolds. The estimated activity, drug-likeness, molecular docking, growing scaffold, and molecular dynamics simulation processes were applied in combination to reduce the number of virtual hits. Results: The potential candidates against PHGDH were screened based on estimated activity, docking scores, predictive absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, and molecular dynamics simulation. Conclusion: Finally, an all-in-one combination was employed successfully to design and develop three potential anti-cancer candidates.

Computational identification and analysis of CNP0269688 as a natural product inhibitor disrupting the interaction between the HIV matrix domain and tRNA.

Our research is dedicated to combating HIV by targeting its Matrix (MA) domain, which is crucial for viral assembly and replication. This strategy specifically aims to interrupt early-stage infection and deter drug resistance by focusing on this essential domain. Due to the MA domain's conservation across different HIV strains, our approach promises broad-spectrum efficacy, which is particularly crucial in regions marked by significant genetic diversity and resistance issues. In our study, we introduce CNP0269688, a natural product that exhibits high affinity for the HIV-1 Matrix. Through detailed molecular dynamics simulations, we have assessed the compound's structural stability and interaction dynamics, particularly its potential to hinder Protein-tRNA interactions. This analysis lays the groundwork for future experimental investigations. Our efforts are steps toward enhancing HIV treatment, reducing viral transmission, and curbing drug resistance, with the ultimate aim of controlling and eradicating the pandemic, thereby contributing significantly to public health and scientific advancement.

The potential of Mitragyna speciosa leaves as a natural source of antioxidants for disease prevention.

Mitragyna speciosa is famous for its addictive effect. On the other hand, this plant has good potential as an antioxidant agent, and so far, it was not explicitly explained what the most contributing compound in the leaves to that activity is. This study has been conducted using several computational methods to determine which compounds are the most active in interacting with cytochrome P450, myeloperoxidase, and NADPH oxidase proteins. First, virtual screening was carried out based on molecular docking, followed by profiling the properties of adsorption, distribution, metabolism, excretion, and toxicity (ADMET); the second one is the molecular dynamics (MD) simulations for 100 ns. The virtual screening results showed that three compounds acted as inhibitors for each protein: (-)-epicatechin, sitogluside, and corynoxeine. The ADMET profiles of the three compounds exhibit good drug ability and toxicity. The trajectories study from MD simulations predicts that the complexes of these three compounds with their respective target proteins are stable. Furthermore, these compounds identified in this computational study can be a potential guide for future experiments aimed at assessing the antioxidant properties through in vitro testing.

Computational Exploration of Isatin Derivatives for InhA Inhibition in Tuberculosis: Molecular Docking, MD Simulations and ADMET Insights.

BACKGROUND: Anti-tubercular drug discovery is a critical research area aimed at addressing the global health burden imposed by Mycobacterium tuberculosis. Nowadays, computational techniques have increased the likelihood of drug development compared to traditional, labor-intensive, and time-consuming drug design approaches. The pivotal goal of drug design is to identify compounds capable of selectively targeting protein, thereby disrupting its enzymatic activity. InhA, or NADH-dependent enoyl-acyl carrier protein reductase, stands at the forefront of targeted approaches in the battle against TB. Isatin derivatives have garnered interest for their diverse pharmacological activities. OBJECTIVE: To identify novel isatin derivatives that could serve as potential chemical templates for anti-TB drug discovery by targeting InhA. METHODS: The present work utilized various computational approaches, including molecular docking, binding free energy calculations, and conformational alignment studies to investigate the binding mode and interactions of carefully selected dataset of 88 isatin derivatives within InhA active site. Study also employed MD simulations of the most promising molecule to check the stability of the protein-ligand complex and in-silico ADMET profiling of the top compounds to predict their pharmacokinetic and toxicity properties. RESULTS: Results provided insights into the structural features contributing to InhA inhibition, assessing overall drug-like characteristics of isatin derivatives and identified compound 48 (BA= -10.4 kcal mol-1 ) with potential for further optimization. MD simulation analysis revealed that compound 48 binds firmly within the InhA protein, exhibiting minimal conformational fluctuations and enhanced stability. CONCLUSION: Considering the aforementioned, isatin derivatives represents a novel framework for creating targeted InhA inhibitors during anti-TB therapy. However, experimental validations and in-depth analyses are crucial to confirm efficacy and safety of these derivatives as potential InhA inhibitors for TB treatment.

Discovery of Arylpiperazines with Broad-Spectrum Antimicrobial Activity and Favorable Pharmacokinetic Profiles.

Microorganisms can induce diseases with significant clinical implications for human health. Multidrug-resistant microorganisms have been on the rise worldwide over the past few decades, and no new antibiotics have been introduced to the market in a considerable amount of time. Such situation highlights the urgency of discovering new antimicrobial drugs to address this pressing issue. Therefore, the objective of this study was to identify bioactive compounds against 15 species of bacteria and 5 species of fungi of clinical relevance through in vitro screening of 58 synthetic compounds from four chemical classes of our internal library of synthetic compounds. Our findings highlight arylpiperazines 18, 20, 26, 27, and 29, and the aminothiazole 50, as potent broad-spectrum antimicrobials (MICs = 12.5 - 15.6 mg.mL-1) against clinically relevant bacteria and fungi. Additionally, these compounds displayed low cytotoxicity against various host cells and a favorable in vitro pharmacokinetic profile for oral administration. Indeed, all six showed adequate lipophilicity, high gastrointestinal permeability, metabolic stability in human and mouse liver microsomes, and satisfactory aqueous solubility. Thus, they emerge as promising starting points for hit-to-lead studies towards new antibacterial and antifungal agents, especially against Staphylococcus epidermidis, Staphylococcus aureus, Lactobacillus paracasei and Candida orthopsilosis.

Novel sulfonylamido benzoxazole derivatives: synthesis, characterisation, molecular docking, DFT, and antimicrobial activity investigations.

In this work, numerous novel 2-(p-substitutedphenyl)-5-[(p-substitutedphenyl)sulfonylamido]benzoxazole derivatives were designed, synthesized, and structurally characterized using mass spectroscopy, 1H-NMR, 13C-NMR, and elemental analysis approaches. The antimicrobial activity against several Gram (+), Gram (-), and fungal species was determined using the in vitro microdilution technique. A molecular docking analysis was performed on all produced compounds utilizing the S. aureus Gyrase complex with Ciprofloxacin and DNA. Two of the most effective compounds against S. aureus, N4 and N9, have binding energies of -8.7 kcal/mol and -8.6 kcal/mol, respectively, and their interactions have been demonstrated in 2D and 3D. Furthermore, utilizing the 6-311G(d,p) base set and DFT/B3LYP theory, MEP analysis, geometric optimization, and molecular reactivity analysis (HOMO-LUMO) of N4 and N9 were performed, and the results were presented. All compounds' theoretical ADMET profiles were computed as well, and they met Lipinski and other strict criteria. With all of this knowledge, this study could be a pioneer in the development of novel anti-S. aureus compounds.

Ergostanes from the mushroom Trametes versicolor and their cancer cell inhibition: In vitro and in silico evaluation.

In this study, five steroid compounds were isolated from the fruiting bodies mushroom Trametes versicolor. The compounds, 9,19-cyclolanostane-3,29-diol (3), ergosta-7,22-dien-3-acetate (4), and ergosta-8(14),22-dien-3ß,5α,6ß,7α-tetrol (5), were identified from T. versicolor for the first time. The five compounds were evaluated for their activity against cancer cell lines. Compound 5α,8α-epidioxyergosta-6,22-dien-3ß-ol (1) was found to be the most effective against most of the cancer cell lines tested. In silico studies showed that compound 1 has good binding affinities to different cancer targets, namely cyclin-dependent kinase 2 (cdk2), human cyclin-dependent kinase 6 (cdk6), Human Topo IIa ATPase/AMP-PNP, anti-apoptotic protein Bcl-2, and Vegfr-2. It's also druglike based on Lipinski's rule of five and it's ADME/Tox properties. Therefore, compound 1 is a good candidate in the management of cancer. These results further show that T. versicolor is a potential source of drugs or drug leads for cancer treatment.

Utilizing mechatronic agilent gas chromatography to validate therapeutic efficacy of Combretum paniculatum against oxidative stress and inflammation.

The quest for novel antioxidant and anti-inflammatory medications from medicinal plants is crucial since the plants contain bioactive compounds with a better efficacy and safety profile than orthodox therapy. This study harnesses the capabilities of mechatronics-driven Agilent Gas Chromatography, deploying in vitro, in vivo, and in silico models to unravel the antioxidant and anti-inflammatory attributes within Combretum paniculatum ethanol extract (CPEE). Employing gas chromatography-mass spectroscopy (GC-MS), our analysis efficiently segregates and evaluates volatile compound mixtures, a technique renowned for identifying organic compounds, as exemplified by its success in detecting fatty acids in food and resin acids in water. Using gas chromatography-mass spectrometry (GC-MS) and GC-FID analyses, this paper ascertains the comprehensive phytochemical composition of CPEE. Also, Molecular interactions of identified compounds with cyclooxygenase (COX-2) implicated in inflammatory urpsurge is verified. GC-MS and GC-FID analyses unveil 41 phytoconstituents within CPEE. Based on the in vitro research, CPEE demonstrated potential in inhibiting thiobarbituric acid-reactive substances, nitric oxide, and phospholipase lipase A2 with inhibition rates of 2.284, 6.547, and 66.8 µg/mL respectively. In vivo experiments confirm CPEE's efficacy in inhibiting granuloma tissue formation, lipid peroxidation, and neutrophil counts compared to untreated rats. Moreover, CPEE elicited a significant (P < 0.05) increase in the activities of SOD, CAT, and GSH concentrations while decreasing C-reactive protein, signifying promising therapeutic potential. Highlighting interactions between top-scoring phytoligands (epicatechin, catechin, and kaempferol) and COX-2, the findings underscore their drug-like characteristics, favorable pharmacokinetics, and enhanced safety toxicity profiles. Results from in vitro, in vivo, and in silico studies, highlights CPEE remarkable antioxidant and anti-inflammatory potentials.

In silico fragment-based design and pharmacophore modelling of therapeutics against dengue virus envelope protein.

Dengue virus, an arbovirus of genus Flavivirus, is an infectious disease causing organisms in the tropical environment leading to numerous deaths every year. No therapeutic is available against the virus till date with only symptomatic relief available. Here, we have tried to design therapeutic compounds from scratch by fragment based method followed by pharmacophore based modelling to find suitable similar structure molecules and validated the same by MD simulation, followed by binding energy calculations and ADMET analysis. The receptor binding region of the dengue envelope protein was considered as the target for prevention of viral host cell entry and thus infection. This resulted in the final selection of kanamycin as a stable binding molecule against the Dengue virus envelope protein receptor binding domain. This study results in selection of a single molecule having high binding energy and prominent stable interactions as determined by post simulation analyses. This study aims to provide a direction for development of small molecule therapeutics against the dengue virus in order to control infection. This study may open a new avenue in the arena of structure based and fragment based therapeutic design to obtain novel molecules with therapeutic potential. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00262-9.

Exploration of 1,3,5-trisubstituted pyrazoline derivatives as human carbonic anhydrase inhibitors: Synthesis, biological evaluation and in silico studies.

The human carbonic anhydrase (hCA) IX and XII isoforms are overexpressed in hypoxic conditions, contributing to cancer. Lack of isoform selectivity has been one of the main challenges associated with the existing drugs targeting hCAs. Hence, the development of alternative approaches, such as tail approach to develop more selective hCA IX and XII inhibitors is need of the hour. In the present work, we designed and synthesized 24 new 1,3.5-trisubstituted-pyrazoline derivatives with diverse substitutions. The synthesized analogs were evaluated for their hCA inhibitory activities against hCA I, II, IX, and XII isoforms. Among the tested compounds, derivative 8 displayed good inhibitory activity against hCA IX (Ki = 331 nM) and XII (Ki = 96.7 nM). In addition, 9a-g also exhibited some inhibitory activities against hCA IX and XII, with Kis ranging from 574 to 799 nM and 137-369 nM, respectively. Molecular modelling studies of compound 8 displayed metal coordination with zinc ion and hydrophobic, hydrophilic interactions with adjacent amino acid residues, and maintained stable interactions throughout 100 ns. In addition, ADMET studies demonstrated that compound 8 obeyed the Lipinski's rule of five and was found to be druggable and non-toxic. Hence, compound 8 was identified as potential lead for further development.

Design, synthesis, in-vitro, in-silico, DFT and POM studies of a novel family of sulfonamides as potent anti-triple-negative breast cancer agents.

In this study, a new family of ethacrynic acid-sulfonamides and indazole-sulfonamides was synthesized and tested in vitro against MDA-MB-468 triple-negative breast cancer cells and PBMCs human peripheral blood mononuclear cells, using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay. The aim of this research is to discover novel compounds with potential therapeutic effects on breast cancer. The antiproliferative activity of these compounds showed a significant dose-dependent activity, with IC50 values ranging between 2.83 and 7.52 µM. The lead compounds 8 and 9 displayed similar IC50 values to paclitaxel with 2.83, 3.84 and 2.72 µM, respectively. This highlights the novelty and potential of these compounds as alternatives to current treatments. The binding properties of 8, 9, and paclitaxel with the active sites of the PARP1(Poly(ADP-ribose) polymérase 1) and EGFR (Epidermal growth factor receptor) proteins were analyzed by molecular docking methods showing, for PARP1 protein, binding affinities of -9.8 Kcal /mol, -10 Kcal /mol, and -9.4 Kcal /mol, respectively. While their binding affinities for EGFR protein are -7.5 Kcal/mol, -7.2 Kcal/mol and -6.9 Kcal/mol, respectively. Moreover, drug-likeness and ADMET (Absorption-distribution-metabolism-excretion-toxicity) analyses demonstrated that both molecules are orally bioavailable and have good pharmacokinetic and non-toxic profiles. DFT (Density functional theory) was also carried out on both compounds 8 and 9 additionally to POM (Petra/Osiris/Molinspiration) studies on all compounds. The outcomes of this study suggest that compounds 8 and 9 are promising candidates for further development as therapeutic agents against triple-negative breast cancer.

Molecular interaction analysis of ferulic acid (4-hydroxy-3-methoxycinnamic acid) as main bioactive compound from palm oil waste against MCF-7 receptors: An in silico study.

Ferulic acid (4-hydroxy-3-methoxycinnamic acid) is a phytochemical compound that is commonly found in conjugated forms within mono-, di-, polysaccharides and other organic compounds in cell walls of grain, fruits, and vegetables. This compound is highly abundant in the palm oil waste. The aim of the study was to predict the anticancer activity of ferulic acid against the breast cancer cell lines (MCF-7) receptors through a computational analysis. MCF-7 receptors with PDB IDs of 1R5K, 2IOG, 4IV2, 4IW6, 5DUE, 5T92, and 5U2B were selected based on the Simplified Molecular Input Line Entry System (SMILES) similarity of the native ligand. Thereafter, the protein was prepared on Chimera 1.16 and docked with ferulic acid on Autodock Vina 1.2.5. The ligand-protein complex interaction was validated by computing the root mean square fluctuation (RMSF) and radius of gyration (Rg) through molecular dynamic simulation. In addition, an absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was performed on ferulic acid using the pkCSM platform. The molecular docking revealed that the ferulic acid could interact with all receptors as indicated by the affinity energy <-5 kcal/mol. The compound had the most optimum interaction with receptor 2IOG (affinity energy=-6.96 kcal/mol), involving hydrophobic interaction (n=12) and polar hydrogen interaction (n=4). The molecular dynamic simulation revealed that the complex had an RMSF of 1.713 Å with a fluctuation of Rg value around 1.000 Å. The ADMET properties of ferulic acid suggested that the compound is an ideal drug candidate. In conclusion, this study suggested that ferulic acid, which can be isolated from palm oil waste, has the potential to interact with MCF-7 receptors.

In silico analysis reveals α-amylase inhibitory potential of Taraxerol (Coccinia indica) and Epoxywithanolide-1 (Withania coagulans): a possible way to control postprandial hyperglycemia-induced endothelial dysfunction and cardiovascular events.

Postprandial hyperglycemia (PPG) exacerbates endothelial dysfunction and impairs vascular function in diabetes as well in healthy people. Though synthetic drugs are available to regulate PPG, the severe gastrointestinal side effects of those medications have prompted the search for alternative treatments. Recently, some phytochemicals captured the attention because of their inhibitory effects on α-amylase to control diabetes. The aim of this study was to investigate and identify potential alpha-amylase inhibitors in C. indica and W. coagulans. This study also aims to understand one of the possible mechanisms of action of plants for their anti-diabetic activity. A total of 36 phytochemical ligands were subjected for protein-ligand docking analysis. Among the phytochemicals, Taraxerol and Epoxywithanolide-I demonstrated significant binding free energy of - 10.2 kcal/mol and - 11.9 kcal/mol respectively, which was higher than the reference acarbose with - 8.6 kcal/mol. These molecules were subjected for molecular dynamics simulation (MDS) analysis with alpha-amylase protein for a duration of 150 ns. Among the three complexes, Taraxerol and Epoxywithanolide-I complexes demonstrates strong potential as inhibitors of the target protein. MDS results were analyzed via root mean square deviation (RMSD), fluctuation of residues, potential energy, radii of gyration and solvent access surface area analysis. Taraxerol demonstrated a significantly low potential energy of - 1,924,605.25 kJ/mol, and Epoxywithanolide-I demonstrated - 1,964,113.3 kJ/mol of potential energy. RMSD plot shows that Epoxywithanolide-I has much higher stability than the other MDS complexes. Drugability and toxicity studies show that the test ligands are demonstrating strong potential as drug like molecules. The results of the study conclude that, Taraxerol of C. indica and Epoxywithanolide-I of W. coagulans are strong inhibitors of alpha-amylase enzyme and that, this is one of the possible mechanisms of action of the plants for their reported anti-diabetic activities. Further in-vitro analysis is in demand to prove the observed results.

Discovery of the therapeutic potential of PPARδ agonist bearing 1,3,4- thiadiazole in inflammatory disorders.

As a defense mechanism against deleterious stimuli, inflammation plays a vital role in the development of many disorders, including atherosclerosis, inflammatory bowel disease, experimental autoimmune encephalomyelitis, septic and non-septic shock, and non-alcoholic fatty liver disease (NAFLD). Despite the serious adverse effects of extended usage, traditional anti-inflammatory medications, such as steroidal and non-steroidal anti-inflammatory medicines (NSAIDs), are commonly used for alleviating symptoms of inflammation. The PPARδ subtype of peroxisome proliferator-activated receptors (PPARs) has attracted interest because of its potential for reducing inflammation and related disorders. In this study, a series of 1,3,4-thiadiazole derivatives were designed, synthesized, and evaluated. Compound 11 exhibited potent PPARδ agonistic activity with EC50 values 20 nM and strong selectivity over PPARα and PPARγ. Furthermore, compound 11 demonstrated favorable in vitro and in vivo pharmacokinetic properties. In vivo experiments using labeled macrophages and paw thickness measurements confirmed compound 11's potential to reduce macrophage infiltration and alleviate inflammation. These findings highlight compound 11 as a potent and promising therapeutic candidate for the treatment of acute inflammatory diseases and warrant further investigation to explore various biological roles.

Experimental and computational evaluation of anti-malarial and antioxidant potential of transition metal (II) complexes with tridentate schiff base derived from pyrrolopyrimidine.

In the twenty-first century, we are experiencing persistent waves of diverse pathogen variations, contributing significantly to global illness and death rates. Within this varied spectrum of illnesses, malaria and oxidative damage emerge as prominent obstacles that have persistently affected human health. The motivation for exploring the antioxidant potential of transition metal (II) complexes with tridentate Schiff base ligands is driven by the need for effective treatments against malaria and oxidative stress-related conditions. Both malaria and oxidative damage are significant global health concerns. Transition metal complexes can potentially offer enhanced anti-malarial and antioxidant activities, providing a dual benefit. To explore the aforementioned facts and examine the therapeutic potential, the previously synthesized pyrrolopyrimidinehydrazide-3-chlorobenzaldehyde, such as HPPHmCB ligand(1)andtheirMn(II),Fe(II),Co(II),Ni(II), Pd(II),Cu(II),Zn(II),Cd(II),Hg(II)complexes(2-10) of benzaldehydes and pyrrolopyrimidinehydrazide were proposed for in vitro anti-malarial and antioxidant investigation. These compounds were assessed for their anti-malarial efficacy against Plasmodium falciparum using a micro assay protocol, with IC50 values indicating the concentration required to inhibit parasite maturation by 50%. The Hg(II) complex displays pronounced antimalarial activity with an IC50 value of 1.98 ± 0.08 µM, closely aligning with the efficacy of quinine, whereas Zn(II), Cu(II), Pd(II) complexes demonstrates most significant anti-malarial activity, with IC50 values close to the reference compound quinine. The antioxidant activity of the compounds was evaluated using the DPPH assay, with several metal complexes such as Cu(II)and Zn(II) showing strong potential in neutralizing oxidative stress. Furthermore, molecular docking simulations were conducted to explore the binding interactions of the compounds with PfNDH2, providing insights into their pharmacological potential. The study also examined the electronic properties, solubility, and potential hepatotoxicity of the compounds. The findings suggest that the metal complexes could be promising candidates for further development as anti-malarial agents, offering enhanced potency compared to the base compound.

In-silico evaluation of phytochemicals for vitiligo: ADMET, molecular docking, and MD simulation approaches.

Vitiligo is a prevalent autoimmune disease affecting the quality of life and self-confidence. Total 25 phytochemicals from plants were screened by using four target proteins involved in the pathogenesis of vitiligo. The binding affinity of the ligands ranged between -10.3 and -4.5 kcal/mol. The top 10 phytochemicals i.e. rosmarinic acid, piperine, tamarixetin, desmethoxycurcumin, bisdemethoxycurcumin, isorhamnetin, quercetin, vicenin II, genkwanin, and aloe-emodin showed good inhibition with binding affinity ranged from -10.3 to 9.4 Kcal. The ADMET profiling revealed that these phytochemicals might be safe for the treatment of vitiligo. In MD simulation, rosmarinic acid, piperine, and tamarixetin with MAO-A formed stable complexes and the free binding energies of the complexes were -34.02 ± 6.94, -33.51 ± 2.65, and -27.17 ± 3.28. Furthermore, the ligands formed hydrogen bonds with targets, suggested that rosmarinic acid, piperine, and tamarixetin have potential to serve as lead compounds for developing novel therapeutics for vitiligo after in vitro and in vivo studies.

A comprehensive review on microbial diversity and anticancer compounds derived from seaweed endophytes: a pharmacokinetic and pharmacodynamic approach.

Seaweed endophytes are a rich source of microbial diversity and bioactive compounds. This review provides a comprehensive analysis of the microbial diversity associated with seaweeds and their interaction between them. These diverse bacteria and fungi have distinct metabolic pathways, which result in the synthesis of bioactive compounds with potential applications in a variety of health fields. We examine many types of seaweed-associated microorganisms, their bioactive metabolites, and their potential role in cancer treatment using a comprehensive literature review. By incorporating recent findings, we hope to highlight the importance of seaweed endophytes as a prospective source of novel anticancer drugs and promote additional studies in this area. We also investigate the pharmacokinetic and pharmacodynamic profiles of these bioactive compounds because understanding their absorption, distribution, metabolism, excretion (ADMET), and toxicity profiles is critical for developing bioactive compounds with anticancer potential into effective cancer drugs. This knowledge ensures the safety and efficacy of proposed medications prior to clinical trials. This study not only provides promise for novel and more effective treatments for cancer with fewer side effects, but it also emphasizes the necessity of sustainable harvesting procedures and ethical considerations for protecting the delicate marine ecology during bioprospecting activities.

In silico and in vivo evaluations of multistage antiplasmodial potency and toxicity profiling of n-Hexadecanoic acid derived from Vernonia amygdalina.

Background: Despite the widely reported potentials of n-Hexadecanoic acid (HA) as a bioactive, its multi-stage antiplasmodial activity and toxicity profiles remain largely unknown. Methodology: Thus, this study uses a combination of in silico approaches and in vivo studies to assess the inhibitory activities of HA at different stages of the Plasmodium lifecycle, antiplasmodial performance, and toxicity profiles. The HA was retrieved from the PubChem database, while antiplasmodial target proteins from different stages of the Plasmodium falciparum life cycle were collated from the Protein Databank (PDB). Molecular Docking and Visualization were conducted between the compound and target proteins using AutoVina PyRx software and Biovia Discovery Studio, respectively. Also, the AdmetLab 3.0 algorithm was used to predict the absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of HA. Based on a 4-day suppressive test, the antiplasmodial activity against the Plasmodium berghei ANKA strain in mice was evaluated. Furthermore, subacute toxicity and micronucleus assays were used for further toxicity assessment. Results: The molecular docking analysis indicates multi-stage, multi-target potentials of HA with favourable ligand-receptor complexes across the four Plasmodium falciparum stages. Meanwhile, the mice administered with 100 mg/kg, 50 mg/kg, and 10 mg/kg of HA demonstrated considerable chemosuppression in a dose-dependent manner of 89.74%, 83.80%, and 71.58% percentage chemosuppression, respectively, at p < 0.05. The ADMET prediction, histopathological tests, and micronucleus assays show that HA is safer at a lower dose. Conclusion: This study showed that n-Hexadecanoic acid is a potential drug candidate for malaria. Hence, it is recommended for further molecular and biochemical investigations.