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In this research, we utilized molecular simulations to create co-amorphous materials (CAMs) of ceritinib (CRT) with the objective of improving its solubility and bioavailability. We identified naringin (NRG) as a suitable co-former for CRT CAMs based on binding energy and intermolecular interactions through computational modeling. We used the solvent evaporation method to produce CAMs of CRT and NRG, expecting to enhance both solubility and bioavailability simultaneously. The solid-state characterization using techniques like differential scanning calorimeter, X-ray powder diffraction, and Fourier-transform infrared spectroscopy affirmed the formation of a single amorphous phase and the presence of intermolecular interactions between CRT and NRG in the CAMs. These materials remained physically stable for up to six months under dry conditions at 40 °C. Moreover, the CAMs demonstrated significant improvements in the solubility and dissolution of CRT (specifically in the ratio CRT:NRG 1:2). This, in turn, led to an increase in cytotoxicity, apoptotic cells, and G0/G1 phase inhibition in A549 cells compared to CRT alone. Furthermore, CRT permeability is also improved twofold, as estimated by the everted gut sac method. The enhanced solubility of CAMs also positively affected the pharmacokinetic parameters. When compared to the physical mixture, the CAMs of CRT:NRG 2:1 exhibited a 2.1-fold increase in CRT exposure (AUC0-t) and a 2.4-fold increase in plasma concentration (Cmax).
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Disponibilidade Biológica , Carcinoma Pulmonar de Células não Pequenas , Flavanonas , Neoplasias Pulmonares , Polifenóis , Solubilidade , Flavanonas/química , Flavanonas/farmacocinética , Flavanonas/administração & dosagem , Humanos , Polifenóis/química , Polifenóis/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Masculino , Ratos , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Difração de Raios X/métodosRESUMO
We describe a 1,2-alkylboration of 3-alkylidene-2-oxindoles with a diboron reagent and alkyl bromides and iodides enabled by copper/bisphosphine catalysis. This scalable alkylboration method provides facile access to 3,3'-dialkyloxindole boronic esters featuring an all-carbon quaternary stereocenter and an increased F(sp3) fraction. In addition to good functional group tolerance and prolific utilization of drug/pesticide-derived alkyl iodides, the conversion of the C-B bond to a C-C/C-X bond offers further opportunities for structural variation of 3,3'-dialkyloxindoles.
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Conventional canonical correlation analysis (CCA) measures the association between two datasets and identifies relevant contributors. However, it encounters issues with execution and interpretation when the sample size is smaller than the number of variables or there are more than two datasets. Our motivating example is a stroke-related clinical study on pigs. The data are multimodal and consist of measurements taken at multiple time points and have many more variables than observations. This study aims to uncover important biomarkers and stroke recovery patterns based on physiological changes. To address the issues in the data, we develop two sparse CCA methods for multiple datasets. Various simulated examples are used to illustrate and contrast the performance of the proposed methods with that of the existing methods. In analyzing the pig stroke data, we apply the proposed sparse CCA methods along with dimension reduction techniques, interpret the recovery patterns, and identify influential variables in recovery.
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Genômica , Acidente Vascular Cerebral , Animais , Suínos , Genômica/métodos , Análise de Correlação Canônica , AlgoritmosRESUMO
Non-small cell lung cancer (NSCLC) is a widespread and often aggressive form of cancer affecting people worldwide. PIK3CA missense mutations play a significant role in the progression of growth factor signaling in cancer, making PI3Kα an important biological target for inhibition against NSCLC. Natural product molecules with PI3Kα inhibitory activity are promising therapeutic agents for the treatment of NSCLC, owing to their selectivity and potentially lower toxicity compared to synthetic compounds. To discover new natural product molecules, we integrated ligand-based virtual screening with structure-based virtual screening. We developed a multi-ligand pharmacophore hypothesis, validated it with 3D Field-based QSAR, and screened a Natural-Product-Based Library (ChemDiv) containing 3601 molecules. After initial screening, 137 hit molecules were generated and further screened using the extra precision (XP) Glide docking protocol. The best ten molecules were selected for free binding energy (ΔG) analysis using MMGBSA and ADME predictions. For further optimization, the top four hits were subjected to induced fit docking (IFD), quantum chemical descriptors analysis by Frontier Molecular Orbital (FMO) studies, and a 100 ns molecular dynamics (MD) simulation. The compounds-S721-1955, CM4579-5085, S721-1963, and S721-1999-exhibited better results than the PI3Kα selective inhibitor alpelisib. In silico prediction analysis of S721-1955 and alpelisib revealed that the former exhibited superior selectivity theoretically, as evidenced by its higher affinity for the target protein. The selective natural product molecule identified in this study holds promise as a potential anti-cancer drug against NSCLC in the near future, but further in vitro and in vivo studies are necessary to confirm its efficacy.
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A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC50 value of 6.34 µM and compound 8m displayed an IC50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC50 = 10.25 µM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamics simulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally.
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Antineoplásicos , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Proteína de Sequência 1 de Leucemia de Células Mieloides , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt , Relação Estrutura-AtividadeRESUMO
Cancer is one of the leading causes of death. Globally a huge number of deaths and new incidences are reported annually. Heterocyclic compounds have been proved to be very effective in the treatment of different types of cancer. Among different heterocyclic scaffolds, quinazoline and quinazolinone core were found versatile and interesting with many biological activities. In the discovery of novel anticancer agents, the Quinazoline core is very effective. The FDA has approved more than 20 drugs as an anticancer bearing quinazoline or quinazolinone core in the last two decades. One prime example is Dacomitinib, which was newly approved for non-small-cell lung carcinoma treatment in 2018. These drugs work by different pathways to prevent the spread of cancer cell progression, including inhibition of different kinases, tubulin, kinesin spindle protein, and so forth. This review presented recent developments of quinazoline/quinazolinone scaffold bearing derivatives as anticancer agents acting as epidermal growth factor receptor (EGFR) vascular endothelial growth factor receptor (VEGFR), and dual EGFR/VEGFR inhibitors.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Receptores de Fatores de Crescimento do Endotélio Vascular , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Quinazolinonas/farmacologia , Quinazolinonas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio VascularRESUMO
We herein report a new series of indole-tethered pyrazoline derivatives as potent anticancer agents. A total of 12 compounds were designed and synthesized by conventional as well as microwave-irradiated synthesis methods. The latter method results in a significant reduction in the duration of reaction along with improved yields. All synthesized derivatives (7a-7l) were evaluated for their cytotoxic activity against A431, HeLa, and MDAMB-231 cell lines. Compounds 7a and 7b were found most potent in the series and demonstrated an IC50 value of 3.17 and 5.16 µM against the A431 cell line, respectively, compared to the standard drug doxorubicin. Compounds 7a and 7b significantly suppress colony formation, migration, and S phase cell cycle arrest of A431 cells. Furthermore, compound 7a regulated the expression of apoptotic proteins causing the downregulation of procaspase 3/9, antiapoptotic protein Bcl-xL, and upregulation of proapoptotic protein Bax in a dose-dependent manner. Topoisomerase enzyme inhibition assay confirmed that compounds 7a and 7b can significantly inhibit topoisomerase IIα. In vivo oral acute toxicity of compounds 7a and 7b revealed that both compounds are safe compared to doxorubicin; cardiomyopathy studies showed normal architecture of cardiomyocytes and myofibrils. In addition, molecular docking studies revealed the possible interaction of compounds 7a and 7b within the active binding site of the topoisomerase enzyme. The 100 ns molecular dynamic simulation of compounds 7a and 7b proved that both compounds validate all screening parameters.
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Antineoplásicos , Humanos , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Estrutura Molecular , Antineoplásicos/química , Doxorrubicina/farmacologia , Indóis/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , ApoptoseRESUMO
Hepatocellular carcinoma (HCC) is one of the most deadly disorders, with a relative survival rate of 36% in the last 5 years. After an extensive literature survey and pathophysiology analysis, PI3Kα was found to be a promising biological target as PIK3CA gene upregulation was observed in HCC, resulting in the loss of apoptosis of cells, which leads to uncontrollable growth and proliferation. Due to superior selectivity and promising therapeutic activity, the PI3K-targeted molecule library was selected, and the ligand preparation was executed. The study mainly focused on e-pharmacophore development, virtual screening and receptor-ligand docking analysis. Then, MMGBSA and ADME prediction analysis was performed with the top 10 molecules; for further analysis of ligand-receptor binding affinity at the catalytic binding site, induced fit docking was performed with the top two molecules. The analysis of quantum chemical stability descriptors, i.e., frontier molecular orbital analysis, was performed followed by molecular dynamics simulation of 100 ns to better understand the ligand-receptor binding. In this study, water map analysis played a significant role in the hit optimization and analysis of the thermodynamic properties of the receptor-ligand complex. The two hit molecules K894-1435 and K894-1045 represented superior docking scores, enhanced stability, and inhibitory action targeting Valine 851 amino acid residue at the catalytic binding site. Hence, the study has significance for the quest for selective PI3Kα inhibitors through the process of hit-to-lead optimization.Communicated by Ramaswamy H. Sarma.
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We describe an organophotoredox-catalyzed sp3 C-S coupling of N-sulfinylamines with bench-stable alkyltrifluoroborates as a latent nucleophilic counterpart en route to alkylsulfinamides in high efficiency. In contrast to the two-electron reactivity of traditional organometallic reagents, this catalytic method reports the single-electron process of an organometallic reagent with N-sulfinylamines in C-S coupling. This mild and scalable protocol offers operational simplicity and exceptional functional group compatibility, including ketone, ester, amide, nitrile, and halides, that is vulnerable to organolithium or Grignard reagents. Additionally, the sulfinamides are conveniently converted to a variety of important S(VI) compounds, like sulfonamides, sulfonimidamides, and sulfonimidates, among others.
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Pigs breeds are an important livestock species mostly reared by economically lower incomesection of people in India. Within North-Eastern (NE) states, pig husbandry is very much popular hence maintain the livelihood of the rural native population. Gastrointentinal (GI) parasitic infectionisone of the major constraint in profitable pig production in this area. In the present study, the GI parasitism was investigated in 388 pigs in the three districts of Tripura, NE State of India. The examination of faecal samples revealed 61.65% overall prevalence of parasitic infestation, precisely6 GI parasitic species; including 4 nematodes and 2 protozoa, while 46.91% were the mixed infections.Metastrongylus spp. (17.53%), Strongyloids spp. (19.33%),Trichuris spp. (15.98%), Coccidia spp. (12.37%), and Balantidium coli (10.82%), were detected, however, Ascaris spp. was the most prevalentrecording 32.47%. The epidemiological factors including: age, sex, season, breed, area and farming system wise when considered as markers of study showed the highest prevalence of GI parasites in grower(6-12 months) stage, female, monsoon season, non-descript breeds, Khowai district and free range farming system, recorded 71.52%, 67.27%, 65.78%, 65.71%, 64.57%, and 69.44%, respectively. Overall, our study provides a baseline data for further investigation and formulation of strategies for control of GI parasitism in pigs in Tripura.
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Deformability is one of the critical attributes of nanoparticle (NP) drug carriers, along with size, shape, and surface properties. It affects various aspects of NP biotransport, ranging from circulation and biodistribution to interactions with biological barriers and target cells. Recent studies report additional roles of NP deformability in biotransport processes, including protein corona formation, intracellular trafficking, and organelle distribution. This review focuses on the literature published in the past five years to update our understanding of NP deformability and its effect on NP biotransport. We introduce different methods of modulating and evaluating NP deformability and showcase recent studies that compare a series of NPs in their performance in biotransport events at all levels, highlighting the consensus and disagreement of the findings. It concludes with a perspective on the intricacy of systematic investigation of NP deformability and future opportunities to advance its control toward optimal drug delivery.
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Alzheimer's disease (AD) is a neurological disorder that affects millions of people worldwide. There are currently no cures for AD, although various drugs are used to manage the symptoms and reduce the disease's progression. AChE inhibitors such as rivastigmine, donepezil, galantamine, and the NMDA glutamate receptor antagonist memantine are currently FDA-approved drugs used in the treatment of AD. Recently, naturally derived biological macromolecules have shown promising results in the treatment of AD. Several biological macromolecules derived from natural sources are in various stages of preclinical and clinical trials. During the literature search, it was observed that there is a lack of a comprehensive review that particularly focuses on the role of naturally derived biological macromolecules (protein, carbohydrates, lipids, and nucleic acids) in the treatment of AD and the structure-activity relationship (SAR) approach for understanding the medicinal chemistry perspective. This review focuses on the SAR and probable mechanisms of action of biological macromolecules derived from natural sources for the treatment of AD, including peptides, proteins, enzymes, and polysaccharides. The paper further addresses the therapeutic possibilities of monoclonal antibodies, enzymes, and vaccines for the treatment of AD. Overall, the review provides insight into the SAR of naturally derived biological macromolecules in the treatment of AD. The ongoing research in this field holds great promise for the future development of AD treatment and provides hope for individuals affected by this devastating disease.Communicated by Ramaswamy H. Sarma.
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Inflammatory bowel disease is a chronic disorder of the large intestine with the prevalence of approximately 400 cases in 100000, and it is rising day by day. However, several drugs like sulfasalazine (composed of sulfapyridine and 5-aminosalicylic acid or 5-ASA), corticosteroids, and immunosuppressants manage the disease. But there are no absolute treatments for the pain and inflammation of the disease. TNFα is an important target, and drugs like infliximab and adalimumab have pharmacological potency but with pronounced toxicity. So, we choose this major target TNFα for the virtual screening of US-FDA-approved drugs for its repurposing using the in silico method. The protein TNFα (PDB ID: 2AZ5) with small molecule inhibitor and the US-FDA-approved drug molecules (from Zinc database) were first imported and prepared using Protein Preparation Wizard and LigPrep, respectively, followed by molecular docking, ADMET analysis and prime MMGBSA. After that, the drugs were shortlisted according to dock score, ADMET parameters and MM GBSA dG binding score. After that, the shortlisted drug molecules were subjected to an induced-fit docking analysis. Two of the most promising molecules, ZINC000003830957 (Iopromide) and ZINC000003830635 (Deferoxamine), were chosen for molecular dynamics simulation. Finally, the bioisosteric replacement was used to improve the ADMET properties of these molecules. This research provides an idea for drug exploration and computational tools for drug discovery in treating inflammatory bowel disease.Communicated by Ramaswamy H. Sarma.
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Doenças Inflamatórias Intestinais , Fator de Necrose Tumoral alfa , Humanos , Simulação de Acoplamento Molecular , Fator de Necrose Tumoral alfa/metabolismo , Reposicionamento de Medicamentos , Simulação de Dinâmica Molecular , Doenças Inflamatórias Intestinais/tratamento farmacológicoRESUMO
Inflammation and oxidative stress can contribute to the etiology of metabolic and chronic illnesses. The ability to prevent oxidative stress induced diseases such as cancer, cardiovascular disease, Alzheimer's disease, and others has been the subject of global research. Drug-induced liver injury (DILI) pathogenesis can be either due to oxidative stress or inflammatory response elicited by the drug, its metabolite, or herbal supplements. Our present research uses computational studies to identify a molecule with anti-inflammatory properties that can operate as an NRF2 activator. Acquiring and preparing the KEAP1-NRF2 Protein (PDB: 4L7D) with Schrodinger Suite was followed by developing a ligand library (Anti-inflammatory library downloaded from ChemDiv database). Molecular docking studies were performed in HTVS, SP, and XP modes, respectively. Based on the docking score, interaction, ADMET and binding free energy, the top ten compounds were selected and subjected to induced-fit docking (IFD) analysis for further study. The top three molecules were chosen for a molecular dynamics (MD) simulation study. Using the Desmond module of the Schrodinger Suite, the stability of the protein-ligand complex and protein-ligand contact throughout 100ns were evaluated during the MD simulation study. In our study, it was observed that three compounds exhibit exceptional stability and retain the essential interaction throughout the studies, and it is anticipated that these compounds may act as effective NRF2 activators. Further in vitro and in vivo assessments can be conducted to determine its potential to prevent DILI via acting as an NRF2 activator for future drug development.
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Doença Hepática Induzida por Substâncias e Drogas , Fator 2 Relacionado a NF-E2 , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Fator 2 Relacionado a NF-E2/metabolismo , Ligantes , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Simulação de Dinâmica Molecular , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Anti-Inflamatórios/farmacologiaRESUMO
Alzheimer's disease (AD) is a complex neurodegenerative disorder involving cognitive dysfunction like short-term memory and behavioral changes as the disease progresses due to other unaltered physiological factors. The solution for this problem is Multi-targeted Drugs (MTDs), which can affect multiple determinants to realize the multifunctional effects. Acetylcholinesterase (AChE) inhibitors donepezil, rivastigmine, galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonist memantine are FDA-approved drugs used to treat AD symptomatically. The key objective of this review is to understand multitargeted bioactive natural molecules that could be considered as leads for further development as effective drugs for treating AD, along with understanding its pharmacology and structure-activity relationship (SAR). Understanding the molecular mechanism of the AD pathophysiology, the role of existing drugs, treatment of AD via amyloid beta (Aß) plaque, and neurofibrillary tangle (NFT) inhibition by natural bioactive molecules were also discussed in the review. The current quest and recent advancements with natural bioactive compounds like physostigmine, resveratrol, curcumin, and catechins, along with the study of in silico SAR, were reported in the present study. This review summarises the structural properties required for bioactive natural molecules to show anti-Alzheimer's activity by emphasizing on SAR of several bioactive natural molecules targeting various AD pathologies, their key molecular interactions that are critical for target specificity, their role as multitargeted ligands, used with adjunctive therapy for AD followed by related US patents granted recently. This article highlights the significance of the structural features of natural bioactive molecules in the treatment of AD and establishes a connection between them.Communicated by Ramaswamy H. Sarma.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Relação Estrutura-AtividadeRESUMO
Single-source white light emitting colloidal semiconductor quantum dots (QDs) is one of the most exciting and promising high-quality solid-state light sources to meet the current global demand for sustainable resources. While most of the previous methods involve dual (green-red) emissive nanostructures coated on blue LEDs to achieve white light, this work describes a single-source white light emitter of robust and superior quality using dual-doping. A modified synthesis method for intense white light emitting Cu, Mn dual-doped ZnSe QDs is engineered such that the extent of doping and concentration of ligands can alter their electronic structures. This is then customized to obtain various types of white light emissions ranging from warm white to cool white. Further, the composition-driven change in the electronic structure of the host QDs is exploited to achieve emission tunability over the entire visible range.
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A visible-light-photocatalyzed 1,2-arylalkylation of N-(arylsulfonyl)acrylamides with ketone-based dihydroquinazolinones is described. The formal C-C bond cleavage of aliphatic ketones is unified with tandem radical alkylation/1,4-aryl migration/desulfonylation to forge two different types of vicinal C-C bonds and construct an all-carbon quaternary α-stereocenter, thus enhancing the carbogenic complexity and tolerating diverse functionalities. Additional to telescopic synthesis and product diversification, this method features a radical dicarbofunctionalization of conjugated N-(arylsulfonyl)acrylamides with a nucleophilic alkyl radical precursor (dihydroquinazolinone) utilizing oxygen as a green oxidant at ambient temperature.
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BACKGROUND: Diabetes mellitus and Alzheimer's disease are two common diseases that majorly affect the elderly population. Patients in both cases are increasing day by day. They are considered two independent diseases, but recent evidence suggests that they have a lot in common. OBJECTIVE: In this review, we focused on the connection between Alzheimer's disease and diabetes and highlighted the importance of antidiabetic drugs against Alzheimer's disease. METHODS: Common pathways such as obesity, vascular diseases, oxidative stress, mitochondrial dysfunction, mutation of the ApoE4 gene, and Sirtuin gene were found to manipulate both diseases. Antidiabetic drugs are found to have promising effects on Alzheimer's disease, acting by reducing insulin resistance, neuronal protection, and reducing amyloid-beta plaques. Some anti-diabetic drugs have shown promising results in vivo and in vitro studies. RESULTS: No review present focuses on the structural features of the antidiabetic molecules against Alzheimer's disease, their crosslinking pathophysiology, the role of natural bioactive molecules, in silico advancements followed by preclinical and clinical studies, and current advancements. Hence, we concentrated on the factors mentioned in the objectives. CONCLUSION: Alzheimer's disease can be considered a form of 'type-3 diabetes,' and repurposing the anti-diabetic drug will open up new paths of research in the field of Alzheimer's disease drug discovery.
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Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Resistência à Insulina , Idoso , Humanos , Doença de Alzheimer/metabolismo , Hipoglicemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Peptídeos beta-AmiloidesRESUMO
Lichens are symbiotic organisms that have been traditionally used for treating different kinds of ailments. As there are only a few reports on the antiviral activity of lichens, we thought of evaluating the anti-Herpes simplex virus-1 (HSV-1) activity of methanolic extract of Roccella montagnei and their isolated compounds. Fractionation of crude methanolic extract of Roccella montagnei by column chromatography isolated two pure compounds. Antiviral activity was assessed using a CPE inhibition assay at non-cytotoxic concentrations on Vero cells. Molecular docking and dynamics studies were carried out against Herpes simplex type-1 thymidine kinase to understand the binding interactions of the isolated compounds with reference to acyclovir. Isolated compounds were characterized as methyl orsellinate and montagnetol by spectral methods. Methanolic extract of Roccella montagnei exhibited an EC50 value of 56.51 µg/ml, while the compounds methyl orsellinate and montagnetol offered EC50 values of 13.50 µg/ml and 37.52 µg/ml, respectively, against HSV-1 viral infection on Vero cell lines. The selectively index (SI) of montagnetol (10.93) was found to be higher when compared to that of methyl orsellinate (5.55), indicating its better anti-HSV-1 activity. The docking and dynamics studies showed montagnetol was stable throughout the 100 ns, having better interactions and docking scores with HSV-1 thymidine kinase than methyl orsellinate, as well as the standard. To understand the mechanism of montagnetol's anti-HSV-1 activity, more research is required, and this could lead to the discovery of new and effective antiviral agents.Communicated by Ramaswamy H. Sarma.
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Herpes Simples , Herpesvirus Humano 1 , Líquens , Animais , Chlorocebus aethiops , Antivirais/química , Células Vero , Líquens/química , Simulação de Acoplamento Molecular , Timidina Quinase/farmacologia , Timidina Quinase/uso terapêutico , Herpes Simples/tratamento farmacológico , Extratos Vegetais/farmacologiaRESUMO
Generally, herbal medicines having remarkable popularity for treating liver ailments, but they are still unacceptable because of the deprivation of herbal drug standardization. Therefore, there is a need for promising synthetic drugs to overcome the critical liver problem. We introduce 1, 3, 4-oxadiazine ring in this study to identify better anti-hepatotoxic agents via a suitable synthetic route. These oxadiazine-based derivatives were structurally confirmed by analytical and spectral data and evaluated for their anti-hepatotoxic potential. Further, in vitro hepatotoxicity studies have been done to check the toxicity level in the synthesized compound. Compounds 5a, 5b, 5c and 9d were selected for further biological evaluation according to in vitro results. After that, CCl4-induced animal model was used to evaluate in vivo anti-hepatotoxicity activity. Compound 5a with 52.99%, 59.3%, 79.34% and 5b with 52.16%, 57.65%, 75.10% revealed to be most promising for reduction in level of SGPT, SGOT and ALKP, respectively. Moreover, it was also observed that the compound 5a with 411.01%, 53.39% and 5b with 378.63%, 48.9% level of albumin and total protein were respectively. The induced-fit docking results of the compounds 5a and 5b reveal some essential binding information and exhibited desirable ADME properties, and obeyed Lipinski's rule of five. In addition, molecular dynamics studies for 100 ns further confirm the protein-ligand complex's stability, supporting the in vitro and in vivo data, and help in establishing the SAR of synthesized compounds. Two compounds, 5a and 5 b, exhibited higher anti-hepatotoxic activity than the standard drug silymarin.