Search

Alcohol is a risk factor for hepatocellular carcinoma (HCC). However, the molecular mechanism by which chronic alcohol consumption contributes to HCC is not well understood. The purpose of the study was to demonstrate the effects of chronic ethanol exposure on the damage of human normal hepatocytes. Our data showed that chronic exposure of hepatocytes with ethanol induced changes similar to transformed hepatocytes that is, exhibited colonies and anchorage‐independent growth. These damaged hepatocytes contained high levels of reactive oxygen species (ROS) and showed induction of the SATB2 gene. Furthermore, damaged hepatocytes gained the phenotypes of CSCs which expressed stem cell markers (CD133, CD44, CD90, EpCAM, AFP and LGR5), and pluripotency maintaining factors (Sox‐2, POU5F1/Oct4 and KLF‐4). Ethanol exposure also induced Nanog, a pluripotency maintaining transcription factor that functions in concert with Oct4 and SOX‐2. Furthermore, ethanol induced expression of EMT‐related transcription factors (Snail, Slug and Zeb1), N‐Cadherin, and inhibited E‐cadherin expression in damaged hepatocytes. Ethanol enhanced recruitment of SATB2 to promoters of Bcl‐2, Nanog, c‐Myc, Klf4 and Oct4. Ethanol also induced activation of the Wnt/TCF‐LEF1 pathway and its targets (Bcl‐2, Cyclin D1, AXIN2 and Myc). Finally, ethanol induced hepatocellular steatosis, SREBP1 transcription, and modulated the expression of SREBP1c, ACAC, ACLY, FASN, IL‐1β, IL‐6, TNF‐α, GPC3, FLNB and p53. These data suggest that chronic alcohol consumption may contribute towards the development of HCC by damaging normal hepatocytes with the generation of inflammatory environment, induction of SATB2, stem cell‐like characteristics, and cellular steatosis. [ABSTRACT FROM AUTHOR]

Aim: Purpose of the present work is to synthesize the pro-pro-drugs of Glycine and evaluate for their anticonvulsant activity in albino rats with brain specific sustained release action in various biological fluids. Materials and Methods: Prepared and synthesized propro-drugs of Glycine nicotinate by esterification with different alcohols and admiration with nicotinic acid. In present work pro-prodrug of Glycine nicotinate were synthesized by taking the Dihydropyridine as carrier molecules. The synthesized compounds have been characterized by IR, IH-NMR, C, H, N analysis and Mass spectral techniques and evaluated for their anticonvulsant activity in albino rats by chemoconvulsion method as well for oxidation in various biological fluids. All the synthesized compounds were found to be active and stable in biological fluids. Oxidized form of the conjugate inside the brain act as pro-pro-drug, which on hydrolysis yields parent drug in sustained release manner. The significance of the work is to treat neurological disorder implicated by Glycine. Results: Pro-pro-drug of Glycine nicotinate were synthesized effectively and showed anticonvulsant activity in slow release manners. Conclusion: This work has given a new synthetic strategy and result of anticonvulsant screening was found encouraging. [ABSTRACT FROM AUTHOR]

The incidence of obesity and type 2 diabetes (T2DM) in the Western world has increased dramatically during the recent decades. According to the American Cancer Society, pancreatic cancer (PC) is the fourth leading cause of cancer‐related death in the United States. The relationship among obesity, T2DM and PC is complex. Due to increase in obesity, diabetes, alcohol consumption and sedentary lifestyle, the mortality due to PC is expected to rise significantly by year 2040. The underlying mechanisms by which diabetes and obesity contribute to pancreatic tumorigenesis are not well understood. Furthermore, metabolism and microenvironment within the pancreas can also modulate pancreatic carcinogenesis. The risk of PC on a population level may be reduced by modifiable lifestyle risk factors. In this review, the interactions of diabetes and obesity to PC development were summarized, and novel strategies for the prevention and treatment of diabetes and PC were discussed. [ABSTRACT FROM AUTHOR]

In silico molecular docking is an efficient technique for drug design that predicts the optimized orientation of the ligand against a specific drug target. This is a cost-effective and time-saving technique that requires limited manpower. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed drugs in various prescriptions. The drawbacks with NSAIDs in its long-term usage are gastric irritation, bleeding, and perforation. Prodrug approach is a commonly used method to overcome these side effects. In this study, the reported prodrugs of mefenamic acid were utilized to validate the molecular docking simulation process by comparing obtained in silico results with the reported in vivo results. The molecules were evaluated for their binding affinity against human cyclooxygenase-2 enzyme as well as their pharmacokinetics profile is predicted on the basis of Lipinski's and Veber rule. The in silico result showed high degree similarity with experimental results. This confirms the efficiency and reliability of the molecular docking technique for identification of potential lead compounds. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Novel p-aminobenzoic acid derivatives were designed, synthesized and characterized. • The compounds exhibited significant inhibitory potential against AChE and BChE. • Compound 22 exhibited significant improvements in working and reference memory. • The ex vivo study confirmed the ability of compound 22 to cross the BBB. • The in silico studies demonstrated the binding to active pocket in a stable manner. Abstract Based on the quantitative structure-activity relationship (QSAR), some novel p-aminobenzoic acid derivatives as promising cholinesterase enzyme inhibitors were designed, synthesized, characterized and evaluated to enhance learning and memory. The in vitro enzyme kinetic study of the synthesized compounds revealed the type of inhibition on the respective acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vivo studies of the synthesized compounds exhibited significant reversal of cognitive deficits in the animal models of amnesia as compared to standard drug donepezil. Further, the ex vivo studies in the specific brain regions like the hippocampus, hypothalamus, and prefrontal cortex regions also exhibited AChE inhibition comparable to standard donepezil. The in silico molecular docking and dynamics simulations studies of the most potent compound 22 revealed the consensual interactions at the active site pocket of the AChE. [ABSTRACT FROM AUTHOR]

Gastrosparing novel prodrugs (MAM and MAT) synthesized consisted of mefenamic acid (MA) with menthol (M) and thymol (T). Structural characterizations of synthesized esters were done by Infra red spectroscopy (IR), proton nuclear magnetic resonance (1HNMR), mass spectroscopy. After evaluation of pharmacological i.e. anti-inflammatory, analgesic and ulcerogenic activities, the preformulation studies were undertaken. Based on these a few formulation (suspensions) were designed and prepared. The formulated suspensions were evaluated for content uniformity, sedimentation volume, recovery studies, redispersibility, viscosity, pH, particle size, zeta potential, effect of temperature and in-vitro dissolution rate. All the above parameters were found to be within the limit these indicated that the synthesized esters are good candidate for liquid dosage form. Thus it can be concluded synthesized prodrugs can be formulated in suspension form. [ABSTRACT FROM AUTHOR]

In this manuscript we have designed and synthesized 1,4-Naphthoquinone analogs substituted with 1,3,4 Oxadiazolenucleus. The synthesized compound (M1-M14) were characterized using the different analytical technique¹H NMR, 13C NMR, FTIR, Mass spectroscopy, melting point, elemental analysis and further subjected for the evaluation of their anticancer activity using MCF-7, Hela and HepG2 cancer cell lines. The compound M-5 was found to exhibit most potent cytotoxicity against cancer cell lines i.e. HeLa (IC50 =10.76 ± 0.11 µM), MCF-7 (IC50 = 9.30 ± 0.14 µM) and HepG2 (IC50 = 11.93 ± 0.38µM). Compound M-5 has also shown potent tyrosine kinase inhibitory activity with IC50 = 1.53 ± 0.05 µM. Moreover, molecular docking has exposed that compound M-5 has strong binding affinity to the active site of tyrosine kinase. These results give promising beginning stages to assist in the improvement of novel and powerful anticancer agents. [ABSTRACT FROM AUTHOR]

In this manuscript, we have designed, synthesized and characterized 1, 4-naphthoquinone derivatives. The synthesized compounds (MB1-MB19) were further subjected for evaluation of their anticancer activity using MCF-7, HeLa and HepG2 cancer cell lines. The compound MB-9 was observed to be most active against these three cancer cell lines i.e. MCF-7 (IC50 = 15.63 ± 0.47 µM), HeLa (IC50 =13.45 ± 0.48 µM), and HepG2 (IC50 = 23.87 ± 0.59µM). Compound MB-9 has also shown potent tyrosine kinase inhibitory activity with IC50 = 1.80 ± 0.06 µM. Moreover, molecular docking investigations revealed that compound MB-9 has strong binding affinity to the active site residues of tyrosine kinase. These outcomes give a promising beginning to assist in the improvement of novel and powerful anticancer agents. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To develope and validate a simple and rapid isocratic reversed-phase highperformance liquid chromatographic method (RP-HPLC) for the simultaneous estimation of amlodipin and telmisartan in combined dosage form. Methods: The chromatographic separation was achieved by using mobile phase acetonitrile and 0.05M sodium dihydrogen phosphate buffer (60:40) adjusted to pH 6.0, a C-18 column, perfectsil target ODS3 (150 mm × 4.6 mm i.d., 5 μm). The mobile phase was pumped at a flow rate of 0.8 mL/min and the eluents were monitered at 254 nm. Results: Retention times were 4.0 min and 8.2 min for amlodipine and telmisartan respectively. The method was validated in terms of accuracy, precision, linearity, range, specificity, limit of detection and limit of quantitation. Linearity for amlodipine besylate and telmisartan was established in the range of 5-30 and 10-60 μg/mL, respectively. The recoveries for the two compounds were above 96%. Conclusions: This method was found to be efficient, accurate, precise, specific and economic and is suitable for routine quality control analyses. [Copyright &y& Elsevier]

Epilepsy is the most common chronic neurological disorder of the brain. For several decades different kinds of medications have been used to treat epilepsy. Even though many surgical advances has been made and implemented, medications remain the basis of treatment. The search for noble antiepileptic drugs (AEDs) with more selective activity and lower toxicity continues to be an area of intensive investigation in medicinal chemistry. Additionally, drug resistance is an important clinical problem in epilepsy and is associated with an increased risk of morbidity and mortality. This review intends to present a comprehensive overview on AED in particular along with discussion on some aspects of associated drug resistance and combination therapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Novel hybrids bearing a 2-aminopyrimidine (2-AP) moiety linked to substituted 1,3,4-oxadiazoles were designed, synthesized and biologically evaluated. Among the developed compounds, 28 noncompetitively inhibited human acetylcholinesterase (hAChE; pIC 50 = 6.52; Ki = 0.17 µM) and showed potential in vitro antioxidant activity (60.0%) when evaluated using the Ellman's and DPPH assays, respectively. Compound 28 competitively displaced propidium iodide (PI) from the peripheral anionic site (PAS) of hAChE (17.6%) and showed high blood-brain barrier (BBB) permeability, as observed in the PAMPA-BBB assay. Additionally, compound 28 inhibited hAChE-induced Aβ aggregation in a concentration-dependent manner according to the thioflavin T assay and was devoid of neurotoxic liability towards SH-SY5Y cell lines, as demonstrated by the MTT assay. The behavioral studies of compound 28 in mice showed a significant reversal of scopolamine-induced amnesia, as observed in Y-maze and passive avoidance tests. Furthermore, compound 28 exhibited significant AChE inhibition in the brain in ex vivo studies. An evaluation of oxidative stress biomarkers revealed the antioxidant potential of 28. Moreover, in silico molecular docking and dynamics simulation studies were used as a computational tool to evaluate the interactions of compound 28 with the active site residues of hAChE. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Biphenyl-3-oxo-1,2,4-triazine linked piperazines were designed and synthesized. • Compound 6g significantly inhibited the AChE and showed good CNS permeability. • In vivo studies showed significant improvement in learning and memory. • Biochemical analysis showed potential antioxidant property by compound 6g. Abstract A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC 50 ; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC 50 : 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (P e (exp) , 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE. [ABSTRACT FROM AUTHOR]

Some promising acetylcholinesterase (AChE) inhibitors with an antioxidant potential were designed, synthesised, and evaluated for their role in treating cognitive dysfunctions. The in silico Gaussian-based quantitative structureactivity relationship (QSAR), virtual screening (VS), QikProp drug-likeliness prediction and docking pose filtration protocols were adapted to design and screen the novel series of diaryl ether derivatives. Further, the selected compounds were investigated for their molecular binding stability using molecular dynamics (MD) simulation analysis and molecular mechanics generalised born surface area (MM-GBSA). The identified hits were synthesised and evaluated for their in vitro AChE inhibition and antioxidant potential. Among all the synthesized compounds, the compound 39 was observed as potent AChE inhibitor (AChE IC50 = 1.30 ± 0.09 μm; Ki = 0.054 ± 0.009 μM), and also the antioxidant potential of compound 39 (52.9%) was observed significantly better than standard donepezil (<10%) and parallel to ascorbic acid (56.6%). Further, compound 39 ameliorated the scopolamine-induced cognitive impairment in the Y-maze and passive avoidance testsin mice models. Ex vivo and biochemical analysis established the brain AChE inhibitory potential and antioxidant properties of compound 39. The results signified compound 39 to be a promising lead for the treatment of cognitive dysfunctions. [ABSTRACT FROM AUTHOR]

Highlights • The pathophysiological roles and underlying mechanisms of several hypotheses involved in AD are extensively reviewed. • A detailed investigation of all the conventional and novel therapeutic targets. • The identification of structural and functional motifs with a comprehensive framework of the active sites involved. • To elucidate and simplify the complexity and call for attention on the crucial areas to discover innovative therapeutics. Abstract AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aβ, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors. [ABSTRACT FROM AUTHOR]

Analgesic drugs containing free acidic group were reacted with N, N' carbonyldiimidazole to prepare the acylimidazole derivatives. They were further reacted with 5-phenyl-2-amino thiazole nucleus to obtain the corresponding amides. All the compounds were found to retain analgesic-antiinflammatory activities with much lesser NSAID-induced GI complications when compared with the standard. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a multifactorial and emerging neurological disorder, which has invoked researchers to develop multitargeted ligands. Herein, hybrid conjugates of 5-phenyl-1,3,4-oxadiazole and piperazines were rationally designed, synthesized, and pharmacologically evaluated against hAChE, hBChE, and hBACE-1 enzymes for the management of AD. Among the series, compound 5AD comprising pyridyl substitution at terminal nitrogen of piperazine contemplated as a paramount lead compound (hAChE, IC 50 = 0.103 ± 0.0172 μM, hBChE, IC 50 ≥ 10 μM, and hBACE-1, IC 50 = 1.342 ± 0.078 μM). Compound 5AD showed mixed-type enzyme inhibition in enzyme kinetic studies against the hAChE enzyme. In addition, compound 5AD revealed a significant displacement of propidium iodide from the peripheral anionic site (PAS) of hAChE and excellent blood-brain barrier (BBB) permeability in a parallel artificial membrane permeation assay (PAMPA). Besides, 5AD also exhibited anti-Aβ aggregation activity in self- and AChE-induced thioflavin T assay. Further, compound 5AD has shown significant improvement in learning and memory ( p < 0.001) against the in vivo scopolamine-induced cognitive dysfunction mice model. The ex vivo study implied that after treatment with compound 5AD , there was a decrease in AChE and malonaldehyde (MDA) levels with an increase in catalase (CAT, oxidative biomarkers) in the hippocampal brain homogenate. Hence, compound 5AD could be regarded as a lead compound and further be explored in the treatment of AD., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial γ-aminobutyric acid (GABA) uptake in vitro. However, nipecotic acid does not readily cross the blood-brain barrier (BBB) following peripheral administration, owing to its hydrophilic nature., Objective: A series of substituted acetonaphthones tethered nipecotic acid derivatives were designed and synthesized with an aim to improve the lipophilicity and the blood-brain barrier (BBB) permeation., Methods: Synthesized compounds were tested in mice models of PTZ, pilocarpine, and DMCM induced epilepsy, in vivo. The rota-rod test was performed to determine the acute neurotoxicity of the potential leads (4a, 4b, and 4i). These potential hybrids were also evaluated for their ability to cross the BBB by an in vitro parallel artificial membrane permeability BBB assay (PAMPA-BBB). The leads were subjected to in silico molecular docking and dynamics studies on homology modelled protein of human GABA (γ-amino butyric acid) transporter 1 (GAT1) and prediction of their pharmacokinetic properties., Result: Amongst the synthesized derivatives, compounds 3a, 3b, 3i, 4a, 4b, and 4i exhibited increased latency of seizures against subcutaneous pentylenetetrazole (scPTZ) induced seizures in mice. Derivatives 4a, 4b, 4i were more effective compared to nipecotic acid ester counterparts 3a, 3b and 3i placing the importance of the presence of free carboxyl group in the centre. The findings revealed that 4i was comparatively more permeable (Pe= 8.89) across BBB than the standard tiagabine (Pe= 7.86). In silico studies proved the consensual interactions of compound 4i with the active binding pocket., Conclusion: Some nipecotic acid-acetonaphthone hybrids with considerable anti-epileptic activity, drug like properties and the ability to permeate the BBB have been successfully synthesized., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Intoroduction: Prodrug approach deals with chemical biotransformation or enzymatic conversion or involves inactive or less active bio-reversible derivatives of active drug molecules. They have to pass through enzymatic or chemical biotransformation before eliciting their pharmacological action., Methods & Materials: The two different pharmacophores combine to give synergistic activity or may help in targeting the active drug to its target. Prodrug super seeds the problems of prodrug designing, for example solubility enhancement, bioavailability enhancement, chemical stability improvement, presystemic metabolism, site specific delivery, toxicity masking, improving patient acceptance, or eradicating undesirable adverse effects., Results: As an outcome the search for a prodrug or mutual prodrug with reduced toxicity has continued during recent years. This present review emphasizes the common help to revamp physiochemical, pharmaceutical and therapeutic effectiveness of drugs., Conclusion: This gives the researcher a common platform where they can find prodrugs of commonly used NSAIDs to overcome the gastrointestinal toxicity (irritation, ulcergenocity and bleeding).

Novel N3 aryl/heteroaryl substituted 2-((benzyloxy and phenylthio) methyl) 6,7-dimethoxyquinazolin-4(3H)- ones (8a-8l) were synthesized and evaluated for their anticonvulsant activity using various models of epilepsy, such as maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and intracerebroventricular AMPA (α-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid)-induced seizures in mice. The rotarod test has been used to determine the acute neurotoxicity. Further, the serum enzymatic activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were assessed along with histopathological examination of liver. Among all the derivatives, compound 8f displayed significant activity profile based on the overall magnitude of activity and minimum neurotoxicity.

A novel mutual prodrug (MA-P) consisting of mefenamic acid (MA) and paracetamol (P) has been synthesized as a gastrosparing NSAID, devoid of ulcerogenic side effects. The structure of synthesized drug was confirmed by elemental analysis, infrared spectroscopy, 1H NMR spectroscopy and mass spectrometry.The kinetics of ester hydrolysis was studied by HPLC at pH 2, pH 7.4 as well as in human plasma. The pharmacological activities (anti-inflammatory, analgesic and ulcerogenic) were evaluated for the synthesized drug. The ulcerogenic reduction in terms of gastric wall mucosa, hexosamine and total proteins were also measured in glandular stomach of rats. The results indicated that MA-P ester has better ulcer index than the parent drug.

Soluble Epoxide Hydrolase (sEH) is an important and promising new pharmacologic target for the treatment of acute systemic inflammation. Inhibition of sEH by a highly selective and potent sEH inhibitor (sEHI) elevates the epoxyeicosatrienoic acids (EETs) level in vivo leading to decreased inflammation. To explore the necessary structural requirement of 1, 3-disubstituted ureas as sEH inhibitors for anti-inflammatory activity, the molecular modeling studies have been pursued. A ligand-based pharmacophoric model and atom-based 3D-QSAR have been generated by Phase. Binding interaction as determined by the docking study revealed that these inhibitors interact at active site (ASP 335 & TYR 383) of sEH enzyme. The pharmacophore model was further used as a 3D query for virtual screening to retrieve potential inhibitors.