Pharmacophore modeling, design, and synthesis of potent antihypertensives, oxazolo/thiazolo-[3,2-a]-pyrimidin-3(2H)-one, and 1,5-dihydroimidazo-[1,2-a]-pyrimidin-3(2H)-one derivatives: A pilot trial.

An improved pharmacophore model, molecular properties, geometric analyses, and SAR led to synthesize oxazolo/thiazolo-[3,2-a]-pyrimidin-3(2H)-one, and 1,5-dihydroimidazo-[1,2-a]-pyrimidin-3(2H)-one derivatives exhibiting potent anti-hypertensive activity. The 6-ethoxycarbonyl-2,7-dimethyl-5-phenyl-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4g), and 6-ethoxycarbonyl-2,7-dimethyl-5-(3-methyl-phenyl)-1,5-dihydroimidazo[3,2-a]pyrimidin-3(2H)-one (4h) showed significant reduction in mean arterial blood pressure (MABP, mm/Hg) of 79.78%, and 92.95% in 6 and 12 h durations, respectively, at 1.5 mg/kg body-weight dose, while at 3.0 mg/kg body-weight dose, the MABP reduction was achieved at 95.46%, and 92.02%, respectively, in 6 and 12 h durations, as compared to the standard drug, nifedipine.

Novel glycoside from Wedelia calendulacea inhibits diethyl nitrosamine-induced renal cancer via downregulating the COX-2 and PEG2 through nuclear factor-κB pathway.

A new compound derivative of glycoside 19-α-hydroxy-ursolic acid glucoside (19-α-hydroxyurs-12(13)-ene-28-oic acid-3-O-ß-D-glucopyranoside (HEG) was isolated from whole plant of Wedelia calendulacea (Compositae). The structure was elucidated and established by standard spectroscopy approaches. Diethylnitrosamine (DEN) (200 mg/kg) and ferric nitrilotriacetate (Fe-NTA) (9 mg/kg) were used for induction of renal cell carcinoma (RCC) in the rats. The rats were further divided into different groups and were treated with HEG doses for 22 weeks. Anti-cancer effect in RCC by HEG was dose dependent to restrict the macroscopical changes as compared to DEN + Fe-NTA-control animals. Significant alteration in biochemical parameters and dose-dependent alleviation in Phase I and Phase II antioxidant enzymes were responsible for its chemo-protective nature. HEG in dose-dependent manner was significant to alter the elevated levels of pro-inflammatory cytokines and inflammatory mediators during RCC. The histopathological changes were observed in the HEG pre-treated group, which was proof for its safety concern as far as its toxicity is concerned. The isolated compound HEG can impart momentous chemo-protection against experimental RCC by suppressing the cyclooxygenase (COX-2) and prostaglandin E2 (PGE2) expression via nuclear factor-kappa B (NF-κB) pathway.

Polysorbate-80-coated, polymeric curcumin nanoparticles for in vivo anti-depressant activity across BBB and envisaged biomolecular mechanism of action through a proposed pharmacophore model.

Depression is a modern world epidemic. Its main causative factor is oxidative stress, as reported in study subjects. Natural products are yet to show significant therapeutic effects in comparison with synthetic drugs. Current study deals with the preparation of brain-targeted polysorbate-80-coated curcumin PLGA nanoparticles (PS-80-CUR-NP), and their characterisation via Spectral and optical methods. PS-80-CUR-NP were evaluated against the oxidative stress-mediated depressant (OSMD) activity via Force despair, Tail suspension tests and stress biomarker assay (SOD and catalase activity). A significant reduction in immobility (p < 0.01) in force despair and tail suspension test and a significant increase (p < 0.001 and p < 0.01) in SOD and catalase activity was found and compared with stress control, which confirmed the OSMD activity of PS-80-CUR-NP at 5 mg equivalent dose. Further, AUC(0.5-15 h) curve of brain homogenates estimated the curcumin concentration of 1.73 ng/g C max at T max 3 h via HPLC technique.

Mechanistic and Etiological Similarities in Diabetes Mellitus and Alzheimer's Disease: Antidiabetic Drugs as Optimistic Therapeutics in Alzheimer's Disease.

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.

Synthesis, biological evaluation and molecular dynamics studies of oxadiazine derivatives as potential anti-hepatotoxic agents.

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.

Structural Activity Relationship based Medicinal Perspectives of Pyrimidine Derivatives as Anti-Alzheimer's Agents: A Comprehensive Review.

Pyrimidine is an aromatic and heterocyclic organic compound containing a 6-membered ring consisting of four carbon and two nitrogen atoms on alternative positions. Pyrimidine scaffolds described their existence in the medicinal chemist's cause for their synthesizing practicability and nonpoisonous nature. However, the reason behind neurological disorders is still an open challenge for scientific research and development organizations. Efficacy voids are widespread before researchers, despite high throughput research in the field of anti-Alzheimer's drugs.Researchers have constantly investigated all the probabilities for restraining the unwanted adverse effects of the anti-Alzheimer's agents and are focusing more extensively to rehabilitate neurological disorders. The scientific literature on drug development has been an aspiration to medicinal chemists and other researchers to facilitate further research. Therefore, this review emphasizes the structure-activity relationship (SAR) based approach and the pharmacological advancements of pyrimidine moiety in the new era of therapeutics as anti-Alzheimer's agents.

Structure-Activity Relationship Insight of Naturally Occurring Bioactive Molecules and Their Derivatives Against Non-Small Cell Lung Cancer: A Comprehensive Review.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a deadly disease that affects millions globally and its treatment includes surgery, chemotherapy, and radiotherapy. Chemotherapy and radiotherapy have many disadvantages, which include potential harmful side effects. Due to the widespread use of drugs in lung cancer, drug treatment becomes challenging due to multidrug resistance and adverse reactions. According to the recent findings, natural products (NPs) and their derivatives are being used to inhibit and suppress cancer cells. OBJECTIVE: Our objective is to highlight the importance of phytochemicals for treating NSCLC by focusing on the structural features essential for the desired activity with fewer side effects compared to synthetic molecules. METHODS: This review incorporated data from the most recent literature, including in vitro, in vivo, nanoformulation-based recent advancements, and clinical trials, as well as the structure-activity relationship (SAR), described for a variety of possible natural bioactive molecules in the treatment of NSCLC. RESULTS: The analysis of data from recent in vitro, in vivo studies and ongoing clinical trials are highlighted. The SAR studies of potential NPs signify the presence of several common structural features that can be used to guide future drug design and development. CONCLUSION: The role of NPs in the battle against NSCLC can be effective, as evidenced by their structural diversity and affinity toward various molecular targets. The main purpose of the review is to gather information about NPs used in the treatment of NSCLC.

Recent Advancement of Pyrazole Scaffold Based Neuroprotective Agents: A Review.

As a source of therapeutic agents, heterocyclic nitrogen-containing compounds and their derivatives are still interesting and essential. Pyrazole, a five-member heteroaromatic ring with two nitrogen atoms, has a major impact in chemical industries as well as pharmaceutical industries. Due to its wide range of biological activities against various diseases, it has been identified as a biologically important heterocyclic scaffold. The treatment of neurological disorders has always been a difficult task in both the past and present. Therefore, identifying therapeutically effective molecules for neurological conditions remains an open challenge in biomedical research and development. For developing novel entities as neuroprotective agents, recently, pyrazole scaffold has attracted medicinal chemists worldwide. The major focus of research in this area is discovering novel molecules as neuroprotective agents with minimal adverse effects and better effectiveness in improving the neurological condition. This review mainly covers recent developments in the neuropharmacological role of pyrazole incorporated compounds, including their structural-activity relationship (SAR), which also further includes IC50 values (in mM as well as in µM), recent patents, and a brief history as neuroprotective agents.

Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives.

In continuance of our search for newer antihepatotoxic agents some novel pyrazoline derivatives containing 1,4-dioxane ring system were synthesized starting from 3-(2,3-dihydro-1,4-benzodioxane-6-yl)-1-substituted-phenylprop-2-en-1-one. Some of the synthesized compounds were evaluated for antihepatotoxic activity against CCl(4)-induced hepatotoxicity in rats. Among them some compounds have shown significant antihepatotoxic activity comparable to standard drug silymarin.

Synthesis and antihepatotoxic activity of 2-(substituted-phenyl)-5-(2,3-dihydro-1,4-benzodioxane-2-yl)-1,3,4-oxadiazole derivatives.

Novel 1,3,4-oxadizole derivatives containing the 1,4-dioxane ring system were synthesised starting from 2,3-dihydro-1,4-benzodioxane-2-carbohydrazide. The synthesised compounds were evaluated for antihepatotoxic activity against CCl4-induced hepatotoxicity in rats. Some compounds demonstrated a significant antihepatotoxic activity comparable to the standard drug Silymarin.

The controversial therapeutic journey of chloroquine and hydroxychloroquine in the battle against SARS-CoV-2: A comprehensive review.

Recently, the pandemic outbreak of a novel coronavirus, officially termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indicated by a pulmonary infection in humans, has become one of the most significant challenges for public health. In the current fight against coronavirus disease-2019, the medical and health authorities across the world focused on quick diagnosis and isolation of patients; meanwhile, researchers worldwide are exploring the possibility of developing vaccines and novel therapeutic options to combat this deadly disease. Recently, based on various small clinical observations, uncontrolled case studies and previously reported antiviral activity against SARS-CoV-1 chloroquine (CQ) and hydroxychloroquine (HCQ) have attracted exceptional consideration as possible therapeutic agents against SARS-CoV-2. However, there are reports on little to no effect of CQ or HCQ against SARS-CoV-2, and many reports have raised concerns about their cardiac toxicity. Here, in this review, we examine the chemistry, molecular mechanism, and pharmacology, including the current scenario and future prospects of CQ or HCQ in the treatment of SARS-CoV-2.

Antihepatotoxic activity of debelalactone, a new oxirano-furanocoumarin from Phyllanthus debilis.

The whole plant of Phyllanthus debilis (Euphorbiacae) afforded a new oxirano-furanocoumarin, characterized as 5-hydroxy-7-methoxy-furanocoumarin-9(14)-cyclohex-12(13)-oxirano-11-one (1), named as debelalactone. Debelalactone exhibited a significant antihepatotoxic activity by reducing the elevated levels of serum enzymes such as serum glutamate oxaloacetate transaminase (SGOT) by 59.14%, serum glutamate pyruvate oxaloacetate transaminase (SGPT) by 61.84%, and alkaline phosphatase (ALP) by 85.93%; while the total protein (TP) levels were increased by 110.35%, when compared with standard drug silymarin that have decreased SGOT by 77.03%, SGPT by 69.67%, ALP by 93.18%, and increased TP levels by 100.48%, respectively, against CCl(4)-induced toxicity in Wistar rats. These biochemical observations were also supplemented by histopathological examinations of the liver sections.

Antihypertensive activity, toxicity and molecular docking study of newly synthesized xanthon derivatives (xanthonoxypropanolamine).

CONTEXT: Xanthone derivatives have been reported to possess a wide range of biological properties. In effort to search new effective antihypertensive compounds, we have synthesizednovel xanthone derivatives (xanthonoxypropanolamines) and got patent for these compounds (The Patent Office, Government of India, S. No.: 011-016308, Patent No.: 250538). OBJECTIVE: In the present work, we attempted to establish the antihypertensive activity, toxicity and molecular docking study forthese newly synthesized compounds (1a, 1b and 2). MATERIALS AND METHOD: The preliminary antihypertensive screening was performed by administering synthesized compounds and standard drugs intraperitonially and orally into wistar rats. The change in systolic, diastolic and the mean blood pressure before and after the treatment of the drugs was measured on a Digital LE-S100 Blood Pressure Meter by Tail-cuff method non-invasively. Toxicity studies were carried out after oral administration of synthesized compounds to rats at doses of 25, 50, and 100mg/kg. The serum samples were tested for different toxicity parameters such as liver function test, kidney function test etc. The docking simulations of all the compounds were performed using Maestro, version 9.4 implemented from Schrodinger software suite. RESULTS AND DISCUSSION: The result showed that the compound 1a, 1b and 2 have greater antihypertensive activity with almost equal or less toxicity profile in comparison to standard drug Propranolol and Atenolol. The docking score for the compound 1b was found -9.1 while for compound 1a and 2 were found -8.7 and -8.6 respectively. CONCLUSION: These novel compounds i.e. 1a, 1b, and 2 have greater antihypertensive activity in comparison to standard drugs Propranolol and Atenolol. All these compounds do not have any toxicity.

Syntheses and anti-depressant activity of 5-amino-1, 3, 4-thiadiazole-2-thiol imines and thiobenzyl derivatives.

A number of new imine derivatives of 5-amino-1, 3, 4-thiadiazole-2-thiol have been synthesized, and their anti-depressant activity was tested using imipramine as reference drug. Two compounds namely 5-{[1-(4-chlorophenyl)-3-(4-methoxy-phenyl)prop-2-en-1-ylidene]-amino}-5-benzylthio-1, 3,4 -thiadiazole 4i(b) and 5-{[1-(4-chlorophenyl)-3-(4-dimethyl-aminophenyl)-prop-2-en-1-ylidene]amino}-5-benzylthio-1,3,4-thiadiazole 4i(c) have shown significant anti-depressant activity, which decreased immobility time by 77.99% and 76.26% compared to the standard imipramine (82%). All the compounds in the series have passed neurotoxicity tests.

Deconvoluting the dual hypoglycemic effect of wedelolactone isolated from Wedelia calendulacea: investigation via experimental validation and molecular docking.

Wedelia calendulacea has a long history of use in the Indian Ayurvedic System of Medicine for the treatment, prevention, and cure of a diverse range of human diseases such as diabetes obesity, and other metabolic diseases. A wide range of chemical constituents, such as triterpenoid saponin, kauren diterpene, and coumestans, has been isolated from the plant. Conversely, no published literature is available in relation to the isolation of wedelolactone (WEL) for its anti-diabetic effect. The aim of the present study was to isolate the bioactive phyto-constituent from Wedelia calendulacea and to scrutinize the antidiabetic effect with its possible mechanism of action. The structure of the isolated compound was elucidated by different spectroscopy techniques. Proteins, such as dipeptidyl peptidase-4 (DPPIV), glucose transporter 1 (GLUT1), and peroxisome proliferator-activated receptors-γ (PPARγ), were also subjected to in silico docking. Later, this isolated compound was scrutinized against α-glucosidase and α-amylase enzyme activity along with an oral glucose tolerance test (OGTT) for estimation of glucose utilization. Streptozotocin (STZ) was used for the induction of type II diabetes mellitus (DM) in Wistar rats. The rats were divided into different groups and received the WEL (5, 10, and 20 mg kg-1, b.w.) and glibenclamide (2.5 mg kg-1, b.w.) for 28 days. The blood glucose level (BGL), plasma insulin, and body weight were determined at regular time intervals. The serum lipid profile hypolipidemic effect for the different antioxidant markers and hepatic tissue markers were scrutinized along with an inflammatory mediator to deduce the possible mechanism. With the help of spectroscopy techniques, the isolated compound was identified as wedelolactone. In the docking study, WEL showed docking scores of -6.17, -9.43, and -7.66 against DPP4, GLUTI, and PRARY, respectively. WEL showed the inhibition of α-glucosidase (80.65%) and α-amylase (93.83%) and suggested an effect on postprandial hyperglycemia. In the OGTT, WEL significantly (P < 0.001) downregulated the BGL, a marker for better utilization of drugs. In the diabetes model, WEL reduced the BGL and enhanced the plasma insulin and body weight. It also significantly (P < 0.001) modulated the lipid profile; this suggested an anti-hyperlipidemia effect. WEL significantly (P < 0.001) distorted the hepatic tissue, acting as an antioxidant marker in a dose-dependent manner. WEL significantly (P < 0.001) downregulated the C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) level. On the basis of the available results, we can conclude that WEL can be an alternative drug for the treatment of type II DM either by inhibiting the production of inflammatory mediator or by the downregulation of oxidative stress.

Crotalic and emarginellic acids: two triterpenes from Crotalaria emarginella and anti-inflammatory and anti-hepatotoxic activity of crotalic acid.

The aerial parts of Crotalaria emarginella Vatke (Leguminosae) has afforded two triterpenes, characterized as 3alpha-hydroxy-arbor-12-ene-28-carboxylic acid, designated as crotalic acid (1), and 2beta,3beta,21-trihydroxy-arbor-12-ene-29-carboxylic acid, designated as emarginellic acid (2). The structures of the isolated products were elucidated on the basis of spectral and chemical studies. On screening the biological activity, the crotalic acid (1) exhibited a significant anti-inflammatory activity (dose: 10mg/kg), which showed 53% inhibitory effect. Whereas, the standard oxyphenyl butazone (100mg/kg) exhibited 69% inhibition with respect to carrageenan (0.05ml, 1%) used to cause inflammation in rat paw method. In addition, it also showed anti-hepatotoxic activity by 13-30% with respect to standard silybon-70 (35-57%) against CCl(4) induced toxicity in Wistar rats.

Advances in preparation and characterization of chitosan nanoparticles for therapeutics.

CONTEXT: Polymers have been largely explored for the preparation of nanoparticles due to ease of preparation and modification, large gene/drug loading capacity, and biocompatibility. Various methods have been adapted for the preparation and characterization of chitosan nanoparticles. OBJECTIVE: Focus on the different methods of preparation and characterization of chitosan nanoparticles. METHODS: Detailed literature survey has been done for the studies reporting various methods of preparation and characterization of chitosan nanoparticles. RESULTS AND CONCLUSION: Published database suggests of several methods which have been developed for the preparation and characterization of chitosan nanoparticles as per the application.

Effect of size on biological properties of nanoparticles employed in gene delivery.

CONTEXT: The size of nanoparticles plays a pivotal role in determining the gene delivery efficiency. OBJECTIVE: A focus on the studies done to investigate the effect of nanoparticles size on biological aspects of gene delivery. METHODS: A through literature survey has been done regarding studies done to investigate the effect of nanoparticles size on uptake, transfection efficiency and biodistribution has been cited in the present review. RESULTS AND CONCLUSION: The gene delivery efficacy may depend on conjugation of several factors such as the chemical structure of polymers, cell type, and nanoparticle size, composition and interaction with cells.

RNA interference technology with emphasis on delivery vehicles-prospects and limitations.

CONTEXT: RNA interference (RNAi)-based therapeutics rely upon safe and efficient delivery of small interfering RNA (siRNA) molecules. OBJECTIVE: This review explores various dimensions of RNAi with emphasis on the development of nanoparticle-based delivery vectors for safe and efficient siRNA delivery. METHODS: An exhaustive database search has been done regarding studies done to investigate the potential of siRNA delivery employing nanoparticles has been cited in the present review. RESULTS AND CONCLUSION: With the current challenges, there is a need for collaborative work allowing for the successful development of nanoparticle/siRNA complexes as health-promoting biotherapeutics.

Three new diterpenes and the biological activity of different extracts of Jasonia montana.

Three new diterpenes, namely jasonin-a (1), jasonin-b (2), and jasonin-c (3) were isolated from the aerial parts of Jasonia montana (Asteraceae). Their structures were elucidated on the basis of spectral data as [(1E)-2-((2S)-1,2,5-trimethylbicyclo[3.2.l]octan-8-yl)vinyl] benzene-3-carboxylic acid (1), [3-((2S, 5S)-1,2, 5-trimethylcycloheptanyl)propyl]benzene-3-carboxylic acid (2), and [(1E)-3-((7R)-1,7-dimethy-4-methylenecycloheptanyl)prop-1-enyl] benzene-3-carboxylic acid (3). In addition, the previously reported 5,7,3'-trihydroxy-3,6,4'-trimethoxy flavone designated as centaureidin (4), was also isolated and characterized from this source. The different extracts of the plant were also screened for hypoglycemic, antidiabetic, and antimicrobial activities, wherein the petroleum ether and ethanolic extracts exhibited hypoglycemic and antidiabetic activity, and the petroleum ether and chloroform extracts showed antimicrobial activity.