Novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives and their antitrypanosomal activities against T.brucei.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense and is invariably fatal unless treated. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work, informed by previous findings, presents novel 4-[4-(4-methylpiperazin-1-yl)phenyl]-6-arylpyrimidine derivatives with promising antitrypanosomal activity.

CYP1-Activation and Anticancer Properties of Synthetic Methoxylated Resveratrol Analogues.

Naturally occurring stilbenoids, such as the ()-stilbenoid resveratrol and the ()-stilbenoid combretastatin A4, have been considered as promising lead compounds for the development of anticancer drugs. The antitumour properties of stilbenoids are known to be modulated by cytochrome P450 enzymes CYP1A1 and CYP1B1, which contribute to extrahepatic phase I xenobiotic and drug metabolism. Thirty-four methyl ether analogues of resveratrol were synthesised, and their anticancer properties were assessed, using the MTT cell proliferation assay on a panel of human breast cell lines.

Thermal degradation of (2R, 3R)-dihydromyricetin in neutral aqueous solution at 100 ℃.

In the field of thermal degradation of flavonoids, current studies mainly focused on flavonols. However, the thermal degradation of dihydroflavonols in aqueous solution has received limited attention compared to flavonols. The single C2-C3 bonds of dihydroflavonols, which differs from the C2-C3 double bond in flavonols, may cause different degradation mechanisms.

Effect of the Citrus Flavone Nobiletin on Circadian Rhythms and Metabolic Syndrome.

The importance of the circadian clock in maintaining human health is now widely acknowledged. Dysregulated and dampened clocks may be a common cause of age-related diseases and metabolic syndrome Thus, circadian clocks should be considered as therapeutic targets to mitigate disease symptoms. This review highlights a number of dietary compounds that positively affect the maintenance of the circadian clock.

Artemisinin Cocrystals for Bioavailability Enhancement. Part 2: Bioavailability and Physiologically Based Pharmacokinetic Modeling.

We report the evaluation and prediction of the pharmacokinetic (PK) performance of artemisinin (ART) cocrystal formulations, that is, 1:1 artemisinin/orcinol (ART-ORC) and 2:1 artemisinin/resorcinol (ART-RES), using murine animal and physiologically based pharmacokinetic (PBPK) models. The efficacy of the ART cocrystal formulations along with the parent drug ART was tested in mice infected with . When given at the same dose, the ART cocrystal formulation showed a significant reduction in parasitaemia at day 4 after infection compared to ART alone.

Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient.

Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability, and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e.

Advance toward isolation, extraction, metabolism and health benefits of kaempferol, a major dietary flavonoid with future perspectives.

As a major ubiquitous secondary metabolite, flavonoids are widely distributed in . Among flavonoids, kaempferol is a typical natural flavonol in diets and medicinal plants with myriad bioactivities, such as anti-inflammatory activity, anti-cancer activity, antioxidant activity, and anti-diabetic activity. However, the natural sources, absorption and metabolism as well as the bioactivities of kaempferol have not been reviewed comprehensively and systematically.

A Brief Overview of Potential Treatments for Viral Diseases Using Natural Plant Compounds: The Case of SARS-Cov.

The COVID-19 pandemic, as well as the more general global increase in viral diseases, has led researchers to look to the plant kingdom as a potential source for antiviral compounds. Since ancient times, herbal medicines have been extensively applied in the treatment and prevention of various infectious diseases in different traditional systems. The purpose of this review is to highlight the potential antiviral activity of plant compounds as effective and reliable agents against viral infections, especially by viruses from the coronavirus group.

Activity of Antioxidants from L. Petals: Potential Preventive Effects towards Cardiovascular System.

The petals of the saffron crocus ( L.) are considered a waste material in saffron production, but may be a sustainable source of natural biologically active substances of nutraceutical interest. The aim of this work was to study the cardiovascular effects of kaempferol and crocin extracted from saffron petals.

The discovery of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines.

Human African trypanosomiasis, or sleeping sickness, is a neglected tropical disease caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense which seriously affects human health in Africa. Current therapies present limitations in their application, parasite resistance, or require further clinical investigation for wider use. Our work herein describes the design and syntheses of novel antitrypanosomal 4-phenyl-6-(pyridin-3-yl)pyrimidines, with compound 13, the 4-(2-methoxyphenyl)-6-(pyridine-3-yl)pyrimidin-2-amine demonstrating an IC value of 0.

Analysis of plant secondary metabolism using stable isotope-labelled precursors.

Introduction: Analysis of biochemical pathways typically involves feeding a labelled precursor to an organism, and then monitoring the metabolic fate of the label. Initial studies used radioisotopes as a label and then monitored radioactivity in the metabolic products. As analytical equipment improved and became more widely available, preference shifted the use stable 'heavy' isotopes like deuterium ( H)-, carbon-13 ( C)- and nitrogen-15 ( N)-atoms as labels.

Flavones as tyrosinase inhibitors: kinetic studies in vitro and in silico.

Introduction: Tyrosinase is a multifunctional copper-containing oxidase enzyme that catalyses the first steps in the formation of melanin pigments. Identification of tyrosinase inhibitors is of value for applications in cosmetics, medicine and agriculture.

Objective: To develop an analytical method that allows identification of drug-like natural products that can be further developed as tyrosinase inhibitors.

The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells.

As part of a programme to develop anticancer prodrugs which are activated by cytochrome P450 (CYP)1B1, a library of 4,6-diaryl-2-pyridones was synthesised in yields of 6-60% from the corresponding chalcones. A number of these derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing little toxicity towards a non-tumour breast cell line with no CYP expression. Metabolism studies provided evidence supporting the involvement of CYP1 enzymes in the bioactivation of these compounds.

Investigation of Linum flavum (L.) Hairy Root Cultures for the Production of Anticancer Aryltetralin Lignans.

hairy root lines were established from hypocotyl pieces using strains LBA 9402 and ATCC 15834. Both strains were effective for transformation but induction of hairy root phenotype was more stable with strain ATCC 15834. Whereas similar accumulation patterns were observed in podophyllotoxin-related compounds (6-methoxy-podophyllotoxin, podophyllotoxin and deoxypodophyllotoxin), significant quantitative variations were noted between root lines.

New Hydrogels Enriched with Antioxidants from Saffron Crocus Can Find Applications in Wound Treatment and/or Beautification.

Saffron extracts have a long history of application as skin protectant, possibly due to their ability to scavenge free radicals. In this work, the performance of a hydrogel enriched with antioxidant compounds isolated from saffron crocus (Crocus sativus L.) petals was tested.

The Synthesis of Chalcones as Anticancer Prodrugs and their Bioactivation in CYP1 Expressing Breast Cancer Cells.

Background: Although the expression levels of many P450s differ between tumour and corresponding normal tissue, CYP1B1 is one of the few CYP subfamilies which is significantly and consistently overexpressed in tumours. CYP1B1 has been shown to be active within tumours and is capable of metabolising a structurally diverse range of anticancer drugs. Because of this, and its role in the activation of procarcinogens, CYP1B1 is seen as an important target for anticancer drug development.

Flavonoids and Their Metabolites: Prevention in Cardiovascular Diseases and Diabetes.

The occurrence of atherosclerosis and diabetes is expanding rapidly worldwide. These two metabolic disorders often co-occur, and are part of what is often referred to as the metabolic syndrome. In order to determine future therapies, we propose that molecular mechanisms should be investigated.

Synthesis and antitrypanosomal activities of novel pyridylchalcones.

A library of novel pyridylchalcones were synthesised and screened against Trypanosoma brucei rhodesiense. Eight were shown to have good activity with the most potent 8 having an IC value of 0.29 μM.

Design, synthesis and antitrypanosomal activities of 2,6-disubstituted-4,5,7-trifluorobenzothiophenes.

Current treatments for Human African Trypanosomiasis (HAT) are limited in their application, have undesirable dosing regimens and unsatisfactory toxicities highlighting the need for the development of a safer drug pipeline. Our medicinal chemistry programme in developing rapidly accessible and modifiable heterocyclic scaffolds led to the design and synthesis of novel substituted benzothiophenes, with 6-benzimidazol-1-ylbenzothiophene derivatives demonstrating significant antitrypanosomal activities (IC50 < 1 μM) against Trypanosoma brucei rhodesiense and no toxicity towards mammalian cells.

Petals of Crocus sativus L. as a potential source of the antioxidants crocin and kaempferol.

Saffron from the province of L'Aquila, in the Abruzzo region of Italy, is highly prized and has been awarded a formal recognition by the European Union with EU Protected Designation of Origin (PDO) status. Despite this, the saffron regions are abandoned by the younger generations because the traditional cultivation of saffron (Crocus sativus L.) is labour intensive and yields only one crop of valuable saffron stamens per year.

Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells.

Recent studies have demonstrated cytochrome P450 CYP1-mediated metabolism and CYP1-enzyme induction by naturally occurring flavonoids in cancer cell line models. The arising metabolites often exhibit higher activity than the parent compound. In the present study we investigated the CYP1-mediated metabolism of the citrus polymethoxyflavone nobiletin by recombinant CYP1 enzymes and MCF7 breast adenocarcinoma cells.

CYP1-mediated antiproliferative activity of dietary flavonoids in MDA-MB-468 breast cancer cells.

Among the different mechanisms proposed to explain the cancer-protecting effect of dietary flavonoids, substrate-like interactions with cytochrome P450 CYP1 enzymes have recently been explored. In the present study, the metabolism of the flavonoids chrysin, baicalein, scutellarein, sinensetin and genkwanin by recombinant CYP1A1, CYP1B1 and CYP1A2 enzymes, as well as their antiproliferative activity in MDA-MB-468 human breast adenocarcinoma and MCF-10A normal breast cell lines, were investigated. Baicalein and 6-hydroxyluteolin were the only conversion products of chrysin and scutellarein metabolism by CYP1 family enzymes, respectively, while baicalein itself was not metabolized further.

The methoxylated flavones eupatorin and cirsiliol induce CYP1 enzyme expression in MCF7 cells.

Flavonoids have often been associated with cancer prevention and activity of the human cytochrome P450 enzymes CYP1A1 and CYP1B1 with the occurrence of cancer. The flavones eupatorin (1) and cirsiliol (2) enhanced CYP1 enzyme activity in a concentration-dependent manner in MCF7 human breast adenocarcinoma cells. In the range of 0-2.

Enhancement of artemisinin concentration and yield in response to optimization of nitrogen and potassium supply to Artemisia annua.

Background And Aims: The resurgence of malaria, particularly in the developing world, is considerable and exacerbated by the development of single-gene multi-drug resistances to chemicals such as chloroquinone. Drug therapies, as recommended by the World Health Organization, now include the use of antimalarial compounds derived from Artemisia annua--in particular, the use of artemisinin-based ingredients. Despite our limited knowledge of its mode of action or biosynthesis there is a need to secure a supply and enhance yields of artemisinin.