A5024933318- Carbohydrate Chemistry and Synthesis
- Chemical Synthesis and Analysis
- X-ray Diffraction in Crystallography
- Synthesis and Catalytic Reactions
- Crystallization and Solubility Studies
- Synthesis of β-Lactam Compounds
- Synthesis and biological activity
- Glycosylation and Glycoproteins Research
- Synthesis and Biological Evaluation
- Analytical Chemistry and Chromatography
- Pharmacogenetics and Drug Metabolism
- HIV/AIDS drug development and treatment
- Inflammatory mediators and NSAID effects
- Fluorine in Organic Chemistry
- Antibiotics Pharmacokinetics and Efficacy
- Malaria Research and Control
- Computational Drug Discovery Methods
- Synthesis of Organic Compounds
- Biochemical and Molecular Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Drug-Induced Adverse Reactions
- Cancer therapeutics and mechanisms
- Chemical Synthesis and Reactions
- Asymmetric Synthesis and Catalysis
- Drug Transport and Resistance Mechanisms
University of Liverpool
2016-2025
Liverpool Hospital
2019
AstraZeneca (United Kingdom)
2003-2014
Medical Research Council
2011-2014
Nottingham University Hospitals NHS Trust
2014
NIHR Nottingham Digestive Diseases Biomedical Research Unit
2014
University of Nottingham
2014
University of Exeter
2011
University of Oxford
1979-2011
Imperial College London
2006-2008
Covalent binding to proteins form neoantigens is thought be central the pathogenesis of penicillin hypersensitivity reactions. We have undertaken detailed mass spectrometric studies define mechanism and protein chemistry hapten formation from benzylpenicillin (BP) its rearrangement product, benzylpenicillenic acid (PA). Mass analysis human serum albumin exposed BP PA in vitro revealed that at low concentrations (drug molar ratio 0.001:1) during short time incubations selectively target...
The sequential activity of gut microbial and host processes can exert a powerful modulatory influence on dietary components, as exemplified by the metabolism amino acids tyrosine phenylalanine to p-cresol microbes, then glucuronide (pCG) enzymes. Although such conjugates are classically thought be biologically inert, there is accumulating evidence that this may not always case. We investigated pCG, studying its interactions with cerebral vasculature brain in vitro vivo. Male C57Bl/6 J mice...
We report the preparation and antiparasitic activity in vitro vivo of a series isoflavone derivatives related to genistein. These analogues retain 5,7-dihydroxyisoflavone core genistein: direct genistein (2-H isoflavones), 2-carboethoxy isoflavones, precursor deoxybenzoins were all evaluated. Excellent against Cryptosporidium parvum was observed for both classes isoflavones cell cultures, lead compound 19, RM6427, shows high efficacy an experimental infection.
In humans, metabolism of the commonly used nonsteroidal antiinflammatory drug diclofenac 1 yields principally 4'-hydroxy 2, 5-hydroxy 3, and acyl glucuronide 4 metabolites. All three metabolites have been implicated in rare idiosyncratic adverse reactions associated with this widely drug. Therefore, for mechanistic toxicological studies 1, substantial quantities 2−4 are required their syntheses characterization described here. Key steps were a convenient two-step preparation aniline 5 from...
We report the syntheses and activities of a wide range thiazolides [viz., 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide, NTZ] 1 is broad spectrum antiinfective agent effective anaerobic bacteria, viruses, parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 novel, potent, selective inhibitor replication (EC50 = 0.33 μm)...
Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities drug AG have been defined in great detail, adducts drugs, such as diclofenac, found liver plasma experimental animals humans. However, the absence definitive molecular characterization, specifically, identification signature glycation conjugates retaining glucuronyl...
The combination of TMSOTf and AgClO(4) promotes the efficient C-10-phenoxylation dihydroartemisinin (3) in good chemical yield excellent stereoselectivity. All new phenoxy derivatives have potent vitro antimalarial activity. On basis stereoselectivity obtained for p-trifluoromethyl derivative 7b, this compound parent phenyl-substituted 5b were selected vivo biological evaluation against Plasmodium berghei mouse model metabolism studies rats. Compound 7b demonstrated potency with an ED(50)...
Unsymmetrical dispiro- and spirotetraoxanes have been designed synthesized via acid-catalyzed cyclocondensation of bis(hydroperoxides) with ketones. Incorporation water-soluble polar functionalities, reductive amination amide bond formation, produces several analogues low nanomolar in vitro antimalarial activity. Several display an unprecedented level oral activity for this class endoperoxide drug.
In two steps from dihydroartemisinin, a small array of 16 semisynthetic C-10 pyrrole Mannich artemisinin derivatives (7a−p) have been prepared in moderate to excellent yield. vitro analysis against both chloroquine sensitive and resistant strains has demonstrated that these analogues nanomolar antimalarial activity, with several compounds being more than 3 times potent the natural product artemisinin. addition profile, molecules also very high therapeutic indices. Analysis optimal side chain...
A high-throughput screen (HTS) was undertaken against the respiratory chain dehydrogenase component, NADH:menaquinone oxidoreductase (Ndh) of Mycobacterium tuberculosis (Mtb). The 11000 compounds were selected for HTS based on known phenothiazine Ndh inhibitors, trifluoperazine and thioridazine. Combined (11000 compounds) in-house screening a limited number quinolones (50 identified ∼100 hits four distinct chemotypes, most promising which contained quinolone core. Subsequent Mtb complete...
Common methods for establishing the presence of enteric bacteria polluting water supplies, or in other samples, rely on detecting hydrolysis model glucuronide substrates by glucuronidases to release a...
Hydroxylated amino acids and their derivatives, including those found in proteins, are important biology medicinal chemistry. Incubation of N-acetyl- l -arginine with clavaminic acid synthase, a key oxygenase clavulanic biosynthesis, affords (3R)-hydroxylated product that is identical to material obtained by total synthesis from Boc-beta alanine. The step employed dynamic kinetic resolution (DKR) β-ketoester precursor, achieved high diastereomeric enantiomeric excess using an...
We report the activities of a number thiazolides [2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis C virus (HCV) genotypes IA and IB, using replicon assays. The structure-activity relationships (SARs) HCV are less predictable than B (HBV), though an electron-withdrawing group at C(5') generally correlates with potency. Among related salicyloylanilides, m-fluorophenyl analogue was most promising; niclosamide close analogues suffered from very low solubility bioavailability....
ABSTRACT The thiazolide nitazoxanide [2-acetolyloxy- N -(5-nitro-2-thiazolyl)benzamide] (NTZ) exhibits a broad spectrum of activities against wide variety intestinal and tissue-dwelling helminths, protozoa, enteric bacteria infecting animals humans. drug has been postulated to act via reduction its nitro group by nitroreductases, including pyruvate ferredoxin oxidoreductase. In this study, we investigated the efficacies number other thiazolides Neospora caninum tachyzoites in vitro. We...
Carboxylic acid-containing drugs are often metabolized to 1-β-O-acyl glucuronides (AGs). These can undergo an internal chemical rearrangement, and the resulting reactive positional isomers bind endogenous proteins, with clear potential for adverse effects. Additionally any 1-β-O-acyl-glucuronidated phase I metabolite of drug also show this propensity, investigation effect a needs consider such metabolites. Here transacylation common ibuprofen two its metabolites is investigated in vitro....
N(α)-Benzyloxycarbonyl-N(τ)-phenacyl-L-histidine (5) and N(α)-benzyloxycarbonyl-N(π)-phenacyl-L-histidine (6) have been prepared. Under carboxy-activating conditions which cause gross racemisation of (5), yields optically pure peptide. N(α)-t-Butoxycarbonyl-N(π)-phenacyl-L-histidine (7) has also prepared the practicability N(π)-phenacyl protective group (which is unchanged by strong aqueous or anhydrous acids essentially alkali, but quantitatively cleaved on treatment with zinc–acetic acid...
Acyl glucuronides are vital metabolites for many carboxylic acid containing drugs. We report an efficient new method the chemical synthesis of these molecules by selective 1β-acylation allyl glucuronate with acids catalyzed HATU and then mild deprotection through treatment Pd(PPh3)4 morpholine. The is effective a range aryl alkyl acids, including important