A5110268605- Trypanosoma species research and implications
- Synthesis and Biological Evaluation
- Research on Leishmaniasis Studies
- Pneumocystis jirovecii pneumonia detection and treatment
- Airway Management and Intubation Techniques
- Cardiac, Anesthesia and Surgical Outcomes
- HIV/AIDS drug development and treatment
- Tracheal and airway disorders
- Anesthesia and Sedative Agents
- Pharmacogenetics and Drug Metabolism
- Biochemical and Molecular Research
- Drug Transport and Resistance Mechanisms
- Medical History and Innovations
- Anesthesia and Pain Management
- Cancer therapeutics and mechanisms
- Antibiotics Pharmacokinetics and Efficacy
- Foreign Body Medical Cases
- Receptor Mechanisms and Signaling
- Tuberculosis Research and Epidemiology
- Synthesis and biological activity
- Anesthesia and Neurotoxicity Research
- Parasitic Infections and Diagnostics
- Drug-Induced Hepatotoxicity and Protection
- Phenothiazines and Benzothiazines Synthesis and Activities
- Ferrocene Chemistry and Applications
Nottingham Trent University
2024
Mercy Health
2023
Cardiff University
2005-2018
AstraZeneca (Sweden)
2018
AstraZeneca (United States)
2006-2018
Wilmington University
1990-2016
The University of Texas at Dallas
2015
Institute of Infection and Immunity
2015
University of North Carolina at Chapel Hill
2004-2013
University of Wales
1997-2008
The syntheses of nine new derivatives 2, 5-bis[4-(N-alkylamidino)phenyl]furans with extended aromatic systems are reported. interaction these dicationic furans poly(dA)poly(dT) and the duplex oligomers d(CGCGAATTCGCG)2 d(GCGAATTCGC)2 was determined by Tm measurement, effectiveness compounds against immunosuppressed rat model Pneumocystis carinii evaluated. At a screening dose 10 micromol/kg, 4 12 amidino described here more active than parent compound 1. In general, extension system in...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDicationic Diarylfurans as Anti-Pneumocystis carinii AgentsDavid W. Boykin, Arvind Kumar, Jaroslaw Spychala, Min Zhou, Richard J. Lombardy, David Wilson, Christine C. Dykstra, Susan K. Jones, James E. Hall, and Cite this: Med. Chem. 1995, 38, 6, 912–916Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAnalogs of 1,5-bis(4-amidinophenoxy)pentane (pentamidine) in the treatment experimental Pneumocystis carinii pneumoniaRichard R. Tidwell, Susan Kilgore Jones, J. Dieter Geratz, Kwasi A. Ohemeng, Michael Cory, and James Edwin HallCite this: Med. Chem. 1990, 33, 4, 1252–1257Publication Date (Print):April 1, 1990Publication History Published online1 May 2002Published inissue 1 April...
African sleeping sickness is a fatal parasitic disease, and all drugs currently in use for treatment have strong liabilities. It essential to find new, effective, less toxic drugs, ideally with oral application, control the disease. In this study, aromatic diamidine DB75 (furamidine) two aza analogs, DB820 DB829 (CPD-0801), as well their methoxyamidine prodrugs amidoxime metabolites, were evaluated against trypanosomes. The active parent diamidines showed similar vitro profiles different...
The aromatic diamidine pentamidine has long been used to treat early-stage human African trypanosomiasis (HAT). Two analogs of pentamidine, DB75 and DB820, have shown be more potent less toxic than in murine models trypanosomiasis. diphenyl furan diamidine, DB75, is the active metabolite prodrug DB289, which currently phase III clinical trials as a new orally candidate drug first-stage HAT. aza analog, DB844, undergoing preclinical evaluation HAT central nervous system. exact mechanisms...
A method for estimating glomerular filtration rate (GFR) has been developed that is based on an analysis of the total area under plasma radioactivity-time curve after a single intravenous injection [125I]iothalamate. Glomerular rates obtained by this (method A) and those with two widely used single-injection techniques, slope-intercept B), two-compartment C), were compared GFRs standard inulin clearance techniques in 14 dogs. Method B consistently over. estimated clearances more than 30%. C...
The syntheses of 12 new 2,5-bis[4-(N-alkylamidino)phenyl]furans are reported. interaction these dicationic furans with poly(dA-dT) and the duplex oligomer d(CGCGAATTCGCG)2 was determined by Tm measurements, effectiveness compounds against immunosuppressed rat model Pneumocystis carinii evaluated. At screening dose 10 μmol/kg, 9 14 N-alkylamidino described here more active than parent compound 1. Substitution an alkyl group on amidino nitrogen, except for in 9, 13, 15, resulted higher...
The antiprotozoal compound 1,5-di(4-amidinophenoxy)pentane (pentamidine) and 36 of its analogs were screened for in vitro activity against Leishmania mexicana amazonensis clone 669 C4S (MHOM/BR/73/M2269) Plasmodium falciparum clones W2 (Indochina III/CDC) D6 (Sierra Leone I/CDC). Pentamidine each the tested exhibited L. m. P. falciparum. pentamidine more effective than amazonensis. was extremely susceptible to these compounds, with 50% inhibitory concentrations as low 0.03 microM. While none...
The antiparasitic activity of aromatic diamidine drugs, pentamidine and furamidine, depends on their entry into the pathogenic protozoa via membrane transporters. However, no such transporter has been identified in mammalian cells. goal this study is to investigate whether these dicationic drugs are substrates for human organic cation transporters (hOCTs, solute carrier family 22A1–3) hOCTs play a role tissue distribution, elimination, toxicity. Inhibitory substrate activities furamidine...
Summary The haemodynamic changes of the prone position were investigated in 40 ASA I–II patients undergoing lumbar spine surgery. Patients randomly assigned, following propofol intravenous induction, to receive maintenance anaesthesia using either isoflurane 1–1.2% air or target controlled 3 μg.ml −1 infusion. Measurements non‐invasive blood pressure, heart rate and cardiac output made supine position. patient was then turned onto a Montreal pattern mattress measurements repeated. Cardiac...
We extended the self-assembly concepts of macromolecules in solutions to create a variety unique nanosized polymeric core−shell nanoparticles by means which allow scale-up for industrial production. This paper describes synthesis methods and mechanisms governing design structural features required beneficial use as performance-enhancing additives rubber vulcanizates well performance such compositions. The were prepared polymerization block copolymers their solvents into micelles followed...
DB289 [2,5-bis(4-amidinophenyl)furan-bis-<i>O</i>-methylamidoxime] is biotransformed to the potent antiparasitic diamidine DB75 [2,5-bis(4-amidinophenyl) furan] by sequential oxidative <i>O</i>-demethylation and reductive <i>N</i>-dehydroxylation reactions. Previous work demonstrated that reactions are catalyzed cytochrome <i>b</i><sub>5</sub>/NADH-cytochrome <i>b</i><sub>5</sub> reductase. Enzymes responsible for catalyzing pathway have not been identified. We report an in vitro metabolism...
Arylimidamides (AIAs) represent a new class of molecules that exhibit potent antileishmanial activity (50% inhibitory concentration [IC(50)], <1 microM) against both Leishmania donovani axenic amastigotes and intracellular Leishmania, the causative agent for human visceral leishmaniasis (VL). A systematic lead discovery program was employed to characterize in vitro vivo activities, pharmacokinetics, mutagenicities, toxicities two novel AIAs, DB745 DB766. They were exceptionally active...
Dicationic 2,4-bis(4-amidinophenyl)furans 5−10 and 2,4-bis(4-amidinophenyl)-3,5-dimethylfurans 14 15 have been synthesized. Thermal melting studies revealed high binding affinity of the compounds to poly(dA-dT) duplex oligomer d(CGCGAATTCGCG)2. All new were effective against Pneumocystis carinii pneumonia in immunosuppressed rat model with up 200-fold increase activity compared control compound pentamidine. No toxicity was noted for 5, 7−10 at dose 10 μmol/kg/d; however, isopropyl analogue 7...
Syntheses of several carbamate analogues 2, 5-bis(4-amidinophenyl)furan (1) under mild conditions and their evaluation as prodrugs against Pneumocystis carinii pneumonia (PCP) in an immunosuppressed rat model are described. Thus, nine new bis-carbamates: methoxycarbonyl (2), 2,2,2-trichloroethoxycarbonyl (3), ethylthiocarbonyl (4), benzyloxycarbonyl (5), (4-methyl-2-oxo-1, 3-dioxol-4-en-5-yl)methoxycarbonyl (6), phenoxycarbonyl (7), 4-fluorophenoxycarbonyl (8), 4-methoxyphenoxycarbonyl (9),...
Crystal structures are reported of complexes two novel furan derivatives berenil with alkyl benzamidine groups bound to the DNA sequence d(CGCGAATTCGCG)2. They have both been determined 2.2 Å resolution and refined R factors 16.9% 18.6%. In substituents, cyclopropyl isopropyl, found be orientated away from floor minor groove. The drugs located in groove by strong amidinium hydrogen bonds, O2 thymines situated at 5' 3' ends AT-rich region. isopropyl-substituted derivative has a tight...
1,5-Di(4-amidinophenoxy)pentane (pentamidine) and 38 analogs of pentamidine were screened for in vitro activity against the enteric protozoan Giardia lamblia WB (ATCC 30957). All compounds active G. as measured by a [methyl-3H]thymidine incorporation assay. Antigiardial varied widely, with 50% inhibitory concentrations (IC50s) ranging from 0.51 +/- 0.13 microM (mean standard deviation) most compound to over 100.0 least compounds. The IC50 potent antigiardial agent,...
On the basis of a previously observed correlation between antimicrobial activity and DNA binding strength dicationic molecules, series 10 dicationically substituted bis-benzimidazoles were tested for in rat model Pneumocystis carinii pneumonia. One compounds, 1,4-bis[5-(2-imidazolinyl)-2-benzimidazolyl]butane, was found to be more potent less toxic than pentamidine.
Diamidines 10a−g and 18a,b were obtained from dinitriles 9a−g 15a,b by treatment with lithium trimethylsilylamide or upon hydrogenation of bis-O-acetoxyamidoximes. Dinitriles prepared via Suzuki reactions between arylboronic acids arylnitriles. Potential prodrugs 12a−f 17 methylation the diamidoximes 11a−f 16a. Significant DNA affinities for rigid-rod molecules observed. Compounds 10a, 10b, 10d, 18a, 18b show IC50 values 5 nM less against Trypanosoma brucei rhodesiense (T. b. r.) 10e, gave...
Human African trypanosomiasis is a devastating disease with only few treatment options, including pentamidine. Diamidine compounds such as pentamidine, DB75, and DB820 are potent antitrypanosomal compounds. Previous investigations have shown that diamidines accumulate to high concentrations in trypanosomes. However, the mechanism of action this class remains unknown. A long-hypothesized has been binding DNA interference DNA-associated enzymes. The fluorescent diamidines, DB75 DB820, localize...