Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 55(17): 7425-36, 2012 Sep 13.
Article in English | MEDLINE | ID: mdl-22877245

ABSTRACT

Plasmodium falciparum causes approximately 1 million deaths annually. However, increasing resistance imposes a continuous threat to existing drug therapies. We previously reported a number of potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase that inhibit parasite in vitro growth with similar activity. Lead optimization of this series led to the recent identification of a preclinical candidate, showing good activity against P. falciparum in mice. As part of a backup program around this scaffold, we explored heteroatom rearrangement and substitution in the triazolopyrimidine ring and have identified several other ring configurations that are active as PfDHODH inhibitors. The imidazo[1,2-a]pyrimidines were shown to bind somewhat more potently than the triazolopyrimidines depending on the nature of the amino aniline substitution. DSM151, the best candidate in this series, binds with 4-fold better affinity (PfDHODH IC(50) = 0.077 µM) than the equivalent triazolopyrimidine and suppresses parasites in vivo in the Plasmodium berghei model.


Subject(s)
Enzyme Inhibitors/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Plasmodium falciparum/enzymology , Pyrimidines/pharmacology , Animals , Dihydroorotate Dehydrogenase , Enzyme Inhibitors/chemistry , Mice , Molecular Mimicry , Plasmodium berghei/drug effects , Pyrimidines/chemistry , Structure-Activity Relationship
2.
J Med Chem ; 52(7): 1864-72, 2009 Apr 09.
Article in English | MEDLINE | ID: mdl-19296651

ABSTRACT

Plasmodium falciparum causes 1-2 million deaths annually. Yet current drug therapies are compromised by resistance. We previously described potent and selective triazolopyrimidine-based inhibitors of P. falciparum dihydroorotate dehydrogenase (PfDHODH) that inhibited parasite growth in vitro; however, they showed no activity in vivo. Here we show that lack of efficacy against P. berghei in mice resulted from a combination of poor plasma exposure and reduced potency against P. berghei DHODH. For compounds containing naphthyl (DSM1) or anthracenyl (DSM2), plasma exposure was reduced upon repeated dosing. Phenyl-substituted triazolopyrimidines were synthesized leading to identification of analogs with low predicted metabolism in human liver microsomes and which showed prolonged exposure in mice. Compound 21 (DSM74), containing p-trifluoromethylphenyl, suppressed growth of P. berghei in mice after oral administration. This study provides the first proof of concept that DHODH inhibitors can suppress Plasmodium growth in vivo, validating DHODH as a new target for antimalarial chemotherapy.


Subject(s)
Antimalarials/chemical synthesis , Malaria/drug therapy , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Plasmodium berghei/enzymology , Plasmodium falciparum/enzymology , Pyrimidines/chemical synthesis , Thiazoles/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Dihydroorotate Dehydrogenase , Humans , In Vitro Techniques , Malaria/parasitology , Male , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Parasitic Sensitivity Tests , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Triazoles/chemistry , Triazoles/pharmacology
3.
J Hazard Mater ; 167(1-3): 237-43, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19185990

ABSTRACT

The electrode characteristics and selectivities of PVC-based mercury(II) selective coated graphite electrode (CGE) and polymeric membrane electrode (PME) incorporating the recently synthesized 1-furan-2-yl-4-(4-nitrophenyl)-2-phenyl-5H-imidazole-3-oxide are reported here. The electrodes exhibit Nernstian slope for mercury(II) ions over wide concentration ranges, i.e. 1.0 x 10(-1)M to 1.0 x 10(-6)M (with CGE) and 1.0 x 10(-1)M to 1.0 x 10(-5)M (with PME). The lower detection limits shown by CGE and PME are 8.91 x 10(-7)M and 6.30 x 10(-6)M, respectively, in the pH range of 1.0-4.0. From the comparative study of these electrodes, CGE has been found to be better than PME in terms of lower detection limit and better selectivity for mercury(II) ions with comparatively less interference from silver(I) ions. The proposed electrodes can be successfully used as an indicator electrode for potentiometric titration of mercury with potassium dichromate. The electrodes have been successfully applied for estimation of mercury content in synthetic water samples, insecticide (parad tablet) and dental amalgam.


Subject(s)
Mercury/analysis , Potentiometry/methods , Dental Amalgam , Electrodes , Hydrogen-Ion Concentration , Imidazoles , Insecticides , Potentiometry/instrumentation , Water Pollutants, Chemical/analysis
4.
Ann Chim ; 97(9): 959-70, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17970311

ABSTRACT

Mercury ion-selective electrodes (ISEs) were prepared with a polymeric membrane based on heterocyclic systems: 2-methylsulfanyl-4-(4-nitro-phenyl)-l-p-tolyl-1H-imidazole (I) and 2,4-diphenyl-l-p-tolyl-1H-imidazole (II) as the ionophores. Several ISEs were conditioned and tested for the selection of common ions. The electrodes based on these ionophores showed a good potentiometric response for Hg2+ ions over a wide concentration range of 5.0 x 10(5-) - 1.0 x 10(-1)M with near-Nernstian slopes. Stable potentiometric signals were obtained within a short time period of 20 s. The detection limits, the working pH range of the electrodes were 1.0 x 10(-5) M and 1.6-4.4 respectively. The electrodes showed better selectivity for Hg2+ ions over many of the alkali, alkaline-earth and heavy metal ions. Also sharp end points were obtained when these sensors were used as indicator electrodes for the potentiometric titration of Hg2+ ions with iodide ions.


Subject(s)
Heterocyclic Compounds/chemistry , Ion-Selective Electrodes , Mercury/analysis , Hydrogen-Ion Concentration , Sensitivity and Specificity
5.
Bioorg Med Chem Lett ; 17(18): 5251-5, 2007 Sep 15.
Article in English | MEDLINE | ID: mdl-17643300

ABSTRACT

Out of 400 virtually designed imidazoline N-oxides, five cyclic nitrones were selected on the basis of PASS prediction as potent nootropics and were evaluated for their biological activities in albino mice. The selected N-alkyl and aryl-substituted nitrones were found to be excellent nootropics. A series of lead compounds acting as cognition enhancers have been provided, which can be further exploited in search of such New Chemical Entities (NCEs).


Subject(s)
Drug Design , Nitrogen Oxides/chemical synthesis , Nitrogen Oxides/pharmacology , Nootropic Agents/chemical synthesis , Nootropic Agents/pharmacology , Animals , Behavior, Animal , Maze Learning/drug effects , Memory/drug effects , Mice , Nitrogen Oxides/chemistry , Nootropic Agents/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...