RESUMO
Trioxaquine PA1259 is an efficient drug on larval- and adult-stage schistosomes, able to alkylate heme inside worms treated with it, leading to the formation of covalent heme-drug adducts. Such a mechanism, similar to one reported for other trioxaquines in Plasmodium, indicates that heme may be a common target of these trioxane-based drugs in different blood-feeding parasites.
Assuntos
Anti-Helmínticos/uso terapêutico , Heme/metabolismo , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/metabolismo , Alquilação , Animais , Anti-Helmínticos/metabolismo , Camundongos , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/parasitologiaRESUMO
Trioxaquines are antimalarial agents based on hybrid structures with a dual mode of action. One of these molecules, PA1103/SAR116242, is highly active in vitro on several sensitive and resistant strains of Plasmodium falciparum at nanomolar concentrations (e.g., IC(50) value = 10 nM with FcM29, a chloroquine-resistant strain) and also on multidrug-resistant strains obtained from fresh patient isolates in Gabon. This molecule is very efficient by oral route with a complete cure of mice infected with chloroquine-sensitive or chloroquine-resistant strains of Plasmodia at 26-32 mg/kg. This compound is also highly effective in humanized mice infected with P. falciparum. Combined with a good drug profile (preliminary absorption, metabolism, and safety parameters), these data were favorable for the selection of this particular trioxaquine for development as drug candidate among 120 other active hybrid molecules.
Assuntos
Aminoquinolinas/farmacologia , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Aminoquinolinas/síntese química , Aminoquinolinas/química , Animais , Antimaláricos/síntese química , Antimaláricos/química , Cristalografia , Sistema Enzimático do Citocromo P-450/metabolismo , Descoberta de Drogas , Eletrofisiologia , Heme/metabolismo , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Camundongos , Testes para Micronúcleos , Estrutura MolecularRESUMO
We report the in vitro activities of trioxaquines against larval and adult-stage schistosomes at 5 and 50 microg/ml, respectively. Such activities are equivalent to that of praziquantel, the major and rather unique drug currently used for the treatment of schistosomiasis. In this range of concentrations, artemisinin derivatives (artesunate and artemether) have no activity.
Assuntos
Aminoquinolinas/farmacologia , Compostos Heterocíclicos/farmacologia , Esquistossomose mansoni/tratamento farmacológico , Esquistossomicidas/farmacologia , Animais , Larva/efeitos dos fármacos , Camundongos , Testes de Sensibilidade ParasitáriaRESUMO
Alzheimer's disease (AD) is a neurodegenerative syndrom involving many different biological parameters, including the accumulation of copper metal ions in Aß amyloid peptides due to a perturbation of copper circulation and homeostasis within the brain. Copper-containing amyloids activated by endogenous reductants are able to generate an oxidative stress that is involved in the toxicity of abnormal amyloids and contribute to the progressive loss of neurons in AD. Since only few drugs are currently available for the treatment of AD, we decided to design small molecules able to interact with copper and we evaluated these drug-candidates with non-transgenic mice, since AD is mainly an aging disease, not related to genetic disorders. We created a memory deficit mouse model by a single icv injection of Aß(1-42) peptide, in order to mimic the early stage of the disease and the key role of amyloid oligomers in AD. No memory deficit was observed in the control mice with the antisense Aß(42-1) peptide. Here we report the capacity of a new copper-specific chelating agent, a bis-8-aminoquinoline PA1637, to fully reverse the deficit of episodic memory after three weeks of treatment by oral route on non-transgenic amyloid-impaired mice. Clioquinol and memantine have been used as comparators to validate this fast and efficient mouse model.
Assuntos
Doença de Alzheimer/fisiopatologia , Aminoquinolinas/farmacologia , Quelantes/farmacologia , Cobre/química , Memória Episódica , Recuperação de Função Fisiológica/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Aminoquinolinas/efeitos adversos , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/farmacologia , Animais , Quelantes/efeitos adversos , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Injeções , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Fatores de TempoRESUMO
Schistosomiasis is among the most neglected tropical diseases, since its mode of spreading tends to limit the contamination to people who are in contact with contaminated waters in endemic countries. Here we report the in vitro and in vivo anti-schistosomal activities of trioxaquines. These hybrid molecules are highly active on the larval forms of the worms and exhibit different modes of action, not only the alkylation of heme. The synergy observed with praziquantel on infected mice is in favor of the development of these trioxaquines as potential anti-schistosomal agents.
Assuntos
Aminoquinolinas/administração & dosagem , Aminoquinolinas/farmacologia , Anti-Helmínticos/administração & dosagem , Anti-Helmínticos/farmacologia , Schistosoma mansoni/efeitos dos fármacos , Esquistossomose mansoni/tratamento farmacológico , Animais , Sinergismo Farmacológico , Feminino , Humanos , Larva/efeitos dos fármacos , Masculino , Camundongos , Praziquantel/administração & dosagem , Praziquantel/farmacologia , Resultado do TratamentoRESUMO
Five lipophilic analogues 1-5 of the active metabolite of the antitubercular drug isoniazid (INH), selected as inhibitors of Mycobacterium smegmatis and Mycobacterium tuberculosis growth, were evaluated for their activity against Corynebacterium glutamicum (lacking in InhA activity), Escherichia coli (to test mycobacteria selectivity), and Plasmodium falciparum (as possible parasite target). Compound 3 was the only one that did not inhibit C. glutamicum growth. The poor InhA inhibitors 1 and 2 were able to inhibit C. glutamicum and their anti(myco)bacterial mechanisms of action involve targets other than InhA. For the effective InhA inhibitors 4 and 5, also active against C. glutamicum and M. tuberculosis strains, more than one pathway should be envisaged to explain their actions. Pyridine-base ring analogues (1, 2, and 3) have no ability to inhibit the growth of E. coli even at a high concentration. Compound 3 thus exhibited a selective inhibitory action toward M. tuberculosis, while it was inactive on C. glutamicum and on E. coli growth. It presented an activity profile similar to that of INH suggesting InhA inhibition as one of the possible mechanisms of action. Finally, although a homologue of the reductase InhA exists in the FAS-II system of P. falciparum, 3 was unable to display antiplasmodial activity.
Assuntos
Antibacterianos/metabolismo , Antibacterianos/farmacologia , Corynebacterium glutamicum/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Isoniazida/metabolismo , Isoniazida/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Antibacterianos/química , Antimaláricos/química , Antimaláricos/metabolismo , Antimaláricos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Isoniazida/química , Testes de Sensibilidade Microbiana , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismoRESUMO
The synthesis, characterization, and antimalarial evaluation of a new series of potential antimalarial molecules, named trioxaferroquines, are reported. Trioxaferroquines are hybrid antimalarial drugs containing a 1,2,4-trioxane covalently linked to ferroquine (Fq), a synthetic ferrocenylquinoline derivative currently under clinical development. The aim was to combine, within a single structure, an iron(II) species, a 1,2,4-trioxane, as in artemisinin, and a substituted quinoline, as in chloroquine.
Assuntos
Aminoquinolinas/síntese química , Antimaláricos/síntese química , Compostos Ferrosos/síntese química , Compostos Heterocíclicos/síntese química , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Animais , Antimaláricos/química , Antimaláricos/farmacologia , Cristalografia por Raios X , Resistência a Medicamentos , Estabilidade de Medicamentos , Feminino , Compostos Ferrosos/química , Compostos Ferrosos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Malária/tratamento farmacológico , Metalocenos , Camundongos , Modelos Moleculares , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
PfATP6, a calcium-dependent ATPase of Plasmodium falciparum, is considered the putative target of the antimalarial drug artemisinin and its derivatives. Herein, the 3D structure of PfATP6 was modeled on the basis of the crystal structure of SERCA 1a, the mammalian homologue. Model validation was achieved using protein structure checking tools. AutoDock4 was used to predict the binding affinities of artemisinin (and analogues) and various other antimalarial agents for PfATP6, for which in vitro activity is also reported. No correlation was found between the affinity of the compounds for PfATP6 predicted by AutoDock4 and their antimalarial activity.