A novel series of chemical structures active in vitro against the trypomastigote form of Trypanosoma cruzi

Hammond, David J.; Cover, B.; Gutteridge, W. E.

doi:10.1016/0035-9203(84)90184-6

Cited by 50 publications

(32 citation statements)

References 8 publications

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“…Intraperitoneal injections of novobiocin also do not prolong the life-span of mice lethally infected with T. cruzi H510 (P. G. Pate, J. S. Wolfson, S. C. Pan, and M. N. Swartz, unpublished data). Finally, T. cruzi Sonya bloodstream stages isolated from mice and suspended in Krebs-Ringer glucose do not decrease in number or alter in morphology when exposed for 24 h at 4°C to novobiocin (600 ,ug/ml) (24). Whether clorobiocin or another of the many analogs of novobiocin (20) might be efficacious is not known and seems worthy of investigation.…”

Section: Resultsmentioning

confidence: 99%

Novobiocin antagonism of amastigotes of Trypanosoma cruzi growing in cell-free medium

Pate¹,

Wolfson²,

McHugh³

et al. 1986

Antimicrob Agents Chemother

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Inhibitors of the enzyme bacterial topoisomerase II (DNA gyrase) were evaluated for activity against Trypanosoma cruzi (Brazil strain), based on the theoretical need for a topoisomerase II in the replication of the kinetoplast DNA network. Novobiocin (500 tig/ml) antagonized amastigotes of T. cruzi growing in a cell-free medium at 37°C, as manifested by inhibition of multiplication, abnormal morphology of Giemsa-stained organisms, and delayed or absent growth of cells upon subculturing in a drug-free medium. In contrast, novobiocin (1,000 ,ug/ml) essentially had no effect on the multiplication and motility of epimastigotes growing in a cell-free medium at 27C. (16,28,29,33) and is needed for segregation of chromosomes in bacteria (46) and in yeasts (6, 48). Englund and Marini suggest that topoisomerase II may be necessary for replication of the kinetoplast DNA network (13). Type II topoisomerases from bacteria and certain eucaryotes, including the kinetoplast-containing organism Crithidiafasciculata (44), are inhibited in vitro by the antibiotic novobiocin (16,18,22,26 (39). Using this culture system, we found that novobiocin and an analog, clorobiocin (7), antagonized growth of amastigotes.(Data from these experiments were presented in part at the

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Section: Resultsmentioning

confidence: 99%

Novobiocin antagonism of amastigotes of Trypanosoma cruzi growing in cell-free medium

Pate¹,

Wolfson²,

McHugh³

et al. 1986

Antimicrob Agents Chemother

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“…Nelfinavir, an HIV protease inhibitor, is active against Toxoplasma gondii (19). Haloperidol, an antipsychotic drug associated with the blockade of postsynaptic dopamine D2 receptors, is also active against Toxoplasma gondii (38) and was previously reported as inactive against the trypomastigote form of T. cruzi (37). Fluphenazine is a member of the phenothiazines that has been shown to inhibit the growth of T. brucei in vitro (58) but was inactive (36) or weakly active (6) against the T. cruzi enzyme trypanothione reductase.…”

Section: Discussionmentioning

confidence: 99%

Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

Engel¹,

Ang

Chen

et al. 2010

Antimicrob Agents Chemother

102

114

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Chagas' disease, caused by infection with the parasite Trypanosoma cruzi, is the major cause of heart failure in Latin America. Classic clinical manifestations result from the infection of heart muscle cells leading to progressive cardiomyopathy. To ameliorate disease, chemotherapy must eradicate the parasite. Current drugs are ineffective and toxic, and new therapy is a critical need. To expedite drug screening for this neglected disease, we have developed and validated a cell-based, high-throughput assay that can be used with a variety of untransfected T. cruzi isolates and host cells and that simultaneously measures efficacy against the intracellular amastigote stage and toxicity to host cells. T. cruzi-infected muscle cells were incubated in 96-well plates with test compounds. Assay plates were automatically imaged and analyzed based on size differences between the DAPI (4,6-diamidino-2-phenylindole)-stained host cell nuclei and parasite kinetoplasts. A reduction in the ratio of T. cruzi per host cell provided a quantitative measure of parasite growth inhibition, while a decrease in count of the host nuclei indicated compound toxicity. The assay was used to screen a library of clinically approved drugs and identified 55 compounds with activity against T. cruzi. The flexible assay design allows the use of various parasite strains, including clinical isolates with different biological characteristics (e.g., tissue tropism and drug sensitivity), and a broad range of host cells and may even be adapted to screen for inhibitors against other intracellular pathogens. This high-throughput assay will have an important impact in antiparasitic drug discovery.

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“…2 In the search for a suitable replacement for blood clearance many compounds have been tested. [3][4][5][6] Kaurenoic acid (1) is known to exhibit interesting biological activities, including antimicrobial, cytotoxic, antiinflammatory and antiprotozoal properties. 7 Alves et al 8 have described its activity against trypomastigote forms of T. cruzi.…”

Section: Introductionmentioning

confidence: 99%

Novel Derivatives of Kaurenoic Acid

Vieira¹,

Takahashi²,

Oliveira³

et al. 2002

J. Braz. Chem. Soc.

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O ácido caurenóico, um diterpeno caurânico, mostrou-se ativo in vitro contra formas tripomastigotas do Trypanosoma cruzi. Uma ação lítica sobre os eritrócitos foi uma das limitações encontradas para esta atividade. A síntese de doze derivados deste ácido: quatro amidas, quatro aminas (e três cloridratos) e quatro oximas foi realizada, com o objetivo de se tentar diminuir ou eliminar esse efeito secundário e, se possível, aumentar a atividade em relação ao material de partida. Dentre esses compostos, um mostrou-se mais ativo que o ácido caurenóico, mas também apresentou lise discreta de eritrócitos; outro não apresentou este efeito, mas a atividade não foi aumentada em relação àquela apresentada pelo ácido caurenóico.Kaurenoic acid, a kauranic diterpenoid, presents in vitro activity against trypomastigote forms of Trypanosoma cruzi, showing, however, lytic activity on blood erythrocytes, as a side effect. The syntheses of twelve new derivatives of kaurenoic acid, four amides, four amines (and three hydroclorides) and four oximes, was carried out aiming at the improvement of the therapeutic activity and without the side effect. Among the derivatives prepared, one compound showed enhanced trypanocidal activity in vitro towards Trypanosoma cruzi trypomastigote erythrocytic forms, when compared to kaurenoic acid, but continued to show discrete lytic activity on erythrocytes; another compound showed a level of activity similar to that of kaurenoic acid, but without lysis.

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A novel series of chemical structures active in vitro against the trypomastigote form of Trypanosoma cruzi

Cited by 50 publications

References 8 publications

Novobiocin antagonism of amastigotes of Trypanosoma cruzi growing in cell-free medium

Novobiocin antagonism of amastigotes of Trypanosoma cruzi growing in cell-free medium

Image-Based High-Throughput Drug Screening Targeting the Intracellular Stage of Trypanosoma cruzi , the Agent of Chagas' Disease

Novel Derivatives of Kaurenoic Acid

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