A Tetrahydrophthalazinone Inhibitor of Phosphodiesterase with In Vitro Activity Against Intracellular Trypanosomatids

The phosphodiesterase inhibitor tetrahydrophthalazinone NPD-008 was explored by phenotypic in vitro screening, target validation and ultrastructural approaches against Trypanosoma cruzi. NPD-008 displayed activity against different forms and strains of T. cruzi (EC50 = 6.6 – 39.5 μM), increased cAMP levels of T. cruzi and its combination with Bz gave synergistic interaction. It was also moderately active against intracellular amastigotes of Leishmania amazonensis and L. infantum, confirming a potential activity profile as an antitrypanosomatid drug candidate.

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In vitro activity of Etanidazole against the protozoan parasite Trypanosoma cruzi

Memórias do Instituto Oswaldo Cruz ◽

10.1590/s0074-02762004000200021 ◽

2004 ◽

Vol 99 (2) ◽

pp. 233-235 ◽

Cited By ~ 12

Author(s):

Patricia B Petray ◽

María J Morilla ◽

Ricardo S Corral ◽

Eder L Romero

Keyword(s):

Trypanosoma Cruzi ◽

Protozoan Parasite ◽

Vitro Activity ◽

In Vitro Activity

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Differential in vitro activity of the DNA topoisomerase inhibitor idarubicin against Trypanosoma rangeli and Trypanosoma cruzi

Memórias do Instituto Oswaldo Cruz ◽

10.1590/s0074-02762012000700018 ◽

2012 ◽

Vol 107 (7) ◽

pp. 946-950 ◽

Cited By ~ 4

Author(s):

Momodou Jobe ◽

Charles Anwuzia-Iwegbu ◽

Ama Banful ◽

Emma Bosier ◽

Mubeen Iqbal ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Vitro Activity ◽

In Vitro Activity ◽

Trypanosoma Rangeli ◽

Dna Topoisomerase ◽

Topoisomerase Inhibitor

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Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Parasitology ◽

10.1017/s0031182020000955 ◽

2020 ◽

Vol 147 (11) ◽

pp. 1216-1228

Author(s):

Cristina Fonseca-Berzal ◽

Cristiane França da Silva ◽

Denise da Gama Jaen Batista ◽

Gabriel Melo de Oliveira ◽

José Cumella ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Positive Impact ◽

Cardiac Cells ◽

In Vivo Studies ◽

Drug Resistant ◽

Activity Profile ◽

Reference Drug ◽

Novel Drugs

AbstractIn previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug.

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Manganese(II) complexes with N4-methyl-4-nitrobenzaldehyde, N4-methyl-4-nitroacetofenone, and N4-methyl-4-nitrobenzophenone thiosemicarbazone: Investigation of in vitro activity against Trypanosoma cruzi

Polyhedron ◽

10.1016/j.poly.2010.04.023 ◽

2010 ◽

Vol 29 (10) ◽

pp. 2232-2238 ◽

Cited By ~ 5

Author(s):

Denise da Gama Jaén Batista ◽

Patrícia Bernardino da Silva ◽

Daniela R. Lachter ◽

Renata S. Silva ◽

Ricardo Q. Aucelio ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Vitro Activity ◽

In Vitro Activity

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Aromatic guanyl hydrazones: Synthesis, structural studies and in vitro activity against Trypanosoma cruzi

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/0960-894x(95)00541-5 ◽

1995 ◽

Vol 5 (24) ◽

pp. 3079-3084 ◽

Cited By ~ 31

Author(s):

J.C. Messeder ◽

L.W. Tinoco ◽

J.D. Figueroa-Villar ◽

E.M. Souza ◽

R. Santa Rita ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Vitro Activity ◽

Structural Studies ◽

In Vitro Activity

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Comparative In Vitro Activity Profile of Oritavancin against Recent Gram-Positive Clinical Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00952-09 ◽

2009 ◽

Vol 53 (11) ◽

pp. 4762-4771 ◽

Cited By ~ 50

Author(s):

Francis F. Arhin ◽

Deborah C. Draghi ◽

Chris M. Pillar ◽

Thomas R. Parr ◽

Gregory Moeck ◽

...

Keyword(s):

Streptococcus Pyogenes ◽

Resistance Rate ◽

Vitro Activity ◽

In Vitro Activity ◽

Activity Profile ◽

Coagulase Negative Staphylococci ◽

Gram Positive ◽

Streptococcal Species ◽

Resistance Rates

ABSTRACT Oritavancin activity was tested against 15,764 gram-positive isolates collected from 246 hospital centers in 25 countries between 2005 and 2008. Organisms were Staphylococcus aureus (n = 9,075), coagulase-negative staphylococci (n = 1,664), Enterococcus faecalis (n = 1,738), Enterococcus faecium (n = 819), Streptococcus pyogenes (n = 959), Streptococcus agalactiae (n = 415), group C, G, and F streptococci (n = 84), and Streptococcus pneumoniae (n = 1,010). Among the evaluated staphylococci, 56.7% were resistant to oxacillin. The vancomycin resistance rate among enterococci was 21.2%. Penicillin-resistant and -intermediate rates were 14.7% and 21.4%, respectively, among S. pneumoniae isolates. Among nonpneumococcal streptococci, 18.5% were nonsusceptible to erythromycin. Oritavancin showed substantial in vitro activity against all organisms tested, regardless of resistance profile. The maximum oritavancin MIC against all staphylococci tested (n = 10,739) was 4 μg/ml; the MIC90 against S. aureus was 0.12 μg/ml. Against E. faecalis and E. faecium, oritavancin MIC90s were 0.06 and 0.12, respectively. Oritavancin was active against glycopeptide-resistant enterococci, including VanA strains (n = 486), with MIC90s of 0.25 and 1 μg/ml against VanA E. faecium and E. faecalis, respectively. Oritavancin showed potent activity against streptococci (n = 2,468); MIC90s for the different streptococcal species were between 0.008 and 1 μg/ml. These data are consistent with previous studies with respect to resistance rates of gram-positive isolates and demonstrate the spectrum and in vitro activity of oritavancin against a wide variety of contemporary gram-positive pathogens, regardless of resistance to currently used drugs. The data provide a foundation for interpreting oritavancin activity and potential changes in susceptibility over time once oritavancin enters into clinical use.

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Antimalarial drug mefloquine kills both trophozoite and cyst stages of Entamoeba

10.1101/501999 ◽

2018 ◽

Author(s):

Conall Sauvey ◽

Gretchen Ehrenkaufer ◽

Anjan Debnath ◽

Ruben Abagyan

Keyword(s):

Antimalarial Drug ◽

Protozoan Parasite ◽

Drug Candidate ◽

In Vitro Activity ◽

Length Of Treatment ◽

Histolytica Infection ◽

The 1960S ◽

Entamoeba Invadens ◽

Spread Of Infection

Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, length of treatment, and the need for additional drugs to prevent transmission. All of these may decrease patient compliance and hence increase disease severity and spread of infection. In this study we identified the antimalarial drug mefloquine as possessing more potent, rapid, amoebicidal in vitro activity against E. histolytica trophozoites than metronidazole. We also showed that mefloquine could kill the cysts of a closely related reptilian parasite Entamoeba invadens unlike metronidazole. Additionally, mefloquine is known to possess a much longer half-life in human patients than metronidazole. This property, along with mefloquine's rapid and broad action against E. histolytica position it as a promising new drug candidate against this widespread and devastating disease.

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Adrenergic nervous control of cAMP-mediated amylase secretion in the rat pancreas

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1984.246.5.g563 ◽

1984 ◽

Vol 246 (5) ◽

pp. G563-G573 ◽

Cited By ~ 1

Author(s):

G. T. Pearson ◽

J. Singh ◽

O. H. Petersen

Keyword(s):

Phosphodiesterase Inhibitor ◽

Amylase Secretion ◽

Receptor Subtypes ◽

Adrenergic Agonists ◽

Adrenergic Stimulation ◽

Nervous Control ◽

Rat Pancreas ◽

Beta 2 ◽

Camp Levels

In this study of nervous control of exocrine secretion, electrical field stimulation (FS) evoked a marked, tetrodotoxin-sensitive increase in the amylase output from in vitro segments of rat pancreas. Blockade of the large cholinergic component of the response by atropine revealed a smaller noncholinergic nerve-mediated secretion. This noncholinergic secretion was unaffected by phentolamine but abolished by propranolol, as were the secretory responses to norepinephrine and other beta-adrenergic agonists. FS also produced an increase in the efflux of radiolabeled norepinephrine from preloaded tissue that was tetrodotoxin sensitive and calcium dependent. Although FS and the adrenergic secretagogues had no effect on 45Ca2+ metabolism or acinar cell electrical properties of atropine-treated rat pancreas, they both evoked increases in tissue cAMP levels. These increases in cAMP concentration were also blocked by propranolol. The phosphodiesterase inhibitor isobutylmethylxanthine potentiated both the elevation of cAMP levels and the amylase secretion evoked by adrenergic stimulation. Since both specific beta 1- and beta 2-adrenergic agonists elevated cAMP levels and caused amylase secretion, it appears that both beta-receptor subtypes are present in the rat pancreas. Of the selective beta 1- and beta 2-antagonists used, the most pronounced reduction, but not complete blockade, of the FS- and norepinephrine-induced cyclic nucleotide and secretory effects was obtained with the beta 1-antagonist metoprolol. It is concluded that stimulation of adrenergic nerves in the rat pancreas evokes an amylase secretion that is mediated via the activation of mainly beta 1-type adrenergic receptors and the utilization of cAMP as an intracellular second messenger.

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