Giardia duodenalis mouse model for the development of novel antigiardial agents

Abraham, Rebecca; O’Dea, Mark; Rusdi, Bertha; Page, Stephen W.; O’Handley, Ryan; Abraham, Sam

doi:10.1016/j.mimet.2017.11.025

Cited by 3 publications

(7 citation statements)

References 16 publications

(14 reference statements)

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“…As yet the drug target of these analogues remains undetermined. However, in our antibiotic studies with related compounds we observed that robenidine analogues affected the bacterial cell wall [31,32,36–39] . It is possible that a similar mechanism, against the trophozoite cell wall is in play.…”

Section: Discussionmentioning

confidence: 64%

“…This would be in keeping with our electron microscopy observations of gross morphological changes to the dorsal cytoplasmic membrane of trophozoites, including membrane rupture. These effects would adversely affect the ability of the Giardia trophozoite to attach to membrane, interrupting a crucial stage in the parasite lifecycle, with the observed parasite killing [31,36] …”

Section: Discussionmentioning

confidence: 99%

“…However, in our antibiotic studies with related compounds we observed that robenidine analogues affected the bacterial cell wall. [ 31 , 32 , 36 , 37 , 38 , 39 ] It is possible that a similar mechanism, against the trophozoite cell wall is in play. This would be in keeping with our electron microscopy observations of gross morphological changes to the dorsal cytoplasmic membrane of trophozoites, including membrane rupture.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…These effects would adversely affect the ability of the Giardia trophozoite to attach to membrane, interrupting a crucial stage in the parasite lifecycle, with the observed parasite killing. [31,36] Table 4. Inhibition of Giardia duodenalis metabolism by Library 4 Robenidine analogues possessing di-, tri-and poly-substituted aromatic rings (34-47).…”

Section: Chemmedchemmentioning

confidence: 99%

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Antigiardial Activity of Novel Guanidine Compounds

et al. 2022

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From four focused compound libraries based on the known anticoccidial agent robenidine, 44 compounds total were synthesised and screened for antigiardial activity. All active compounds were counter-screened for antibiotic and cytotoxic action. Of the analogues examined, 21 displayed IC 50 < 5 μM, seven with IC 50 < 1.0 μM. Most active were 2,2'-bis{ [4-(trifluoromethoxy)phenyl]methylene}carbonimidic dihydrazide hydrochloride (30), 2,2'-bis{[4-(trifluoromethylsulfanyl)phenyl]methylene}carbonimidic dihydrazide hydrochloride (32), and 2,2'-bis[(2-bromo-4,5-dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride ( 41) with IC 50 = 0.2 μM. The maximal observed activity was a 5 h IC 50 value of 0.2 μM for 41. The clinically used metronidazole was inactive at this timepoint at a concentration of 25 μM. Robenidine off-target effects at bacteria and cell line toxicity were removed. Analogue 41 was well tolerated in mice treated orally (100 mg/kg). Following 5 h treatment with 41, no Giardia regrowth was noted after 48 h.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Chemmedchemmentioning

confidence: 99%

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Antigiardial Activity of Novel Guanidine Compounds

et al. 2022

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Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis

Hart,

Riches,

Tiash

et al. 2023

International Journal for Parasitology: Drugs and Drug Resistan

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Effects of Tinidazole on Food Intake in Chinchillas (Chinchilla lanigera)

Tournade

Fink

Williams

et al. 2021

j am assoc lab anim sci

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Tinidazole is a second-generation nitroimidazole compound that is used as an antimicrobial to treat anaerobic bacterialand protozoal infections in humans and, less frequently, in veterinary medicine. However, metronidazole, another secondgeneration nitroimidazole, is more commonly used. Nonetheless, tinidazole has proven to be a superior therapy for parasitic infections in humans, particularly in the treatment of giardiasis. Furthermore, in chinchillas, metronidazole has been shown to cause a clinically relevant reduction in food intake after oral administration at published dosages. This study’s objective was to evaluate the effect of orally administered tinidazole on food intake in healthy chinchillas. In 2 randomized, placebocontrolled,blinded, crossover studies, tinidazole was evaluated at 2 single high doses (100 mg/kg and 200 mg/kg PO, n =9) and a repeated dosing schedule at a lower dose (20 mg/kg PO q12h for 10 doses, n = 12). Food intake was measured over24-h periods before and after drug administration. The single-dose treatment groups both displayed significantly reducedfood intake (200 mg/kg: −26 ± 21%; 100 mg/kg: −9 ± 21%, P < 0.01) as compared with the control group during the first 24 hafter drug administration. Food intake returned to pretreatment values within 4-5 d. Repeated administration at 20 mg/kg q12h was not associated with any significant changes in food intake. No other adverse effects were noted during this study. Tinidazole administration at single higher doses resulted in an acute self-limiting reduction in food intake. In comparison, repeated administration of lower doses (20 mg/kg PO q12h) had no significant effects on food intake in healthy chinchillas. Therefore, tinidazole may be a more suitable drug for treating Giardia and anaerobic bacterial infections in this species than the more commonly used metronidazole.

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Giardia duodenalis mouse model for the development of novel antigiardial agents

Cited by 3 publications

References 16 publications

Antigiardial Activity of Novel Guanidine Compounds

Antigiardial Activity of Novel Guanidine Compounds

Thieno[3,2-b]pyrrole 5-carboxamides as potent and selective inhibitors of Giardia duodenalis

Effects of Tinidazole on Food Intake in Chinchillas (Chinchilla lanigera)

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