Design, structure–activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi

Keenan, Martine; Alexander, Paul W.; Diao, H.; Best, Wayne M.; Khong, Andrea; Kerfoot, Maria; Thompson, R.C.A.; White, Karen L.; Shackleford, David M.; Ryan, Eileen; Gregg, Alison; Charman, Susan A.; Geldern, Thomas W von; Scandale, Ivan; Chatelain, Eric

doi:10.1016/j.bmc.2013.01.050

Cited by 30 publications

(44 citation statements)

References 26 publications

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“…21,23 A gate of IC 50 ≤ 30 nM was applied for progression into physicochemical and in vitro ADME assays. Cytotoxicty was measured in L6 cells as a counterscreen, but no overt cellular toxicity was observed, with selectivity indices >1000-fold in most cases.…”

Section: Resultsmentioning

confidence: 99%

“…17 Inhibition of T. cruzi CYP51 affects sterol composition, damages parasite ultrastructure, and leads to parasite kill. 17 A growing number of T. cruzi CYP51 inhibitors have been reported in the literature encompassing early hits, 23−27 thoroughly investigated leads, 28,29 and potential clinical candidates. 19,30 The widely different experimental protocols used to evaluate these inhibitors (and other T. cruzi inhibitor compounds) make a comparison of compound effectiveness challenging, 31 particularly in in vivo efficacy experiments.…”

Section: Discussionmentioning

confidence: 99%

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Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease

et al. 2013

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Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease

et al. 2013

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“…Recently developed and optimized lead compounds include the ergosterol biosynthesis inhibitors EPL-BS1937, EPL-BS2391, EPL-BS0967, and EPL-BS1246. All have recently been shown to be non-azole inhibitors of T. cruzi CYP51 (Hargrove et al., 2013, Keenan et al., 2013a, Keenan et al., 2013b). …”

Section: Introductionmentioning

confidence: 99%

In vitro drug susceptibility of two strains of the wildlife trypanosome, Trypanosoma copemani : A comparison with Trypanosoma cruzi

Botero

Keatley

Peacock

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Trypanosomes are blood protozoan parasites that are capable of producing illness in the vertebrate host. Within Australia, several native Trypanosoma species have been described infecting wildlife. However, only Trypanosoma copemani has been associated with pathological lesions in wildlife hosts and more recently has been associated with the drastic decline of the critically endangered woylie (Bettongia penicillata). The impact that some trypanosomes have on the health of the vertebrate host has led to the development of numerous drug compounds that could inhibit the growth or kill the parasite. This study investigated and compared the in vitro susceptibility of two strains of T. copemani (G1 and G2) and one strain of Trypanosoma cruzi (10R26) against drugs that are known to show trypanocidal activity (benznidazole, posaconazole, miltefosine and melarsoprol) and against four lead compounds, two fenarimols and two pyridine derivatives (EPL-BS1937, EPL-BS2391, EPL-BS0967, and EPL-BS1246), that have been developed primarily against T.cruzi. The in vitro cytotoxicity of all drugs against L6 rat myoblast cells was also assessed. Results showed that both strains of T. copemani were more susceptible to all drugs and lead compounds than T. cruzi, with all IC50 values in the low and sub-μM range for both species. Melarsoprol and miltefosine exhibited the highest drug activity against both T. copemani and T. cruzi, but they also showed the highest toxicity in L6 cells. Interestingly, both fenarimol and pyridine derivative compounds were more active against T. copemani and T. cruzi than the reference drugs benznidazole and posaconazole. T. copemani strains exhibited differences in susceptibility to all drugs demonstrating once again considerable differences in their biological behaviour.

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“…The synthesis was carried out by analogy to the methods reported elsewhere (38,39). Both compounds were prepared by a short synthetic sequence from readily available precursors.…”

Section: Testing Udo (Epl-bs1246) and Udd (Epl-bs0967) As Antiprotozomentioning

confidence: 99%

Complexes of Trypanosoma cruzi Sterol 14α-Demethylase (CYP51) with Two Pyridine-based Drug Candidates for Chagas Disease

Hargrove

Wawrzak

Alexander

et al. 2013

Journal of Biological Chemistry

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114

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Background: Two pyridine derivatives were identified as promising drug candidates in animal models of Chagas disease. Results: They were tested as sterol 14␣-demethylase (CYP51) inhibitors, and x-ray co-structures with T. cruzi CYP51 were determined. Conclusion:The structures explain the potency and selectivity of the compound. Significance: Structural information contributes to a better understanding of P450 inhibition and will facilitate rational design of pathogen-specific drugs.

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Design, structure–activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi

Abstract: Accepted ManuscriptDesign, structure-activity relationship and in vivo efficacy of piperazine analogues of fenarimol as inhibitors of Trypanosoma cruzi

Cited by 30 publications

References 26 publications

Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease

Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease

In vitro drug susceptibility of two strains of the wildlife trypanosome, Trypanosoma copemani : A comparison with Trypanosoma cruzi

Complexes of Trypanosoma cruzi Sterol 14α-Demethylase (CYP51) with Two Pyridine-based Drug Candidates for Chagas Disease

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