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

Keenan, Martine; Chaplin, Jason H.; Alexander, Paul W.; Abbott, Michael J.; Best, Wayne M.; Khong, Andrea; Botero, Adriana; Perez, Catherine; Cornwall, Scott; Thompson, RC Andrew; White, Karen L.; Shackleford, David M.; Koltun, Maria; Chiu, Francis Chi Keung; Morizzi, Julia; Ryan, Eileen; Campbell, Michael G.; Geldern, Thomas W von; Scandale, Ivan; Chatelain, Eric; Charman, Susan A.

doi:10.1021/jm401610c

Cited by 43 publications

(42 citation statements)

References 34 publications

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“…Moreover, these four compounds showed better activity against T. cruzi than the T. cruzi reference drug, benznidazole. These results are consistent with those obtained by Keenan (Keenan et al., 2013c), who showed that both FN1 and FN2 exhibited curative activity in mice infected with the Tulahuen strain of T. cruzi and significant activity in vitro against T. cruzi amastigotes, as well as low toxicity in L6 cells. However, the T. cruzi IC50s of both fenarimol compounds obtained in the present study are generally higher than those previously reported (Keenan et al., 2013c).…”

Section: Discussionsupporting

confidence: 94%

“…Posaconazole was purchased as an oral suspension (Noxafil Schering Corporation, 40 mg/mL) and isolated from the suspension by dilution with water and centrifugation, followed by extraction and recrystallization from hot i-propyl alcohol (Keenan et al., 2012). Four CYP51 inhibitor lead compounds that have been shown to be inhibitors of T. cruzi , incluiding two pyridine derivatives EPL-BS0967 and EPL-BS1246 (PDB1 and PDB2 respectively - also known as UDD and UDO), and two non-azole antifungal fenarimoles EPL-BS1937 and EPL-BS2391 (FN1 and FN2 respectively) were kindly provided by Epichem Pty Ltd (Hargrove et al., 2013, Keenan et al., 2012, Keenan et al., 2013c). Their molecular structures are shown in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Attempts to develop new compounds with potent activity against trypanosomes and low toxicity in mammalian cells has led to the discovery of different ergosterol biosynthesis inhibitor compounds with demonstrated in vitro and in vivo activity against all T. brucei subspecies and T. cruzi . For example, inhibition of T. cruzi CYP51 (sterol 14α-demethylase) has been shown to affect sterol composition and consequently cause damage to the parasites ultrastructure leading to their death (Lepesheva and Waterman, 2011, Hargrove et al., 2013; Keenan et al., 2013c). Recently developed and optimized lead compounds include the ergosterol biosynthesis inhibitors EPL-BS1937, EPL-BS2391, EPL-BS0967, and EPL-BS1246.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is an increasing threat to global health. To our delight, the key intermediate (8a) to an inhibitor of T. cruzi 45 was synthesized in a yield of 75% in only one step by employing this amination method (Fig. 2).…”

Section: Nature Catalysismentioning

confidence: 99%

Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis

et al. 2018

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A mines are one of the most important structural motifs in pharmaceuticals, agrochemicals and organic materials 1,2 . Alkylation and reductive amination reactions are still commonly used to prepare and modify amines, and new methods derived from reductive amination, such as the borrowing hydrogen 3 strategy, have been reported [4][5][6][7] . Nevertheless, the most significant development in amine synthesis has been transition-metal-catalysed C-N coupling of aryl electrophiles (halides and pseudo halides) with amine nucleophiles [8][9][10][11] (Fig. 1a). The C-N coupling of alkyl electrophiles, however, is largely under-developed (Fig. 1a). A perceived difficulty is β -hydrogen elimination from a metal alkyl intermediate originated from oxidative addition of the alkyl electrophile, which has posed considerable challenges in analogous C-C crosscoupling of alkyl electrophiles [12][13][14] . Moreover, the product-yielding C(sp 3 )-N reductive elimination step is rarely demonstrated 15 . A notable exception is the light-induced, copper-catalysed C-N coupling of alkyl halides recently developed [16][17][18] . Nevertheless, the scope of amine nucleophiles is limited to carbazoles 16,18 and amides 17,19 . Alternative, formal C-N coupling of alkyl electrophiles via the addition of alkyl radicals to nitroarenes has been reported 20,21 .The group of Baran has recently trailblazed the use of redox-active esters derived from alkyl carboxylic acids as superior surrogates of alkyl halides in decarboxylative C-C cross-coupling reactions [22][23][24] . Extension to a decarboxylative carbon-heteroatom, particularly C-B bond formation has also been reported 19,[25][26][27][28][29] . The key attributes of alkyl carboxylic acids 30,31 are their unparalleled availability, stability and non-toxic nature, which are in stark contrast with alkyl halides, ketones and aldehydes. While several precedents of decarboxylative imidation 32 and amination 19,33 are known, they are limited to a narrow scope of very special substrates or intramolecular reactions. A general metal-catalysed decarboxylative C-N coupling of redox-active esters with anilines will provide valuable methodology for the synthesis of alkylated anilines (Fig. 1b), which requires alkyl halides and carbonyl compounds 6 as starting reagents using the currently standard methods of alkylation and reductive amination, respectively. Further foreseen advantages of such a decarboxylative amination include applicability to bulky primary and secondary alkyl groups and immunity to over-alkylation, both of which are major limitations of direct alkylation (Fig. 1b). Despite its conceptual simplicity and resemblance to decarboxylative C-C coupling, the intermolecular decarboxylative C-N coupling of redoxactive esters poses significant hurdles. The activation principle of redox-active esters originates from amide-bond synthesis; thus, amide formation can compete when amine nucleophiles are used. Moreover, decarboxylative C-C coupling reactions of redox-active esters were, until now, all init...

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“…Physicochemical and metabolic stability properties and CYP inhibition were assessed as described previously (5). Both enantiomers exhibited good aqueous solubility (50 to 100 g/ml) and moderate lipophilicity (a distribution constant [log D pH 7.4 ] of 2.1) and were metabolically stable in the presence of human hepatic microsomes (in vitro intrinsic clearance of Ͻ7 l/min/mg of protein).…”

mentioning

confidence: 99%

Enantiomers of Nifurtimox Do Not Exhibit Stereoselective Anti-Trypanosoma cruzi Activity, Toxicity, or Pharmacokinetic Properties

Moraes

White

Braillard

et al. 2015

Antimicrob Agents Chemother

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e With the aim of improving the available drugs for the treatment of Chagas disease, individual enantiomers of nifurtimox were characterized. The results indicate that the enantiomers are equivalent in their in vitro activity against a panel of Trypanosoma cruzi strains; in vivo efficacy in a murine model of Chagas disease; in vitro toxicity and absorption, distribution, metabolism, and excretion characteristics; and in vivo pharmacokinetic properties. There is unlikely to be any therapeutic benefit of an individual nifurtimox enantiomer over the racemic mixture.

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

Cited by 43 publications

References 34 publications

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

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

Decarboxylative C(sp3)–N cross-coupling via synergetic photoredox and copper catalysis

Enantiomers of Nifurtimox Do Not Exhibit Stereoselective Anti-Trypanosoma cruzi Activity, Toxicity, or Pharmacokinetic Properties

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