- Analogues of fenarimol are potent inhibitors of trypanosoma cruzi and are efficacious in a murine model of chagas disease
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We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi (T. cruzi), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC50s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
- Keenan, Martine,Abbott, Michael J.,Alexander, Paul W.,Armstrong, Tanya,Best, Wayne M.,Berven, Bradley,Botero, Adriana,Chaplin, Jason H.,Charman, Susan A.,Chatelain, Eric,Von Geldern, Thomas W.,Kerfoot, Maria,Khong, Andrea,Nguyen, Tien,McManus, Joshua D.,Morizzi, Julia,Ryan, Eileen,Scandale, Ivan,Thompson, R. Andrew,Wang, Sen Z.,White, Karen L.
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experimental part
p. 4189 - 4204
(2012/07/27)
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- Estrogen Synthetase Inhibitors. 2. Comparison of the in Vitro Aromatase Inhibitory Activity for a Variety of Nitrogen Heterocycles Substituted with Diarylmethane or Diarylmethanol Groups
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The preparation and in vitro aromatase inhibitory activity of a wide variety of heterocyclic (4,4'-dichlorodiphenyl)methanes and -methanols are described.The choice of the two diaryl-bearing moieties as a vehicle for the evaluation of the heterocycles was made by the comparison of series of imidazole and pyridine-derived compunds with similar pyrimidine compounds reported previously.A structural model for the most active compounds is also presented.The activity of a related series of compounds which contain two heterocyclic moieties was found to be consistent with the model.Many of the compounds evaluated, including representatives of the pyridine, imidazole, pyrimidine, pyrazole, triazole, thiazole, and isothiazole classes, exhibit EC50 potencies for aromatase inhibition at low nanomolar levels.These compunds are at least as potent as other nonsteroidal aromatase inhibitors reported previously.
- Jones, C. David,Winter, Mark A.,Hirsch, Kenneth S.,Stamm, Nancy,Taylor, Harold M.,et al.
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p. 416 - 429
(2007/10/02)
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- Method of regulating the growth of aquatic weeds with pyridine derivatives
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A method of regulating the growth of submerged and floating aquatic weeds which comprises adding a 3-substituted pyridinemethane, pyridinemethanol, or derivative thereof, to a body of water containing the submerged and floating aquatic weeds to be regulated, in quantities sufficient to regulate the growth of the said submerged and floating aquatic weeds. The disclosure also relates to novel compositions for carrying out the method.
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