Parasiticidal 2-alkoxy- and 2-aryloxyiminoalkyl trifluoromethanesulfonanilides Abdelselam Ali, a Timothy M. Altamore, a Marianne Bliese, a Petr Fisara, b Andris J. Liepa, a Adam G. Meyer, a, * Oahn Nguyen, a Roger M. Sargent, b David G. Sawutz, c David A. Winkler, a Kevin N. Winzenberg a and Angela Ziebell a a CSIRO Molecular and Health Technologies, Bag 10, Clayton South, Vic. 3169, Australia b Schering-Plough Pty. Ltd, 11 Gibbon Road, Baulkham Hills, NSW 2153, Australia c Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033-1300, USA Received 7 September 2007; revised 22 October 2007; accepted 25 October 2007 Available online 30 October 2007 Abstract—A series of novel 2-alkoxy- and 2-aryloxyiminoalkyl trifluoromethanesulfonanilide derivatives have shown significant in vitro parasiticidal activity against the ectoparasites Ctenocephalides felis and Rhipicephalus sanguineus. A number of these com- pounds also displayed significant in vitro endoparasite activity against the nematode Haemonchus contortus. Crown copyright Ó 2007 Published by Elsevier Ltd. All rights reserved. The cat flea, Ctenocephalides felis, and the brown dog tick, Rhipicephalus sanguineus, are prevalent nuisance ectoparasite species afflicting companion animals. 1,2 These pests cause blood loss anemia, allergic dermatitis, and are vectors for infectious pathogens. 3 Although the introduction of the topical insecticides fipronil, imida- cloprid, and selamectin has revolutionized flea control on cats and dogs, of these, only fipronil and selamectin are known to be efficacious as acaricides. Moreover, since development of resistance to these parasiticides is a distinct possibility, 4 new agents to control fleas and ticks must continue to be discovered. Trifluoromethanesulfonanilide (TFMS) derivatives 1 are reported to display potent insecticidal, acaricidal, and nematicidal properties. 5,6 For example, 4-chloro-2- methoxycarbonyl TFMS 1a (amidoflumet) is under development for use against house dust mites, 5 whereas the 4-fluoroalkoxy TFMS compounds 1b, 1c control Haemonchus contortus in sheep at low dosages 6 (Fig. 1). Compounds containing the TFMS moiety are known to act as uncouplers of oxidative phosphoryla- tion in mitochondria. 6 As part of a program to discover new drugs to control important ectoparasites afflicting companion animals, a set of novel 2-alkoxyiminoalkyl TFMS compounds 2 were screened in a commercial, single-dose (1.26 lg/ cm 2 ) cat flea assay. 7 An O-alkyloxime ether, 4-chloro- 2-[1-(cyclohexylmethoxyimino)propyl] TFMS 2a, gave 100% mortality in the cat flea assay, with a correspond- ing LC 50 = 29 ng/cm 2 for C. felis. This compound subse- quently gave 100% mortality in a single-dose (10 lg/tick) brown dog tick assay and an LD 50 = 3.4 lg/tick for R. sanguineus, 7 demonstrating that the 2-alkoxyimi- noalkyl TFMS template may deliver significant insecti- cidal and acaricidal activity. Furthermore, 2a showed activity against the endoparasite H. contortus 0960-894X/$ - see front matter Crown copyright Ó 2007 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.10.090 Keywords: Trifluoromethanesulfonanilide; Oxime ether; Parasiticide; Ctenocephalides felis (cat flea); Rhipicephalus sanguineus (brown dog tick); Haemonchus contortus. * Corresponding author. Tel.: +61 3 9545 2476; fax: +61 3 9545 2376; e-mail: adam.meyer@csiro.au 2 1b R = 4-OCF 3 1c R = 4-OCF 2 CHF 2 1a R = 4-Cl, 2-CO 2 Me CF 3 SO 2 HN R CF 3 SO 2 HN R N R 1 O R 2 2a R = 4-Cl, R 1 = Et, R 2 = -CH 2 -cyclohexyl 1 Figure 1. Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 252–255