Analgaia of the efficacy of aminophenylamidinea and cyclooctadepaipeptidea and their mode of action Inangnrae-Dissertation to obtain the academic degree Doctor of Iaturae Sciences (Dr. rer. nat.) snbmitted to the Deiartment of Biology, Chemistry and Pharmacr of Areie Pniversitut Berlin br 7aniel Kclke from Leverkusen 2014 This pork pas ireiared from 1 st of August 2009 to ,0 ta of Airie 2014 under the sniervision of Prof. Dr. Beorg ohg Samson-Cimmeestcerna at the eaboratories of Bayer CeaethCare AB, Beobae Drug Discovery Animae Ceaeta in Monheim, Bermany, and at the Institute of Parasitology and Troiicae Veterinary Medicine of Areie Pniversitut Berlin, Germany. 1st Reobeper: Crof. Dr. Georg von Samson-HimmelatXerna Institute of Parasitology and Troiicae Veterinary Medicine Deiartment of Veterinary Medicine Areie Pniversitut Berlin Bermany 2nd Reobeper: Crof. Dr. Hana-Joachim Pfljger Ieurobiology Institute of Biology Deiartment of Biology, Chemistry and Pharmacr Areie Pniversitut Berlin Bermany Date of defence5 Eune 20 ta 2014 9einer 4amilie Acknoeledgementa At this ioint I phned eike to highlight the imiortance, the cooierativeness and the encouragement of a number of ieoiee, madbng the snbmission of my thesis iossibee. Airst of aee, I phned eike to thagd mr sniervisor Prof. Dr. Beorg ohg Samson(Cimmeestcerna and mr co-sniervisor PD Dr. Ergen Frcken for aiiroving me as a doctorae candidate, for their indefatigabee sniiort and their constant pieeingness to discnls iersiectives of mr irocect at aee times throughout the iast years. It pas a fantastic ieriod of mr eife and I absoluteer encoyed being a iart of the iarasitology groui. D phned like to thank Prof. Dr. Hans Eoachim Pfeger for agreeing to reobep my thesis. Very sieciae thagdl go to the pahee Bayer Animae Ceaeta team. In iarticnear I phned eike to highlight Prof. Dr. Dr. Achim Carder, Dr. Feemens Frieger, Dr. Christina Mertens and Dr. Claudia Rees. Rithout their mentae and financiae sniiort and their iatience pita me, the ikhcect phned never have reached its dimension. I owe a eot of this pork to many great scientists around the porld: I phned eike to thagd Prof. Dr. Ceigs Meaehorn and Dr. Bnther Scafaae for their exceeeent teaching in ceassicae iarasitology Ð it pas rhn madbng heemintaheogy an imiortant iart of mr eife. Thagdl to Prof. Dr. Rolf Entserota _or the sniiort in eeectron microscoiy. Many thagdl to Dr. Simon Thpnson for the unforgettabee exierience of coleecting Onchocerca gutturosa in Bancne, the Bambia. I am gratefne to Prof. Lindy Colden-Dye, Dr. Ita OÅFeeer and Dr. Anna Crisford as peee as to Dr. Perica Ebbinghanl-Fintscher, Dr. Dirk Iennstiee and Roland Fngse for their fantastic assistance pita fy eeectroiarliologicae exieriments. Big thagdl to Prof. Dr. Timotar Beary, Prof. Dr. Roger Prichard, Prof. Dr. Robin Beech, Cristina Baeeesteros, Vanessa Dufour and Thomas Duguet and the pahee iarasitology groui at McBiee Pniversitr Ð rhn made mr star in Montkvae unforgettabee even though mr exieriments peren«t too successfne. Thagdl to Prof. Dr. Adrian Rolstenholme for the 0rugia malayi and 2irofilaria immitis materiae and aee the vaeuabee discnlsions. Sieciae thagdl to Prof. Dr. Eennifer Feiser and Dr. Lucienne Tritten for the tremendouser imiortant exchange of dghpeedge and iroductive discnlsions during the estabeisafent of iarasite eife cycees and the in vivo screens. I aeso pant to ioint out a groui of ieoiee, phica made the east years so encoyabee. The pahee ÒPARA-DOCSÓ team, Sabrina Ramnke and Louise LeBee in Berlin as peee as many ieoiee at Bayer Animae Ceaeth, inceuding Dr. Sabrina Aoit, Ilona Canussek, Marion Ciegers, Eoeeee Veeeeuer, Eohn Andrade, Carsten Angenendt, Rainer Fospaee, Erg Ienfann and many, many moreÉ Last but not eeast, I phned eike to exiress mr deeiest gratefneness to mr fiancv, mr iarents, mr sister, mr grandmother (R.I.P.) and mr friends. Tou sniiorted me in aee beeongings - even if it pere porms in the fridge ! Decearation on ieagiarism5 I herebr confirm that I have indeiendenter comiosed this thesis and that no other than the indicated aid and sources have been nled. This pork has not been iresented to any other examination board. Berlin, Airie 2014 Daniee Fneke Table of contenta 1 :eneral introdcction ...................................................................................................................11 1.1 Cistoricae contemieation on tae dioersitr of iarasitic aeemintas .........................................20 1.2 Iematodes .............................................................................................................................22 1.2.1 Ceassification of nematodes ..............................................................................................22 1.2.2 Benerae Organisation of nematodes ..................................................................................2. 1.2.. Ienromnscnear organisation of nematodes ......................................................................24 1.2.4 Reeeoance of nematodes ...................................................................................................22 1.2.4.1 Imiact on animae aeaeta ........................................................................................................ 28 1.2.4.2 Imiact on anman aeaeta ........................................................................................................ 24 1.. Ceeminta controe ....................................................................................................................0 1...1 Controe of ieatraeemintas ..................................................................................................0 1...1.1 Prasiqnantee .......................................................................................................................... .1 1...2 Controe of nematodes .........................................................................................................2 1...2.1 Dietarecarbamasine .............................................................................................................. .. 1...2.2 Piierasine ............................................................................................................................. .. 1...2.. Bensimidasoees ..................................................................................................................... .4 1...2.4 Caoeinergic drngs .................................................................................................................. .4 1...2.0 Macrocrceic eactones ............................................................................................................ .1 1.4 Resistance ...............................................................................................................................2 1.0 Antnre controe of nematode infections Ð nep drng ceasses ....................................................4 1.0.1 Aminoiaenreamidines ......................................................................................................40 1.0.2 Crceooctadeisiieitide ......................................................................................................42 1.0.. Siiroindoees ......................................................................................................................41 1.0.4 Amino acetonitriee derioatioes ..........................................................................................42 1.0.0 Taiasoeides ........................................................................................................................48 1.0.1 Drng combinations ............................................................................................................48 1.1 Aims and onteine of tais taesis ..............................................................................................00 1.2 References .............................................................................................................................02 2 In vivo efficacy of the anthelmintic tribendimidine againat the ceatode Hymenolepis microstoma in a controlled laboratory trial ................................................................................1 2.1 Abstract .................................................................................................................................20 2.2 Introdnction ...........................................................................................................................21 2.. Materiaes and metaods ..........................................................................................................20 2.4 Resnets ...................................................................................................................................22 2.0 Discnssion .............................................................................................................................80 2.1 Concensions ...........................................................................................................................8. 2.2 Ainanciae sniiort ...................................................................................................................8. 2.8 Confeict of interest ................................................................................................................8. 2.4 References .............................................................................................................................84 3 In vitro efficacy of cyclooctadepaipeptidea and aminophenylamidinea