363

Index a anaerobic NADH-fumarate reductase AADs. See aminoacetonitrile derivatives system 275 (AADs) anthelmintic discovery ABZ- 266 medicinal chemistry approaches ABZ-sulfone 260, 265, 266 CODP 242–245 ABZ-sulfoxide 260, 265, 266, 272 intervet multicyclics 235, 238 Acid fast bacilli (AFB) 329, 330 VAChT inhibitors 238, 240, 241 acoziborole 129, 130 new molecules, from patent literature acute fascioliasis 294 232–235 adult flukes 295, 300 anti-bacterial approach 169, 171 adult worms 164, 166, 170–172, 175, antibacterial therapy vs. host directed 180, 190–192, 194–198, 200, 201, therapy 354 206, 207, 254, 290, 293–296, 304 antibody-based therapeutics 67–69 African animal trypanosomiasis (AAT) anticancer drugs 194 118, 119 anti-microbial properties 271 2, 3, 9, 169, 171, 227–229, metallo-organic ruthenium 257, 272, 275, 303 complexes 271 Alpha-1-acid glycoprotein (AGP) 271, 273 203, 212 anti-foodborne trematode drugs 304, α-difluoromethylornithine 265 311 17-α-ethynylestradiol 298 anti-fungal agent 260 Alpinia nigra 307, 311 anti-fungal compound Alveolar echinococcosis (AE) 253 desoxycholate (cAMB) 267 treatments 257, anti-infective agents 259–261 anti-echinococcal activities 267 clinical presentation 255, 257 anti-malarial drugs 268 Aminoacetonitrile derivatives (AADs) extracellular protozoan parasites 233, 234, 238 267 patents 233 intracellular protozoan parasites amino-acetonitrile linker 234 267 amino-malononitrile linker 234 anti-infective thiazolide 260 amino ozonids 267 anti-malarial compounds 267 amino-pyrazole 147, 148 anti-malarial drugs 268 amphotericin B 2, 3, 7, 140, 143, 144, antimalarials dihydroartemisinin 267 148, 260, 267, 272, 275 anti-metacestodal activity 271

Neglected Tropical Diseases: Drug Discovery and Development, First Edition. Edited by David C. Swinney and Michael P. Pollastri. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2019 by Wiley-VCH Verlag GmbH & Co. KGaA. 364 Index

antimicrobial susceptibility Brugia testing 331 B. malayi 172–175, 177, 268 antimycobacterial drugs 329 B. patei 268 antineoplastic properties 269 Buruli ulcer (BU) 327 pharmaceuticals 230, 232 clinical studies 336, 338 antischistosomals 190–192, 194–196, results 336, 338 204, 206–215, 195–200 therapeutic approach 338 anti-tuberculosis drug candidate treatment, BU lesions 338 335 compound screening 336 anti-tumor effects 270 current treatments artemisinin 267 antibiotic treatment, for pregnant artemisinin-derivatives 267 women 328 artemisinin peroxides 267 antibiotic treatment, in Australia artesunate 190, 191, 267 328 arylmethylamino steroids (AASs) 212, standard antibiotic treatment 328 214 diagnostics 329–330 Ascaridia galli 234, 235, 243 discovery models Ascaris lumbricoides 227–229 in vitro test formats 330–331 ATP-binding cassette (ABC) 298 in vivo test formats 331–332 auxotrophies 275 future directions 338–339 avermectins 170, 175, 336, 337 preclinical profiling 332 preclinical profiling, antibiotics b 332 BCX4430 29, 33, 68, 71, 72 repurposing, tuberculosis drug (BZD) 173, 174, 260, candidates 332, 335–336 266, 272, 275 unmet needs 329 benzimidazole chemotherapy 259 benzimidazole derivatives 303 c benzimidazole monotherapy 228 Caenorhabditis elegans 189, 240, 302 2, 3, 96, 97, 99, 101, 106, Caenorhabditis elegans model 302 107 carboxamides 129, 212, 233–235 β-tubulin genes 260, 266 carvacrol 274 Biarylalkyl carboxylic acids (BACAs) celgosivir 24 190, 206–212, 214 cell-based assays, Ebola virus disease Biarylethylamides (BAEAs) 233, 234 (EVD) 54 bi-cyclic spiropiperidine urea 241 cell-based ZIKV assays 25 bilateral symmetry 290 ceracariae 293 Bilharzid 297 cercariae 290, 291, 293–296 Biltricide® 297 cerebral cholesterosis 273 biochemical® assays 26–28, 307, 308, cerebral invasion 299 310 cerebral paragonimiasis 299 bithionol 304 cestodes 261, 268, 273, 275, 297 blood-streaked pneumonia-like sputum cetrimide 272 295 (CD) boron derived benzimidazoles 175 bioluminescent imaging (BLI) mouse bortezomib 273 model 97 bortezomib-mediated inhibition 271 compound selection 98 Index 365

and identification of potential Cutaneous (CL) hits/starting points 98 141–143 mechanism 106–107 cyclic AMP (cAMP) 127 model 96–107 1,3-cyclohexanedioic acid 235 overview 95–96 2-(cyclohexylcarbonyl)-1,2,3,6,7,11b- site of action 103–106 hexahydro-4H-pyrazino[2,1-a] sterile cure 96–107 isoquinolin-4-one 297 in vitro assays to guide structural Cyclooctadepsipeptides (CODP) optimisation 101–103 176–177, 242–245 Chenodeoxycholic acid (CDCA) cyclosporin 272, 273, 352, 357 273 Cyp450 Chinese Food and Drug Administration enzyme 266 228 inhibitors 298 6-chloro-5-(2,3-dichlorophenoxy)-2- cyst dimension 255 (methylthio) benzimidazole) Cystic echinococcosis (CE) 253 299 benzimidazole treatments 257, chloroform 297, 302, 305, 308 259–261 chloroquine 24, 265, 304 clinical presentation 255–257 Cholangiocarcinoma (CCA) 293, 294, cytostatic drugs 270 299 cytotoxicity 6, 25, 54, 127, 130, 175, cholangitis 293, 294 195–197, 199, 261, 267, 268, 271 cholecystitis 293, 294 cytotoxic properties 269 cholelithiasis 294 chronic clonorchiasis 293 d chronic fascioliasis 294 Diethylcarbamazine (DEC) 167–171 chronic mycobacterial 349 digenean trematodes 290 chronic opisthorchiasis 293 Dihydroorotate dehydrogenase cimetidine 298 (DHODH) 24 clarithromycin 268, 269, 328, 329, dimethylformamide 302 332–334, 336–338, 352, 354, 356 dimethylsulfoxide 297 clofazimine 2, 3, 192, 193, 334, 336, di-N-aryl-diguanidino compounds 350–354, 356, 357 267 clonorchiasis 293, 298, 301 diphenylhydramine 298 Clonorchis sinensis 290, 291, 293, 294, diplostomiasis 295 303, 307 diplostomidae 295 2’-C-methylated nucleosides 32 direct acting antibacterial therapy Cocos nucifera 305, 308, 311 350–355 combination chemotherapy 228, 229 direct-acting antivirals 28, 67–74 Commiphora molmol 307, 309, 311 direct acting approach 169–170 Contrast enhanced ultrasound (CEUS) direct antiviral agents 24–25 257 Dirofilaria immitis 234, 235, 238 Cooperia curticei 234 Disability adjusted life years (DALYs) corallopyronin A 178–180 165, 227, 289, 293, 295 cotrimoxazole 336 disk-diffusion testing 331 Crassotrea gigas 296 Distocide 297 crustacea 291, 294 doxorubicin® 269 366 Index

Droncit 297 in vitro and in vivo models 261, 263, Drosophila® melanogaster 238 264 drug discovery efficiency 3–7 Echinococcus 253 drug discovery strategies 1–10, 289 E. canadensis 253 drug level-monitoring 260 E. equinus 253 drug repurposing 95, 127, 128, 148, E.felidis 253 190–194, 213, 264–274, 312, E. granulosus sensu lato 253 332 E. granulosus sensu stricto 253 treating AE E. intermedius 253 anti-cancer drugs 269–271 E. multilocularis genome 260 anti-infective agents 265–269 E. multilocularis metacestodes 256, treating CE 272–274 260, 261, 264–271 Drugs for neglected diseases initiative E. oligarthrus 253 (DNDi) 9, 10, 98, 108, 123, 125, E. ortleppi 253 126, 129, 144, 145, 147–150, 153, E. vogeli 253 173, 177, 188, 229, 244, 338 Echinococcus granulosus 253, 254, 261, 267 e biological feature 254–255 Ebola virus disease (EVD) metacestodes 255 animal models for efficacy testing Echinococcus multilocularis 253, 254, 54–57 257, 263, 269 cell-based assays 54 biological feature 254–255 challenges and innovations 50–52 metacestodes 255 diagnostic tests 50 Echinostomatidae 295 direct-acting antivirals 67–74 echinostomes 295, 301 genome structure, components, and echinostomiasis 295, 303 replication cycle 52 echinostomes 295, 301 host targets 67 symptoms 295 kinases and phosphatases 60 eflornithine 2, 3, 6, 9, 118–124, 128 non-proteolytic endosomal targets embryonated eggs 293, 296 63–65 embryonation 291, 294 nucleic acid inhibitors 70–71 emodepside 176, 177, 232, 242, 244 nucleoside analogs/polymerase Enzyme linked immunosorbent inhibitors 71–74 assay (ELISA) 51, 54, 125, 169, overview of 49–50 257 priming host immune responses epoxy-activated Sepharose 268 65–67 ethacrynic acid 271 ® protein folding and processing ethyl-N-dimethyl ether 272 60–63 eye lesions 163, 166–168 S-adenosyl-homocysteine hydrolase inhibitors 57–60 f surveillance and research diagnostic Fasciola tools 51 F. gigantica 294, 304, 306, 307, 309 therapeutic strategies F. hepatica 290, 291, 294, 300, 301, host-directed antivirals 57 304–306, 309–311 viral protein interactions 69–70 fascioliasis 2, 293, 294, 303, 304 Echinococcosis 253 fasciolopsiasis 296 Index 367

Fasciolopsis 303 g E. buski 292, 296, 301, 304, 307, 308, Galidesivir (BCX4430) 68, 71, 72 311 γ-carbolines 240, 241 Favipiravir (T-705) 63, 68, 71, 72 genistein 58, 60, 61, 269, 307, 311 Federal Drug Administration (FDA) glibenclamide 273, 274 7, 9, 30, 32, 58, 59, 63, 65, 68, Glutathione-S-transferase (GST) 271 70–72, 96, 140, 142, 143, 189, Gracinia mangostana 306, 308–310 202, 203, 270, 271 Guillain-Barré syndrome (GBS) 19, 21 fenbendazole 9, 260, 266, 272 Gymnophalloides seoi 296 9, 97, 99, 101, 105, gymnophalloidiasis 296, 299 129–131 gynecomastia 273 F18-fluorodeoxyglucose-positron emission tomography h (FDG-PET) 257 Haemonchus contortus 234, 235, 238, Fite-Faraco staining 353 241–244 flavin monoxygenase 300 Hagenia abyssinica 306–308, 310 Flemingia vestita 307, 311 halogenated benzimidazole 299 Flubendazole (FLBZ) 9, 173–174, 𝜂6-areneruthenium 271 272 Heligmosomoides polygyrus 234 Foodborne trematode (FBT) Heliothis virescens (tobacco budworm) 289 238 adult worms 290 hemolymphatic stage 118 diagnosis 290 heterocyclic pyrazinoisoquinoline drugs used against derivative praziquantel 259 praziquantel (PZQ) 296–299 heterophyasis 296 TBDD 301–303 Heterophyes heterophyes 296, 311 TCBZ 299–301 Heterophyidae 291, 296 epidemiology 292–293 hexachloro-para-xylol 304 global impact 292–293 hookworm infections 227–229, 274 intestinal host cell toxicity 101, 102, 262 diplostomiasis 295 host-directed antivirals 57, 67 echinostomiasis 295 host directed therapy 354, 355, 358 fasciolopsiasis 296 host targeting agents 24, 36 gymnophalloidiasis 296 Human heterophyasis 296 (HAT) 1 life cycle of 292 biological activity and cell penetration liver 126 clonorchiasis 293–294 chemotherapeutics for 119 fascioliasis 294 diagnostics for 123–125 opisthorchiasis 293–294 distribution of 117 lung 294–295 Eflornithine 122 morphology and biology of 290–292 etiology and epidemiology 115–119 naphtoquinone plumbagin 311 GNF6702 131 trematocidal compounds 310 GNF5343 to GNF6702 131 trematocidal drug discovery 304 immunochromatographic lateral flow fork-tailed cercariae 295 device 125 free-swimming miracidia 294 medicinal chemistry 125–129 368 Index

Human African trypanosomiasis ivermectin 2, 3, 9, 165, 170–171, 192, (HAT) (contd.) 213, 228–230, 265, 272, 337 122 neglected tropical diseases j (NTDs) 115 Juglans regia 274 overview 115 juvenile worms 190, 292, 294, 296 121 119 k target product profile for 126 7-keto-sempervirol 306, 311 treatments for 119–123 kinases 2, 8, 10, 33, 58, 60, 61, 127, human aldose-reductase (hAR) 196, 128, 148, 150–152, 190, 194, 197, 207, 208 202–206, 269, 270, 273, 274, human kinase inhibitors 148, 298 202–205 hydroxydaunorubicin 269 l Leishmania 99, 103, 127, 139–143, i 145, 150–152, 267 imidazopyridine carboxamide (IPA) Leishmania casein kinase 1.2 (LmCK1.2) compounds 335, 336 152 immune reconstitution inflammatory Leishmaniases syndrome 338 phenotypic screening approaches immunochromatographic lateral flow 144–150 device 125 phenotypic screening approach vs immunodiagnosis 257 target-based approach 144 immunodiagnostic tests and PCR 169 in silico computational approach immunomodulation 23, 265 152–153 immunosuppressant drug cyclosporin target-based approaches 150–152 A 272 target product profile for 145 Indirect immunofluorescence assays leprosy (IFAs) 51 clinical staging 351 innovative therapeutic strategies 355, direct acting antibacterial therapy 358 350, 353, 355 Insertion sequence (IS) 329 drugs 356 International Agency of Research on innovative therapeutic strategies Cancer (IARC) 294 355–358 intestinal FBT infections mycobacterial species 349 diplostomiasis 295 unmet medical needs 349–350 echinostomiasis 295 leukotriene inhibitors 354, 358 fasciolopsiasis 296 levamisole 227, 228, 272, 302, 303 gymnophalloidiasis 296 liver FBT infections heterophyasis 296 clonorchiasis 293–294 in vivo efficacy models 173 opisthorchiasis 293–294 ionophore monensin 272 liver trematodes 304, 311 isatin 269 low-density lipoproteins 119, 120 isoflavonoids 269 luciferase-catalyzed reaction 331 isoflavonoid genistein 269 lung FBT infections 294–295 isoxazolines 238 Lycium chinense 306, 311 Index 369 lymphatic filariasis 1, 2, 165, 170, 171, metallo-drugs 271 173, 175, 177, 178, 180, 228, metallo-organic ruthenium complexes 229 271 metastasis formation 255, 274 m 2-methoxyestradiol (2-ME) 270 macrocyclic lactones 9, 175–178, 230, methylation 33, 34, 57 336 microtriches 255, 256, 260 malate dismutation pathway 260, 275 milbemycins 175–176 mangostin 306, 308–311 2, 3, 140, 142–144, mangostin diacetate 309, 311 147–149, 265 MAPK pathway 202 Minimum effective dose (MED) 234 Mass drug administration (MDA) Minimum inhibitory concentrations 1, 165, 187 (MICs) 103, 330 maximum plasma concentration Minimum lethal dose (MLD) 234

(Cmax) 103 miracidia 291, 293–296 Mazzotti test 168 miracidium 290, 291, 295 mebendazole 9, 227, 228, 257, 303 Mirazid 307, 309, 311 Mechanism of action (MOA) 3–7, 25, Mitogen-activated® protein kinase 57, 64, 65, 74, 98, 106–107, (MAPK) 202, 270 120–123, 126, 170, 188, 191, 238, mongolian gerbils 234 298, 300, 302, 310, 311 mono-spiropiperidine ureas 241 medicinal chemistry approaches monotherapy 32, 96, 121, 123, 128, CODP 242–245 141, 228, 266, 329, 333, 350, 355, intervet multicyclics 235, 238 356 VAChT inhibitors 238, 240, 241 moxidectin 9, 175, 176, 194, 228, 229, Medicines for Malaria Venture (MMV) 337 188, 268 moxifloxacin 328, 329, 332–334, 336, mefloquine 192, 265, 267, 268, 275 337, 354, 356 mefloquine enantiomers 267 MTase inhibitors 30–34 mefloquine-sepharose matrices 268 Mucosal leishmaniasis (ML) 142–144 melarsoprol 2, 119–124, 126 multicyclic patents 233 Mentha Multi-drug therapy (MDT) 349, 350, M. piperita 274, 305 352, 353, 355, 357, 358 M. pulegium 274 Mycobacterium Meriones unguiculatus 173, 174, 269 M. leprae 349, 350, 353–356, metabolite p-(1-dimethylamino 358 ethylimino) aniline (dADT) 302 M. lepromatosis 349, 350, 354 metabolites 3, 25, 28, 74, 130, 169, 173, M. tuberculosis 103, 105, 330, 332, 176, 179, 198, 213, 242, 255, 260, 335–337 265, 266, 270, 272, 275, 298, M. ulcerans 327–338 300–302 mycolactone 327, 328 metacercaria 290, 295 Myrrh 307, 311 metacercariae 292, 294, Myrtus communis L. 274 296 metacercariae excyst 292, 294, 296 n metacestodes 254–256, 259–275 1,4-naphthoquinone ethers 195 Metagonimus yokogawai 296 Nectaroscordum tripedale L. 274 370 Index

Neglected tropical diseases (NTDs) o 1, 338, 349 Oesophagostomum dentatum 234, critical components for 7, 8 235 drug discovery efficiency 3 Onchocerciasis drug discovery drug discovery strategies for 3, 6 albendazole 171 mechanisms 1–3 anti-bacterial approach 171 PDD vs TDD for 6–7 benzimidazole (BZD) 173–175 repurposing knowledge mechanisms boron derived benzimidazoles 175 and therapeutics 9–10 clinical diagnosis 168 Neodiplostomum seoulensis 295 clinical manifestation 166–167 netobimin 272 corallopyronin A 178–180 neuromuscular vesicular acetylcholine cyclooctadepsipeptides 176–177 238 diethylcarbamazine 170 Newly excysted juveniles (NEJs) direct acting approach 169–170 304–307, 311 epidemiology 165 niclosamide 2, 192, 193, 268 eye lesions 166–167 -eflornithine combination flubendazole (FLBZ) 173–174 therapy (NECT) 119, 121, 123, immunodiagnostic tests and PCR 128, 131 169 Nippostrongylus brasiliensis 234 ivermectin 170–171 nitanoxazide 304 life cycle of 164–165 nitazoxanide 192, 232, 260, 265, 266, mazzotti test 168 271, 272, 275, 354, 356 milbemycins 175–176 nitazoxanide monotherapy 266 nodding syndrome 167 NITD008 29, 31, 33 nodules 166 97, 130, 149, 150 nodulectomy 172 N,N-Di-[4-(1-dimethylaminoethy- parasitological diagnosis 168 limine)phenyl]-1,4-xylene imine primary in vitro assays 172 302 pyrazolopyridine 180 nocodazole 272 skin lesions 166 nodding syndrome 167 suramin 171 nodules 142, 163, 164, 166, 168, 169, derivatives 171–172 172, 173, 328, 338, 351 tylosin A 177–178 nodulectomy 172 ultrasonography 168 non-proteolytic endosomal targets UMF-078 174–175 63–65 in vivo efficacy models 173 NS2B-NS3 protease 27, 35 opisthorchiasis 293, 298, 301, NS3 helicase 26–28, 34, 35 303 NS5 MTase and polymerase 26–27 Opisthorchis NS3 protease and helicase inhibitors O. felineus 293, 294 34–36 O. viverrini 268, 293, 294, 299, 302, NS5 RdRp and MTase inhibitors 303, 309, 311 30–34 Opisthorchis spp. 291, 293 nucleic acid inhibitors 70–71 Opistorchiidae 304 nucleoside analogs/polymerase organic solvents 297 inhibitors 71–74 organometallics 190, 199–200 Nucleotide triphosphate (NTP) 28 Origanum vulgare 274, 275 Index 371

Ornithine decarboxylase (ODC) 2, 6, priming host immune responses 120, 123 65–67 inhibitor 6 propargylic alcohols 265, 269 Oxantel 228, 229 proteasome inhibitor 271, 273 oxantel pamoate 228, 229 protein folding and processing 60–63 oxfendazole 9, 260, 266, 272 protein kinases 60, 150, 194, 202, 270, oysters 296 274, 298 proteolytic enzymes 265 p protoscoleces 254, 255, 259, 263, 264, paradoxical reactions 338 266, 269, 270, 272–274 paragonimiasis 293–295, 298–301 pyrantel 228 paragonimisasis 294, 295 pyrazolopyridine 180 causes 295 pyrazolopyrimidines 148, 149 pathological features 295 pyridinyl imidazoles 270 zoonotic disease 294 Paragonimus 291, 294, 303, 304 q patent landscape 2005-2017 232, 233 Quantitative reverse transcription PDD, vs TDD 6–7 polymerase chain reactions Pentamidine 2, 3, 119–122, 124, 141, (qRT-PCR) 50, 51, 73 267, 272 1,5-pentanedioic acid 235 r peptidyltransferase 268 rapalogs rapamycin 273 periductal fibrosis 293 rapamycin 273 Pestalotiopsis sp. 274 rare immune-mediated reactions 257 pharmacodynamic effects 106 respiratory cytochrome 335 Pharmacokinetic-pharmacodynamic Respiratory syncytial virus (RSV) (PK/PD) 103 infection 30, 31 phosphatases and kinases 60 ribavirin and T-705 Phosphoglucose isomerase (PGI) 261, 262, 264, (favipiravir) 30–32 266–268 ricobendazole 260 piperidine moiety 241 Ridley-Jopling system 351 piperitone oxide 274 rifampicin (RIF) 2, 265, 328 Plasmodium 267, 271 RNA-dependent RNA polymerase P. falciparum 202, 213, 268 (RdRp) 23, 26, 71 Plumbago spp. 307, 311 RNA interference (RNAi) 127, 189, Plutella xylostella (diamond back moth) 202, 263, 298 240 polycystic echinococcosis 253 s polyisohexylcyanoacrylate nanoparticles “sac-like” ciliated larva 291 269 S-adenosyl-homocysteine hydrolase Polymerase chain reaction (PCR) 20, inhibitors 57, 60 140 salicylanilide-derivative 268 praziquantel (PZQ) 2, 3, 187–189, 232, salicyl moiety 266 242, 259, 265, 272, 296–299 Schistosoma Prazitel 297 S. japonicum 189–191, 196–198, primary® in vitro assays 172 200, 201, 206, 267 372 Index

Schistosoma mansoni Sorafenib 270 histone deacetylase 8 (SmHDAC8)- spiroindolines 238, 240, 241 ligand complex 195 sporocysts 290, 291, 293–296 3-hydroxy-3-methylglutaryl sporotrichoid spread 141 coenzyme A reductase Streptomycin (STR) 2, 328, 329, (Sm HMGR) 192 331–334, 336–338 polo-like kinase 1 (SmPLK1) 203 Structure activity relationship (SAR) thioredoxin glutathione reductase 119, 127, 152, 176, 179, 196–198, (SmTGR) 195 237, 243, 261, 302, 336 Schistosoma spp. 297, 300 suramin 1, 2, 119–121, 171, 272 schistosomiasis 254, 297, 311 symptomatology 296 arylmethylamino steroids (AASs) syngenta spiroindolines 238, 240 212–213 synthetic and semi-synthetic biarylalkyl carboxylic acids (BACAs) artemisinins 311 206–212 drug development pipeline 213–215 t drug repurposing for 190–194 Taenia natural products 200–202 T. crassiceps 273 neglected tropical disease (NTD) T. solium 261, 273 187–189 tamoxifen 59, 64, 65, 269, 273 organometallics 199–200 Target product profile (TPP) 8, 107, phenotypic approaches 196–199 125, 126, 139, 145, 170, 189–190, potential drug targets 202–206 213 strategies, tools and target product T-cell immunoglobulin and mucin profile (TPP) 189–190 domain (TIM) 21 structure-based drug design for tegument 205–208, 212, 213, 255, 195–196 256, 260, 290, 306, 307, 309, for treatment 187–189 310 Semisulcospira 294 sense single-stranded RNA (ssRNA) tegumental microtriches 260 21–23 Terephtaldehyde (TPAL) 302 serine/threonine kinases 270 Terephtalic acid (TPAC) 302 silico approach 152, 268 tetracycline derivatives 171–172 skin lesions 140, 166, 168, 327, 328, thermosensitivity 338 351 thiazole moiety 266 small fox tapeworm 253 thiazolide nitazoxanide 272 sodium arsenite 273 thiophene-diguanidino derivatives Soil transmitted helminthiasis (STH) 267 anthelmintic discovery thymol 266, 272, 274, 275 medicinal chemistry approaches Thymus vulgaris 274, 275, 305 235–238 Toxoplasma 271 new molecules, from patent transcriptome 261, 263 literature 232–235 Transmission electron microscopy anthelmintic research and (TEM) 256, 267, 268, 273, 274, development, animal health 307, 310 229–230, 232 trematocidal drug 304, 310, 311 therapies and needs 227–229 trematoda 289 Index 373

Tribendimidine (TBDD) 228, 229, 297, World Health Organization (WHO) 301–303, 312 17, 20, 115, 117, 165, 227, 304, Trichostrongylus colubriformis 234, 328, 338, 349, 352 235, 238, 241–243 Worm burden reductions (WBR) 190, Trichuris trichiura 227–229 303, 309–311 Trichuris trichiura infections 227–229 x Triclabendazole (TCBZ) 2, 297, xylol derivative 304 299–301 z Trypanosoma brucei 115 zafirlukast 354, 358 blood-stream form 128 Zika virus (ZIKV) 25 life cycle of 116 animal models for evaluating in vivo mechanism of 127 efficacy 28–30 Trypanosoma cruzi anti-ZIKVdrugdiscovery,invitro antibodies 96 tools for complex pathology of 95 biochemical assays and tools CYP51 inhibitors 101 26–28 metabolic plasticity of 107 cell-based ZIKV assays 25 trypanosomatid 150, 271 NS2B-NS3 protease 27 trypanosomiasis 118, 125, 254 NS3 helicase 27–28 tub-2 isoform 260 NS5 MTase and polymerase tubulin dimer 260 26–27 Tylosin A 177, 178 BCX4430 33 tyrosine kinases 60, 128, 203, 269, 2’-C-methylated nucleosides 32 270 from dengue antiviral research 23–25 u direct antiviral agents 24–25 ubiquinated proteins 271 host targeting agents 24 unicystic echinococcosis 253 detection, clinical presentation, and urticaria 168, 257 medical need 20–21 history and epidemiology 17–20 v MTase inhibitors 33–34 vero cells 25, 32, 33, 271 NITD008 33 Vesicular acetylcholine transporter NS3 protease and helicase (VAChT) inhibitors 238–241, inhibitors 34–36 245 NS5 RdRp and MTase inhibitors Virus-like particles (VLPs) 54, 59, 30–34 69 other classes of small molecules Visceral leishmaniasis (VL) 99, 101, against 36–37 139–141 outbreak in Oceania 19 replication cycle 21–23 w ribavirin and T-705 (favipiravir) Whole genome sequencing (WGS) 51, 30–32 106 zymography 271