Antiprotozoal Drug Development and Delivery (Topics in Medicinal Chemistry, 39)

This book reviews new promising drug targets for Neglected Tropical Diseases (NTDs), with a special focus on antiprotozoal drugs against trpyanosomatids Trypanosoma cruzi and Leishmania spp. The book offers a comprehensive overview of the most recent studied targets, and it outlines classical and new treatments and delivery strategies. Expert contributors describe new methods of analysis and bio-prospecting for new compounds, and provide a critical perspective of the translational process used in the research and development of new drug candidates. The book will appeal not only to researchers, students and professionals interested in drug development to protozoan diseases, but also to medicinal chemists in general. Preface 6 Contents 9 Classical and Modern Drug Treatments for Leishmaniasis 11 1 Introduction 12 2 Current Drugs in Use for the Treatment of Leishmaniasis 15 2.1 Antimonials 16 2.2 Amphotericin B Deoxycholate and Liposomal Amphotericin B 17 2.3 Pentamidine 18 2.4 Paromomycin 18 2.5 Miltefosine 19 3 New Drugs Available for Leishmaniasis Treatment 20 3.1 Drug Delivery Systems 20 3.2 Immucillins 21 3.3 Drugs from Natural Sources 21 4 Combination Therapy 22 5 Alternative Therapies 22 5.1 Sitamaquine 22 5.2 Ketoconazole, Fluconazole, and Itraconazole 23 5.3 Physical Treatment 23 6 Drug Resistance 23 7 Perspectives 24 8 Conclusion 25 References 25 Saponins as Potential Antiprotozoal Agents 32 1 Introduction 33 2 Saponin Structures 33 3 Distribution of Saponins in the Vegetable Kingdom 34 4 Pharmacological Activities of Saponins 35 4.1 Biological Activities 35 4.2 Antiprotozoal Activity of Saponins 39 4.2.1 Protozoal Diseases 39 4.2.2 Antiprotozoal Activity of Saponin Extracts 40 Antitrypanosomal Activity 40 Antitrichomonas Activity 40 Antileishmanial Activity 41 4.2.3 Antiprotozoal Activity of Isolated Saponins 42 5 General Considerations 42 References 53 Chagas Disease: Drug Development and Parasite Targets 58 1 Introduction 59 1.1 Chagas Disease: A Problem for Public Health 59 2 Targets for the Treatment of Chagas Disease 61 2.1 Drug Targets 62 2.1.1 Cysteine Peptidase-Cruzipain 62 2.1.2 Kinetoplast Proteasome 63 2.1.3 Carbonic Anhydrase 64 2.1.4 Sirtuins 64 2.1.5 Cyclophilin 65 2.1.6 N-myristoyltransferase 65 2.1.7 Pentose Phosphate Pathway: Glucose-6-Phosphate Dehydrogenase and Trypanothione Reductase 65 2.1.8 Ergosterol Biosynthesis Inhibitors 66 2.1.9 Sphingolipids 68 2.1.10 Intracellular Calcium Homeostasis 68 2.1.11 Acidocalcisomes 69 2.1.12 Kinetoplast 69 3 Current Treatments for Chagas Disease 70 4 New Drugs and Clinical Trials 72 4.1 Drugs in Clinical Trials 72 4.1.1 Fexinidazole: First Global Approval 73 4.1.2 E1224/Ravuconazole 73 4.1.3 New Drugs Discovery 74 5 Omics Platforms in Chagas Disease 75 6 Perspectives: Challenges in New Drugs Discovery 79 References 80 Targeting Carbonic Anhydrases from Trypanosoma cruzi and Leishmania spp. as a Therapeutic Strategy to Obtain New Antiprotozoal... 91 1 Introduction 92 2 TcCA, the α-CA from Trypanosoma cruzi 93 2.1 TcCA Inhibition 94 2.2 TcCA Activation 106 3 LdcCA, the β-CA from Leishmania Donovani 108 3.1 LdcCA Inhibition 108 3.2 LdcCA Activation 115 4 Conclusions 115 References 116 New Compounds for the Management of Trypanosoma brucei Infection 120 1 Introduction 121 2 Clinical Relevance 122 3 The Life Cycle of T. brucei 123 4 Current Status in Antitrypanosomal Therapy 124 5 New Therapeutic Strategies and Emerging Targets 128 5.1 New Trypanothione Reductase Inhibitors and Other Deregulators of the Oxidative Status 129 5.2 Nitro(Hetero)Cycle-Based Inhibitors of Nitro-Reductase 132 5.3 New Pteridine Reductase 1 Inhibitors 134 5.4 Selective Methionyl-tRNA Synthetase Inhibitors 136 5.5 Phthalazinone Derivatives as Novel T. brucei Phosphodiesterase Inhibitors 137 5.6 Advances in Trypanosome Peptidases: The Case Study of Cysteine Protease Rhodesain Inhibitors 139 6 Conclusion 142 References 143 Polyamine and Trypanothione Pathways as Targets for Novel Antileishmanial Drugs 149 1 Introduction 150 2 Leishmaniasis Chemotherapy 152 3 Polyamine Pathway 154 3.1 Arginase 155 3.2 Ornithine Decarboxylase (ODC) 158 3.3 S-Adenosylmethionine Decarboxylase (AdoMetDC) 161 3.4 Spermidine Synthase (SpdS) 162 4 Trypanothione Pathway 162 4.1 Glutathionylspermidine Synthetase (GspS) 163 4.2 Trypanothione Synthetase (TryS) 164 4.3 Trypanothione Reductase (TryR) 165 5 General Considerations 170 References 178 Nano and Microstructured Delivery Systems for Current Antileishmanial Drugs 187 1 Introduction 188 1.1 Leishmaniasis 188 1.2 Current Chemotherapy 189 1.3 Drug Delivery Systems (DDS) 191 1.4 How DDS Entries into Cells 197 2 DDS for Leishmaniasis 200 2.1 Antimonials 200 2.2 Amphotericin B (AmB) 203 2.3 Pentamidine 209 2.4 Miltefosine 211 2.5 Paromomycin 212 3 Conclusion 215 References 215 Pharmacological Treatment of Malaria 224 1 Introduction 225 1.1 Life Cycle of Malaria Parasites 226 2 Drugs Against Malaria 228 2.1 Chloroquine 229 2.2 Primaquine 230 2.3 Artemisinin-Based Combination Therapy (ACT) 230 2.3.1 Dihydroartemisinin, Artemether, and Artesunate 231 2.3.2 Lumefantrine 232 2.3.3 Amodiaquine 233 2.3.4 Mefloquine 234 2.3.5 Sulfadoxine/Pyrimethamine (SP) 235 2.3.6 Piperaquine 235 2.4 Non-artemisinin-Based Drug Combinations 236 2.4.1 Amodiaquine + Sulfadoxine-Pyrimethamine (AQ + SP) 236 2.4.2 Atovaquone-Proguanil 236 2.4.3 Quinine + Antibiotics (Doxycycline and Clindamycin) 236 3 Conclusion 238 References 241 η-Class Carbonic Anhydrases as Antiplasmodial Drug Targets: Current State of the Art and Hurdles to Develop New Antimalarials 246 1 Introduction 247 1.1 Protozoan Infections 247 1.2 Existing Antimalarial Strategies 248 2 A New Druggable Enzyme from Plasmodium falciparum 250 2.1 Carbonic Anhydrase 250 2.2 Plasmodium falciparum CA 252 2.3 PfCA1 and PfCAdom Kinetic Parameters 252 3 PfCAdom Inhibition 253 3.1 The Most Investigated CA Inhibitors 253 3.2 Sulfonamide Inhibition Profile 254 3.3 Anion Inhibition Profile 255 3.4 In Vitro Inhibition of Plasmodium falciparum Growth 255 4 PfCAdom Inhibition with Phenolic Compounds 255 4.1 Phenolic Compounds 255 5 Conclusions 256 References 257 Management of Entamoeba histolytica Infection: Treatment Strategies and Possible New Drug Targets 264 1 Biology and Pathogenesis of Entamoeba histolytica 265 2 Epidemiology of E. histolytica Infection 266 3 Diagnosis of E. histolytica Infection 266 4 Current Treatment Options for E. histolytica Infections 267 5 Future Therapeutics and Vaccine Development 269 6 Concluding Remarks 271 References 271 Trichomonas vaginalis Pharmacological Treatment 275 1 Prevalence and Symptoms of Trichomoniasis 276 2 Diagnosis of Trichomoniasis 277 3 Pharmacological Treatment of Trichomoniasis 278 4 Nitroimidazole Resistance of T. vaginalis 279 5 Future Perspectives 279 References 280 Beta-Carbonic Anhydrase 1 from Trichomonas Vaginalis as New Antiprotozoan Drug Target 283 1 Introduction 284 2 TvaCA1 Biochemical, Kinetic, and Structural Characterization 286 3 TvaCA1 Inhibition with Anions and Sulfonamides 288 4 Conclusions and Future Perspectives 292 References 292 Treatment of Toxoplasmosis: An Insight on Epigenetic Drugs 297 1 Introduction 298 2 Toxoplasmosis Treatment 299 3 T. Gondii Inhibitors: An Overview 301 4 Epigenetics: A New Opportunity for T. Gondii Inhibitors? 304 5 Epigenetic Drugs for the Treatment of Toxoplasmosis 306 5.1 Cyclic Tetrapeptide HDAC Inhibitors 306 5.2 Hydroxamate-Based and Short-Chain Fatty Acid HDAC Inhibitors 310 5.3 GCN5 Inhibitors 313 6 Conclusions 315 References (in original ms) [2] and [6]; [4] and [38] were identical and Reference [6], [38] has been deleted. The subsequent ... 315 Challenges and Promises for Obtaining New Antiprotozoal Drugs: What ́s Going Wrong? 324 1 Introduction 325 2 Antiprotozoal Drugs in Clinical Use 326 3 New Drugs and Compounds in Clinical Trials 328 4 Challenges for the Future after the COVID-19 Pandemic 329 References 330 Correction to: Chagas Disease: Drug Development and Parasite Targets 333 Correction to: Chapter ``Chagas Disease: Drug Development and Parasite Targets ́ ́ in: Alane Beatriz Vermelho and Claudiu T. Sup... 333