Metal Compounds against Neglected Tropical Diseases Yih Ching Ong, †,∥ Saonli Roy, ‡,∥ Philip C. Andrews,* ,§ and Gilles Gasser* ,† † Laboratory for Inorganic Chemical Biology, Chimie ParisTech, PSL University, 11 rue Pierre et Marie Curie, F-75005 Paris, France ‡ Department of Chemistry, University of Zurich, Wintherthurerstrasse 190, CH-8057 Zurich, Switzerland § School of Chemistry, Monash University, Wellington Road, Clayton, Victoria 3800, Australia ABSTRACT: Many first-line treatments for neglected tropical diseases identified by the World Health Organization (WHO) are limited by one or more of the following: the development of drug resistance, toxicity, and side effects, lack of selectivity, narrow therapeutic indices, route of administration, and bioavailability. As such, there is an urgent need to develop viable alternatives to overcome these limitations. The following review provides an overview of all existing metal complexes studied and evaluates the status of these complexes on the respective disease of choice. CONTENTS 1. Introduction and the Main Challenges for Developing Metal-Based Drugs for Neglected Tropical Diseases B 2. Chagas Disease B 2.1. Background B 2.2. Main Challenges in the Current Treatments for Chagas Disease C 2.3. Current Literature C 2.3.1. Metal Complexes Containing Bioactive Ligands C 2.3.2. Metal Complexes of Nonbioactive Li- gands O 3. Dengue P 3.1. Introduction to Dengue P 3.2. Mechanism of Infection P 3.3. Symptoms P 3.4. Main Challenges for Treatment of Dengue P 3.5. Current Literature P 3.5.1. Use of Metal Complexes as Antiviral Treatment Candidates P 4. Echinococcosis R 4.1. Symptoms R 4.2. Main Challenges for the Current Treatment of Echinococcosis R 4.3. Current Studies R 5. Leishmaniasis S 5.1. Leishmania and Leishmaniasis S 5.1.1. Life Cycle of the Leishmania Parasite S 5.1.2. Leishmaniasis and Its Epidemiology T 5.2. Main Challenges for the Current Treatments of Leishmaniasis T 5.2.1. Challenges in Using First-Line Pentava- lent Antimonials T 5.2.2. Challenges in Using Alternative Drugs U 5.3. Reviewing Metal-Based Antileishmanial Compounds in the Literature U 5.4. Molecular Targets and Mechanisms U 5.4.1. Trypanothione and Trypanothione Re- ductase V 5.4.2. Generation of ROS Species AA 5.4.3. Inhibition of Iron Superoxide Dismutase (Fe−SOD) AC 5.4.4. Synergistic Metal−Ligand Interactions AC 5.4.5. DNA Intercalation as a Mode of Action AE 5.4.6. Cathepsin B as the Target of Interest AL 5.4.7. Interleukin-1β AM 5.5. Bismuth in Medicine AM 5.6. Encapsulation as a Mode of Delivery AO 5.6.1. Background on Types of Encapsulation AO 5.6.2. Studies Involving Encapsulation AP 6. Lymphatic Filariasis AQ 6.1. Introduction and Main Challenges for Treat- ment of Lymphatic Filariasis AQ 6.2. Current Literature AR 7. Onchocerciasis (River Blindness) AR 7.1. Introduction and Main Challenges for Treat- ment of Onochocerciasis AR 7.2. Current Literature AR 8. Schisotosomiasis AR Special Issue: Metals in Medicine Received: July 5, 2018 Review pubs.acs.org/CR Cite This: Chem. Rev. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/acs.chemrev.8b00338 Chem. Rev. XXXX, XXX, XXX−XXX Chem. Rev. Downloaded from pubs.acs.org by TULANE UNIV on 12/03/18. For personal use only.