ABSTRACT
Leishmaniasis and Chagas disease remain a significant global problem. Current treatments have serious disadvantage due to cost, toxicity, long therapy duration and resistance. In the last years increasing interest has arisen in drug development to fight both diseases. Recently, metal-based drugs have revealed as promising drugs in a variety of therapeutic areas. Herein we describe six newly synthesized transition metal complexes with a bioactive molecule 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp). All of them have been characterized by X-ray, spectroscopic and thermal methods. In vitro and in vivo studies (murine model) on the antiproliferative activity of these complexes against Leishmania spp. (Leishmania infantum, Leishmania braziliensis) and Trypanosoma cruzi have been carried out. Our results reveal a strong potential of three of the assayed compounds as antiparasitic agents against the above-mentioned infectious diseases.
Subject(s)
Chagas Disease/parasitology , Leishmaniasis/parasitology , Organometallic Compounds/chemistry , Organometallic Compounds/pharmacology , Transition Elements/chemistry , Triazoles/chemistry , Animals , Chagas Disease/drug therapy , Chlorocebus aethiops , Extracellular Space/drug effects , Extracellular Space/parasitology , Female , Inhibitory Concentration 50 , Intracellular Space/drug effects , Intracellular Space/parasitology , Leishmania braziliensis/drug effects , Leishmania infantum/drug effects , Leishmaniasis/drug therapy , Mice , Models, Molecular , Molecular Conformation , Organometallic Compounds/therapeutic use , Organometallic Compounds/toxicity , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use , Trypanocidal Agents/toxicity , Trypanosoma cruzi/drug effects , Vero CellsABSTRACT
Access to basic drugs is a major issue in developing countries. Chagas disease caused by Trypanosoma cruzi is a paradigmatic example of a chronic disease without an effective treatment. Current treatments based on benznidazole and nifurtimox are expensive, ineffective, and toxic. N,N'-Squaramides are amide-type compounds that feature both hydrogen bond donor and acceptor groups and are capable of multiple interactions with complementary sites. When combined with amine and carboxylic groups, squaramide compounds have increased solubility and therefore make suitable therapeutic agents. In this work, we introduce a group of Lipinski's rule of five compliant squaramides as candidates for treating Chagas disease. The in vivo studies confirmed the positive expectations arising from the preliminary in vitro studies, revealing compound 17 to be the most effective for both acute and chronic phases. The activity, stability, low cost of starting materials, and straightforward synthesis make amino squaramides appropriate molecules for the development of an affordable anti-Chagasic agent.
