1,2,3-Triazole derivatives: synthesis, docking, cytotoxicity analysis and in vivo antimalarial activity
| Autor: | Pedro Henrique Fazza Stroppa, Juliane Aparecida Marinho, Adilson David da Silva, Priscila Vanessa Zabala Capriles Goliatt, Clarice Abramo, Roberta Reis Soares, Fernanda Valério Lopes, Lara de Azevedo Alves |
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| Rok vydání: | 2021 |
| Předmět: |
Plasmodium berghei
In silico Drug Evaluation Preclinical Protozoan Proteins Toxicology Hemolysis Antimalarials Mice Structure-Activity Relationship In vivo Chloroquine Catalytic Domain parasitic diseases medicine Animals Humans Computer Simulation Protein Structure Quaternary Cytotoxicity L-Lactate Dehydrogenase biology Chemistry General Medicine Triazoles medicine.disease biology.organism_classification In vitro Malaria Molecular Docking Simulation Biochemistry Docking (molecular) Macrophages Peritoneal Female medicine.drug |
| Zdroj: | Chemico-Biological Interactions. 350:109688 |
| ISSN: | 0009-2797 |
| DOI: | 10.1016/j.cbi.2021.109688 |
| Popis: | Malaria remains one of the most important parasitic diseases in the world. The multidrug-resistant Plasmodium strains make the treatment currently available for malaria less effective. Therefore, the development of new drugs is necessary to overcome therapy resistance. Triazole derivatives exhibit several biological activities and provide a moiety that is promising from the biological perspective. Due to the structural similarity to NADH, it is believed that triazoles can bind to the active site of the Plasmodium lactate dehydrogenase (pLDH) enzyme. The present work evaluates the antimalarial activity of 1,2,3-triazole derivatives by in silico, in vitro, and in vivo studies. Preliminary in silico ADMET studies of the compounds demonstrated good pharmacokinetic properties. In silico docking analysis against LDH of Plasmodium berghei (PbLDH) showed that all compounds presented interactions with the catalytic residue in the active site and affinity similar to that presented by chloroquine; the most common antimalarial drug. Cytotoxicity and hemolysis by these derivatives were evaluated in vitro. The compounds 1, 2, 5, 8, and 9 proved to be non-cytotoxic in the performed tests. In vivo antimalarial activity was evaluated using mice infected with Plasmodium berghei NK65. The five compounds tested exhibited antimalarial activity until nine days post-infection. The compound 5 showed promising activities, with about 70% parasitemia suppression. Considering the in vitro and in vivo studies, we believe the compound 5 to be the most promising molecule for further studies in antimalarial chemotherapy. |
| Databáze: | OpenAIRE |
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