Author | Lara, Leonardo S. | |
Author | Lechuga, Guilherme C. | |
Author | Moreira, Caroline dos S. | |
Author | Santos, Thais B. | |
Author | Ferreira, Vitor F. | |
Author | Rocha, David R. da | |
Author | Pereira, Miriam C. S. | |
Access date | 2021-05-25T19:50:13Z | |
Available date | 2021-05-25T19:50:13Z | |
Document date | 2021 | |
Citation | LARA, Leonardo S. et al. Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi. Molecules, v. 26, n. 2, 21p, 2021. | pt_BR |
ISSN | 1420-3049 | pt_BR |
URI | https://www.arca.fiocruz.br/handle/icict/47369 | |
Language | eng | pt_BR |
Publisher | MDPI | pt_BR |
Rights | open access | pt_BR |
Subject in Portuguese | Trypanosoma cruzi | pt_BR |
Subject in Portuguese | Atividade tripanocida | pt_BR |
Subject in Portuguese | Naftoquinonas | pt_BR |
Subject in Portuguese | Quimioterapia | pt_BR |
Subject in Portuguese | Otimização composta | pt_BR |
Title | Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against Trypanosoma cruzi | pt_BR |
Type | Article | pt_BR |
DOI | 10.3390/molecules26020423 | |
Abstract | Chagas disease (CD) still represents a serious public health problem in Latin America,
even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are
considered inadequate, especially because of undesirable side effects and low efficacy in the chronic
stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small
library of compounds (1a–i and 2a–j) was designed based on the structural optimization of a Hit
compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity,
structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone
derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some
substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the
thiophenol benzene ring for trypanocidal activity, highlighting 1g, which exhibit a drug-likeness
profile, as a promising compound against Trypanosoma cruzi. SAR analysis also revealed 1g as cliff
generator in the structure-activity similarity map (SAS maps). However, compounds C2 and 1g
were unable to reduce parasite load, and did not prevent mouse mortality in T. cruzi acute infection.
Phenotypic screening and computational analysis have provided relevant information to advance
the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological
profile. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, Brasil. | pt_BR |
Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil. | pt_BR |
Subject | Trypanosoma cruzi | pt_BR |
Subject | Naphthoquinones | pt_BR |
Subject | Trypanocidal activity | pt_BR |
Subject | Chemotherapy | pt_BR |
Subject | Compound optimization | pt_BR |