Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i>
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 o...
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| Format: | Article |
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MDPI AG
2021-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/2/423 |
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| author | Leonardo S. Lara Guilherme C. Lechuga Caroline dos S. Moreira Thaís B. Santos Vitor F. Ferreira David R. da Rocha Mirian C. S. Pereira |
| author_facet | Leonardo S. Lara Guilherme C. Lechuga Caroline dos S. Moreira Thaís B. Santos Vitor F. Ferreira David R. da Rocha Mirian C. S. Pereira |
| author_sort | Leonardo S. Lara |
| collection | DOAJ |
| description | 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 (<b>1a</b>–<b>i</b> and <b>2a</b>–<b>j</b>) 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 <b>1g,</b> which exhibit a drug-likeness profile, as a promising compound against <i>Trypanosoma cruzi</i>. SAR analysis also revealed <b>1g</b> as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and <b>1g</b> were unable to reduce parasite load, and did not prevent mouse mortality in <i>T. cruzi</i> 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. |
| first_indexed | 2024-03-09T04:43:47Z |
| format | Article |
| id | doaj.art-38cb4a7db9c64998a57e6cfb45109be6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T04:43:47Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-38cb4a7db9c64998a57e6cfb45109be62023-12-03T13:18:13ZengMDPI AGMolecules1420-30492021-01-0126242310.3390/molecules26020423Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i>Leonardo S. Lara0Guilherme C. Lechuga1Caroline dos S. Moreira2Thaís B. Santos3Vitor F. Ferreira4David R. da Rocha5Mirian C. S. Pereira6Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilDepartamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Rua Outeiro São João Batista, Niterói 24020-141, Rio de Janeiro, BrazilDepartamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Rua Outeiro São João Batista, Niterói 24020-141, Rio de Janeiro, BrazilDepartamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Rua Outeiro São João Batista, Niterói 24020-141, Rio de Janeiro, BrazilDepartamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Rua Outeiro São João Batista, Niterói 24020-141, Rio de Janeiro, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilChagas 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 (<b>1a</b>–<b>i</b> and <b>2a</b>–<b>j</b>) 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 <b>1g,</b> which exhibit a drug-likeness profile, as a promising compound against <i>Trypanosoma cruzi</i>. SAR analysis also revealed <b>1g</b> as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and <b>1g</b> were unable to reduce parasite load, and did not prevent mouse mortality in <i>T. cruzi</i> 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.https://www.mdpi.com/1420-3049/26/2/423<i>Trypanosoma cruzi</i>naphthoquinonestrypanocidal activitychemotherapycompound optimization |
| spellingShingle | Leonardo S. Lara Guilherme C. Lechuga Caroline dos S. Moreira Thaís B. Santos Vitor F. Ferreira David R. da Rocha Mirian C. S. Pereira Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i> Molecules <i>Trypanosoma cruzi</i> naphthoquinones trypanocidal activity chemotherapy compound optimization |
| title | Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i> |
| title_full | Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i> |
| title_fullStr | Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i> |
| title_full_unstemmed | Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i> |
| title_short | Optimization of 1,4-Naphthoquinone Hit Compound: A Computational, Phenotypic, and In Vivo Screening against <i>Trypanosoma cruzi</i> |
| title_sort | optimization of 1 4 naphthoquinone hit compound a computational phenotypic and in vivo screening against i trypanosoma cruzi i |
| topic | <i>Trypanosoma cruzi</i> naphthoquinones trypanocidal activity chemotherapy compound optimization |
| url | https://www.mdpi.com/1420-3049/26/2/423 |
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