Novel Quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione Derivatives Against Chloroquine-resistant Plasmodium falciparum
| Autor: | Cláudio Tadeu Daniel-Ribeiro, Cedric Stephan Graebin, Luana Santos Oliveira, Vitoria de Souza Fernandes da Silva, Leonardo J M Carvalho, Nubia Boechat, Luiza Helena Pinto Domingues, Kamilla R. Rogério |
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| Rok vydání: | 2020 |
| Předmět: |
Pyrimidine
medicine.drug_class Stereochemistry Plasmodium falciparum 030231 tropical medicine Drug Resistance Ring (chemistry) 01 natural sciences Cell Line Antimalarials Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Parasitic Sensitivity Tests Drug Discovery medicine Animals Methylene Cytotoxicity Dose-Response Relationship Drug Molecular Structure biology Quinoline Chloroquine Haplorhini General Medicine biology.organism_classification Quinolone 0104 chemical sciences 010404 medicinal & biomolecular chemistry Pyrimidines chemistry Quinolines Linker |
| Zdroj: | Current Topics in Medicinal Chemistry. 20:99-110 |
| ISSN: | 1568-0266 |
| DOI: | 10.2174/1568026619666191019100711 |
| Popis: | Introduction: In this work DHPMs were combined with the quinoline nucleus to obtain new quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione compounds with improved antiplasmodial activity as well as decreased cytotoxicity. Nineteen quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives connected by a linker group to quinolone ring moieties with different substituents were synthesized and assayed against P. falciparum. Materials and Methods: Nineteen quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives connected by a linker group to quinoline ring moieties with different substituents were synthesized and assayed against chloroquine-resistant Plasmodium falciparum, along with the reference drug chloroquine. Among these compounds, the derivatives with two methylene carbon spacers showed the best activity accompanied by low cytotoxicity. Results: The derivative without substituents on the aromatic ring (2a) and the derivative with a chlorine group at position 4 (2d) provided the best results, with IC50 = 1.15 µM and 1.5 µM, respectively. Conclusion: Compared to the parent drugs, these compounds presented marked decreases in cytotoxicity, with MDL50 values over 1,000 µM and selectivity indexes of >869.5 and >666.6, respectively. The quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione framework appears to be promising for further studies as an antimalarial for overcoming the burden of resistance in P. falciparum. |
| Databáze: | OpenAIRE |
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