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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Research Article

Novel Quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione Derivatives Against Chloroquine-resistant Plasmodium falciparum

Author(s): Kamilla Rodrigues Rogerio, Cedric Stephan Graebin, Luiza Helena Pinto Domingues, Luana Santos Oliveira, Vitoria de Souza Fernandes da Silva, Claudio Tadeu Daniel-Ribeiro, Leonardo J.M. Carvalho* and Nubia Boechat*

Volume 20, Issue 2, 2020

Page: [99 - 110] Pages: 12

DOI: 10.2174/1568026619666191019100711

Price: $65


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.

Keywords: Multicomponent reactions, Biginelli, Malaria, Plasmodium falciparum, Quinolinyl-pyrrolo[3, 4-d]pyrimidine-2, 5- dione, Plasmodium falciparum.

Graphical Abstract
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