Kamilla Rodrigues Rogerio
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Cedric Stephan Graebin
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Luiza Helena Pinto Domingues
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Luana Santos Oliveira
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Vitoria de Souza Fernandes da Silva
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...
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.