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  • Title: Novel Quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione Derivatives Against Chloroquine-resistant Plasmodium falciparum.
    Author: Rogerio KR, Graebin CS, Pinto Domingues LH, Oliveira LS, de Souza Fernandes da Silva V, Daniel-Ribeiro CT, Carvalho LJM, Boechat N.
    Journal: Curr Top Med Chem; 2020; 20(2):99-110. PubMed ID: 31648638.
    Abstract:
    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.
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