Novel quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives against chloroquine-resistant plasmodium falciparum

TY - JOUR

T1 - Novel quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione derivatives against chloroquine-resistant plasmodium falciparum

AU - Rogerio, Kamilla Rodrigues

AU - Graebin, Cedric Stephan

AU - Domingues, Luiza Helena Pinto

AU - Oliveira, Luana Santos

AU - da Silva, Vitoria de Souza Fernandes

AU - Daniel-Ribeiro, Claudio Tadeu

AU - Carvalho, Leonardo J.M.

AU - Boechat, Nubia

N1 - Publisher Copyright: © 2020 Bentham Science Publishers.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - Biginelli

KW - Malaria

KW - Multicomponent reactions

KW - Plasmodium falciparum

KW - Quinolinyl-pyrrolo[3,4-d]pyrimidine-2,5-dione

UR - https://www.scopus.com/pages/publications/85080850492

U2 - 10.2174/1568026619666191019100711

DO - 10.2174/1568026619666191019100711

M3 - Article

C2 - 31648638

AN - SCOPUS:85080850492

SN - 1568-0266

VL - 20

SP - 99

EP - 110

JO - Current Topics in Medicinal Chemistry

JF - Current Topics in Medicinal Chemistry

IS - 2

ER -