Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds

dc.creatorRogerio, Kamilla Rodrigues
dc.creatorCarvalho, Leonardo J. M.
dc.creatorDomingues, Luiza Helena Pinto
dc.creatorNeves, Bruno Junior
dc.creatorMoreira Filho, José Teófilo
dc.creatorCastro, Rosane Nora
dc.creatorBianco Júnior, Cesare
dc.creatorDaniel-Ribeiro, Cláudio Tadeu
dc.creatorAndrade, Carolina Horta
dc.creatorGraebin, Cedric Stephan
dc.date2018-07-10T15:37:52Z
dc.date2018-07-10T15:37:52Z
dc.date2018
dc.date.accessioned2023-09-26T23:50:34Z
dc.date.available2023-09-26T23:50:34Z
dc.identifierROGERIO, Kamilla Rodrigues; et al.Synthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds. Mem Inst Oswaldo Cruz,v.113, n.8, e170452, 9p, 2018.
dc.identifier0074-0276
dc.identifierhttps://www.arca.fiocruz.br/handle/icict/27415
dc.identifier10.1590/0074-02760170452
dc.identifier1678-8060
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8894810
dc.descriptionBACKGROUND Malaria is responsible for 429,000 deaths per year worldwide, and more than 200 million cases were reported in 2015. Increasing parasite resistance has imposed restrictions to the currently available antimalarial drugs. Thus, the search for new, effective and safe antimalarial drugs is crucial. Heterocyclic compounds, such as dihydropyrimidinones (DHPM), synthesised via the Biginelli multicomponent reaction, as well as bicyclic compounds synthesised from DHPMs, have emerged as potential antimalarial candidates in the last few years. METHODS Thirty compounds were synthesised employing the Biginelli multicomponent reaction and subsequent one-pot substitution/cyclisation protocol; the compounds were then evaluated in vitro against chloroquine-resistant Plasmodium falciparum parasites (W2 strain). Drug cytotoxicity in baseline kidney African Green Monkey cells (BGM) was also evaluated. The most active in vitro compounds were evaluated against P. berghei parasites in mice. Additionally, we performed an in silico target fishing approach with the most active compounds, aiming to shed some light into the mechanism at a molecular level. RESULTS The synthetic route chosen was effective, leading to products with high purity and yields ranging from 10-84%. Three out of the 30 compounds tested were identified as active against the parasite and presented low toxicity. The in silico study suggested that among all the molecular targets identified by our target fishing approach, Protein Kinase 3 (PK5) and Glycogen Synthase Kinase 3β (GSK-3β) are the most likely molecular targets for the synthesised compounds. CONCLUSIONS We were able to easily obtain a collection of heterocyclic compounds with in vitro anti-P. falciparum activity that can be used as scaffolds for the design and development of new antiplasmodial drugs.
dc.formatapplication/pdf
dc.languageeng
dc.publisherFundação Oswaldo Cruz. Instituto Oswaldo Cruz
dc.rightsopen access
dc.subjectMalária
dc.subjectPlasmodium falciparum
dc.subjectreações multicomponentes
dc.subjectmodelagem molecular
dc.subjectReação de Biginelli
dc.subjectpirimidinonas
dc.subjectMalaria
dc.subjectPlasmodium falciparum
dc.subjectmulticomponent reactions
dc.subjectBiginelli reaction
dc.subjectpyrimidinones
dc.subjectmolecular modelling
dc.titleSynthesis and molecular modelling studies of pyrimidinones and pyrrolo[3,4-d]-pyrimidinodiones as new antiplasmodial compounds
dc.typeArticle


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