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  • br Conclusion The present work

    2019-07-11


    Conclusion The present work describes the synthesis of 18 naphthoquinonolyl-1,2,3-triazole compounds based on natural product modification with antiplasmodial activity. Lapachol derivatives disclosed higher activity than the natural product. Six of these final modified lapachol 1,2,3-triazole compounds showed SI > 100. The most promising compounds such as compounds 17, 22 and 25 have some structural similarities such as a substituted aryl side chain in the triazole ring. The triazole naphthoquinolyl compounds with only phenyl (compound 19 with SI = 5.3) or benzyl (compound 15 with SI = 53.0) moieties had moderate activity. However, the presence of heteroatoms such as a chlorine substituent or a nitrogen on the aromatic ring played an important role (SI = 51.0, 75.6, 128.8 and 197.7 for compounds 22, 16, 7 and 17, respectively). Other promising compounds such as 25 (SI of 171.0) demonstrate that nitro and methoxy groups also can play an important role, depending upon their site of attachment. Atovaquone and Calphostin C 11 with terminal alkyne and pyrimidine moieties, with SI of 112.7 and 124.0, respectively, also provide important information for future studies. Docking studies support the possibility that these compounds do target PfDHODH. Based on the best docking scores, 16 was identified as the best lead compound against PfDHODH. Structure-activity relationship studies could further be explored by incorporating small substitutions on the 3-pyridyl ring of 17. Doing so is vagina expected to enhance enzyme binding affinity and thus lead to compounds with higher potency against the Pf parasite.
    Materials and methods
    Acknowledgment Thanks to Dr. J. R. Stehmann, Departamento de Botânica, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Brazil, for taxonomic identification of H. serratifolius. This work was supported by funds from FAPEMIG – Fundação de Amparo à Pesquisa de Minas Gerais (Brazil), CAPES - Coordenação e Aperfeiçoamento de Pessoal de Nível Superior (Brazil) and CNPq-Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil) for financial support to ABO through PRONEX Rede Malária Processes No. APQ-01129-10 and Process 555655/.2009-1, and GRP to Process numbers FIP 2013/8322-2S, APQ 00050-014 and GCB to Process number APQ 01529-15, respectively, and scholarships provided from FAPEMIG, CAPES and CNPq to Alaide Braga de Oliveira, Geraldo Célio Brandão, Guilherme Rocha Pereira and Franciele Caroline R. Missias are also acknowledged for undergraduate student Jéssica Chequer dos Santos from PUC Minas. This investigation was conducted in part in a facility constructed with support from the Research Facilities Improvements Program (C06-RR14503) from the National Institutes of Health (NIH) National Center for Research Resources.