Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity , docking to Pf DHODH and SAR of lapachol-based compounds
| Autor: | Kuldeep K. Roy, Lucas M. Arantes, Alaíde Braga de Oliveira, Robert J. Doerksen, Guilherme Rocha Pereira, Franciele C. Rocha Missias, Geraldo Célio Brandão, Luciana Ferreira Soares |
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| Rok vydání: | 2018 |
| Předmět: |
Models
Molecular 0301 basic medicine Cell Survival Plasmodium falciparum Drug Resistance Respiratory chain Triazole 01 natural sciences Antimalarials Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Parasitic Sensitivity Tests Drug Discovery medicine Humans Lapachol Pharmacology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Chloroquine Hep G2 Cells General Medicine Combinatorial chemistry Naphthoquinone 0104 chemical sciences 030104 developmental biology Docking (molecular) Click chemistry Click Chemistry Lead compound Atovaquone Naphthoquinones medicine.drug |
| Zdroj: | European Journal of Medicinal Chemistry. 145:191-205 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2017.12.051 |
| Popis: | Lapachol is an abundant prenyl naphthoquinone occurring in Brazilian Bignoniaceae that was clinically used, in former times, as an antimalarial drug, despite its moderate effect. Aiming to search for potentially better antimalarials, a series of 1,2,3-triazole derivatives was synthesized by chemical modification of lapachol. Alkylation of the hydroxyl group gave its propargyl ether which, via copper-catalyzed cycloaddition (CuAAC) click chemistry with different organic azides, afforded 17 naphthoquinonolyl triazole derivatives. All the synthetic compounds were evaluated for their in vitro activity against chloroquine resistant Plasmodium falciparum (W2) and for cytotoxicity to HepG2 cells. Compounds containing the naphthoquinolyl triazole moieties showed higher antimalarial activity than lapachol (IC50 123.5 μM) and selectivity index (SI) values in the range of 4.5–197.7. Molecular docking simulations of lapachol, atovaquone and all the newly synthesized compounds were carried out for interactions with PfDHODH, a mitochondrial enzyme of the parasite respiratory chain that is essential for de novo pyrimidine biosynthesis. Docking of the naphthoquinonolyl triazole derivatives to PfDHODH yielded scores between −9.375 and −14.55 units, compared to −9.137 for lapachol and −12.95 for atovaquone and disclosed the derivative 17 as a lead compound. Therefore, the study results show the enhancement of DHODH binding affinity correlated with improvement of SI values and in vitro activities of the lapachol derivatives. |
| Databáze: | OpenAIRE |
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