Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
| Autor: | Jelena Srbljanović, Donatella Taramelli, Tijana Štajner, Jovana Burojević, Tatjana Ž. Verbić, Stevan Pecic, Mario Zlatović, Nataša Terzić, Inês S. Albuquerque, Mikloš Tot, Olgica Djurković-Djaković, Richard J. Sciotti, Sarah D'Alessandro, Bogdan A. Šolaja, Jelena Konstantinović, Miguel Prudêncio, Marta Machado |
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| Přispěvatelé: | Repositório da Universidade de Lisboa |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Plasmodium berghei Plasmodium falciparum Drug Evaluation Preclinical Pharmacology In Vitro Techniques Parasite Load Aminoquinoline 03 medical and health sciences Antimalarials Mice Structure-Activity Relationship In vivo Drug Discovery medicine Animals Humans Tetraoxanes Aminoquinolines IC50 biology Chemistry biology.organism_classification Ether-A-Go-Go Potassium Channels 3. Good health 030104 developmental biology Biochemistry Liver Hepatocytes Microsomes Liver Molecular Medicine Hemin Pharmacophore medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry |
| Popis: | © 2015 American Chemical Society The syntheses and antiplasmodial activities of various substituted aminoquinolines coupled to an adamantane carrier are described. The compounds exhibited pronounced in vitro and in vivo activity against Plasmodium berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intrahepatocytic parasite inhibitors, with compound 25 having an IC50 = 0.31 μM and reducing the liver load in mice by up to 92% at 80 mg/kg dose. Screening our peroxides as inhibitors of liver stage infection revealed that the tetraoxane pharmacophore itself is also an excellent liver stage P. berghei inhibitor (78: IC50 = 0.33 μM). Up to 91% reduction of the parasite liver load in mice was achieved at 100 mg/kg. Examination of tetraoxane 78 against the transgenic 3D7 strain expressing luciferase under a gametocyte-specific promoter revealed its activity against stage IV-V Plasmodium falciparum gametocytes (IC50 = 1.16 ± 0.37 μM). To the best of our knowledge, compounds 25 and 78 are the first examples of either an 4-aminoquinoline or a tetraoxane liver stage inhibitors. This research was supported by The Ministry of Science and Technological Development of Serbia (grant nos. 172008 and 41019), the Serbian Academy of Sciences and Arts, Fundação para a Ciência e Tecnologia, Portugal (grant PTDC/SAU-MIC/117060/2010), the Bill & Melinda Gates Foundation (grant OPP1040394). |
| Databáze: | OpenAIRE |
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