Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
Authorized Users Only
Konstantinović, Jelena M.
Albuquerque, Ines S.
Sciotii, Richard J.
Šolaja, Bogdan A.
Article (Published version)
MetadataShow full item record
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 mu M 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 mu M). 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 mu M). 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.
Source:Journal of Medicinal Chemistry, 2016, 59, 1, 264-281
- Amer Chemical Soc, Washington
- The synthesis of aminoquinoline-based antimalarials and botulinum neurotoxin A inhibitors (RS-172008)
- Control of infections by Apicomplexan pathogens: from novel drug targets to prediction (RS-41019)
- Bill & Melinda Gates Foundation [OPP1040394]
- Serbian Academy of Sciences and Arts
- Fundacao para a Ciencia e Tecnologia, Portugal [PTDC/SAUMIC/117060/2010]
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3606