Title |
Reinvestigating Old Pharmacophores: Are 4‑Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?
|
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Published in |
Journal of Medicinal Chemistry, December 2015
|
DOI | 10.1021/acs.jmedchem.5b01374 |
Pubmed ID | |
Authors |
Natasa Terzić, Jelena Konstantinović, Mikloš Tot, Jovana Burojević, Olgica Djurković-Djaković, Jelena Srbljanović, Tijana Štajner, Tatjana Verbić, Mario Zlatović, Marta Machado, Inês S. Albuquerque, Miguel Prudêncio, Richard J. Sciotti, Stevan Pecic, Sarah D’Alessandro, Donatella Taramelli, Bogdan A. Šolaja |
Abstract |
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 P. berghei in the Thompson test. Tethering a fluorine atom to the aminoquinoline C(3) position afforded fluoroaminoquinolines that act as intra-hepatocytic 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 P. 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 1 | 50% |
Unknown | 1 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 2 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
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Portugal | 2 | 4% |
Unknown | 55 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Ph. D. Student | 9 | 16% |
Researcher | 7 | 12% |
Student > Master | 7 | 12% |
Professor > Associate Professor | 5 | 9% |
Professor | 5 | 9% |
Other | 12 | 21% |
Unknown | 12 | 21% |
Readers by discipline | Count | As % |
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Chemistry | 22 | 39% |
Agricultural and Biological Sciences | 5 | 9% |
Biochemistry, Genetics and Molecular Biology | 3 | 5% |
Immunology and Microbiology | 2 | 4% |
Pharmacology, Toxicology and Pharmaceutical Science | 1 | 2% |
Other | 4 | 7% |
Unknown | 20 | 35% |