Reinvestigating Old Pharmacophores: Are 4-Aminoquinolines and Tetraoxanes Potential Two-Stage Antimalarials?

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• 作者：Natasa Terzi? ; Jelena Konstantinovi? ; Miklo? Tot ; Jovana Burojevi? ; Olgica Djurkovi?-Djakovi? ; Jelena Srbljanovi? ; Tijana ?tajner ; Tatjana Verbi? ; Mario Zlatovi? ; Marta Machado ; Inês S. Albuquerque ; Miguel Prudêncio ; Richard J. Sciotti ; Stevan Pecic ; Sarah D’Alessandro ; Donatella Taramelli ; Bogdan A. ?olaja
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 14, 2016
• 年：2016
• 卷：59
• 期：1
• 页码：264-281
• 全文大小：766K
• ISSN：1520-4804

文摘

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.