Identification, Design and Biological Evaluation of Heterocyclic Quinolones Targeting Plasmodium falciparum Type II NADH:Quinone Oxidoreductase (PfNDH2)

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• 作者：Suet C. Leung ; Peter Gibbons ; Richard Amewu ; Gemma L. Nixon ; Chandrakala Pidathala ; W. David Hong ; B茅n茅dicte Pacorel ; Neil G. Berry ; Raman Sharma ; Paul A. Stocks ; Abhishek Srivastava ; Alison E. Shone ; Sitthivut Charoensutthivarakul ; Lee Taylor ; Olivier Berger ; Alison Mbekeani ; Alasdair Hill ; Nicholas E. Fisher ; Ashley J. Warman ; Giancarlo A. Biagini ; Stephen A. Ward ; Paul M. O鈥橬eill
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：55
• 期：5
• 页码：1844-1857
• 全文大小：729K
• 年卷期：v.55,no.5(March 8, 2012)
• ISSN：1520-4804

文摘

Following a program undertaken to identify hit compounds against NADH:ubiquinone oxidoreductase (PfNDH2), a novel enzyme target within the malaria parasite Plasmodium falciparum, hit to lead optimization led to identification of CK-2-68, a molecule suitable for further development. In order to reduce ClogP and improve solubility of CK-2-68 incorporation of a variety of heterocycles, within the side chain of the quinolone core, was carried out, and this approach led to a lead compound SL-2-25 (8b). 8b has IC₅₀s in the nanomolar range versus both the enzyme and whole cell P. falciparum (IC₅₀ = 15 nM PfNDH2; IC₅₀ = 54 nM (3D7 strain of P. falciparum) with notable oral activity of ED₅₀/ED₉₀ of 1.87/4.72 mg/kg versus Plasmodium berghei (NS Strain) in a murine model of malaria when formulated as a phosphate salt. Analogues in this series also demonstrate nanomolar activity against the bc₁ complex of P. falciparum providing the potential added benefit of a dual mechanism of action. The potent oral activity of 2-pyridyl quinolones underlines the potential of this template for further lead optimization studies.