Synthesis and Insight into the Structure鈥揂ctivity Relationships of Chalcones as Antimalarial Agents

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• 作者：Narender Tadigoppula ; Venkateswarlu Korthikunta ; Shweta Gupta ; Papireddy Kancharla ; Tanvir Khaliq ; Awakash Soni ; Rajeev Kumar Srivastava ; Kumkum Srivastava ; Sunil Kumar Puri ; Kanumuri Siva Rama Raju ; Wahajuddin ; Puran Singh Sijwali ; Vikash Kumar ; Imran Siddiqi Mohammad
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：31-45
• 全文大小：844K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

Licochalcone A (I), isolated from the roots of Chinese licorice, is the most promising antimalarial compound reported so far. In continuation of our drug discovery program, we isolated two similar chalcones, medicagenin (II) and munchiwarin (III), from Crotalaria medicagenia, which exhibited antimalarial activity against Plasmodium falciparum. A library of 88 chalcones were synthesized and evaluated for their in vitro antimalarial activity. Among these, 67, 68, 74, 77, and 78 exhibited good in vitro antimalarial activity against P. falciparum strains 3D7 and K1 with low cytotoxicity. These chalcones also showed reduction in parasitemia and increased survival time of Swiss mice infected with Plasmodium yoelii (strain N-67). Pharmacokinetic studies indicated that low oral bioavailability due to poor ADME properties. Molecular docking studies revealed the binding orientation of these inhibitors in active sites of falcipain-2 (FP-2) enzyme. Compounds 67, 68, and 78 showed modest inhibitory activity against the major hemoglobin degrading cysteine protease FP-2.