5-Phenoxy Primaquine Analogs and the Tetraoxane Hybrid as Antimalarial Agents |
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Authors: | Somruedee Jansongsaeng Nitipol Srimongkolpithak Jutharat Pengon Sumalee Kamchonwongpaisan Tanatorn Khotavivattana |
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Affiliation: | 1.Centre of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand;2.National Center for Genetic Engineering and Biotechnology (BIOTEC), Pathum Thani 12120, Thailand; (N.S.); (J.P.); (S.K.) |
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Abstract: | The rapid emergence of drug resistance to the current antimalarial agents has led to the urgent need for the discovery of new and effective compounds. In this work, a series of 5-phenoxy primaquine analogs with 8-aminoquinoline core (7a–7h) was synthesized and investigated for their antimalarial activity against Plasmodium falciparum. Most analogs showed improved blood antimalarial activity compared to the original primaquine. To further explore a drug hybrid strategy, a conjugate compound between tetraoxane and the representative 5-phenoxy-primaquine analog 7a was synthesized. In our work, the hybrid compound 12 exhibited almost a 30-fold increase in the blood antimalarial activity (IC50 = 0.38 ± 0.11 μM) compared to that of primaquine, with relatively low toxicity against mammalian cells (SI = 45.61). Furthermore, we found that these 5-phenoxy primaquine analogs and the hybrid exhibit significant heme polymerization inhibition, an activity similar to that of chloroquine, which could contribute to their improved antimalarial activity. The 5-phenoxy primaquine analogs and the tetraoxane hybrid could serve as promising candidates for the further development of antimalarial agents. |
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Keywords: | primaquine, structure– activity relationship, tetraoxane, hybrid drug, antimalarial activity, heme polymerization inhibition activity |
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