Journal
MOLECULES
Volume 26, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/molecules26133991
Keywords
primaquine; structure-activity relationship; tetraoxane; hybrid drug; antimalarial activity; heme polymerization inhibition activity
Funding
- Chulalongkorn University's fund (Ratchadaphiseksomphot Endowment Fund)
- Thailand Graduate Institute of Science and Technology (TGIST) scholarship [SCA-CO-2562-9780-TH]
- National Science and Technology Development Agency scholarship
- National Science and Technology Development Agency Grant [P1750501, P1850116]
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A series of 5-phenoxy primaquine analogs were synthesized and one hybrid compound showed significantly increased antimalarial activity with low toxicity against mammalian cells. These compounds also exhibited heme polymerization inhibition, which could contribute to their improved antimalarial activity and make them promising candidates for further development of antimalarial agents.
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 mu M) 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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