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.
Highlights
IntroductionMalaria is a mosquito-borne, life-threatening tropical disease caused by Plasmodium parasites
The chlorinated product 2 was used as the key intermediate in the electrophilic aromatic substitution with various phenols, leading to analogs that bear a range of subaromatic substitution with various phenols, leading to analogs that bear a range of subaromatic substitution with various phenols, leading to analogs that bear a range of substituents on the
Reactions were monitored by thin-layer chromatography (TLC) using aluminum Merck TLC plates coated with silica gel 60 F254
Summary
Malaria is a mosquito-borne, life-threatening tropical disease caused by Plasmodium parasites. It was estimated by the World Health Organization (WHO) that in 2019, there were over 200 million malaria cases and 409,000 deaths reported globally [1]. P. falciparum, the most life-threatening species, has developed resistance against most drugs [2]. Even after successful treatment of the blood stage infection, some species such as P. vivax could form dormant liver-stage hypnozoites that could be reactivated to cause clinical relapse [3]. The development of novel antimalarial agent that is active in both the blood and liver stages is highly in demand
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