Synthesis and in vivo antimalarial activity of novel naphthoquine derivatives with linear/cyclic structured pendants

Naphthoquine (NQ) was discovered by our institute as an antimalarial candidate in 1980s, and currently employed as an artemisinin-based combination therapy partner drug. Resistance to NQ was found in mouse model in laboratory, and might emerge in future as widely used.

We herein report the design and synthesis of NQ derivatives by replacing t-butyl moiety with linear/cyclic structured pendants. All the target compounds 6a-l and intermediates 5a-h were tested for their in vivo antimalarial activity against Plasmodium berghei K173 strain in mice.

Compounds 6a and 6j were found to have a comparable or slightly more potent activity (the 50% effective dose [ED₅₀], which is required to decrease parasitemia by 50%: 0.38-0.43 mg/kg) than NQ (ED₅₀: 0.48 mg/kg).

The newly designed compounds 6a and 6j might be promising antimalarial candidates for further research.