2-Hydroxy-1,4-Naphthoquinones With 3-Alkyldiarylether Groups: Synthesis and Plasmodium Falciparum Inhibitory Activity

Abstract

Background: In 1948, the synthesis and Plasmodium lophurae activity of 2-hydroxy-1,4-naphthoquinones containing 3-alkyldiarylether side chains was reported. Method/results: The synthesis of five related compounds, designed to be more metabolically stable, was pursued. The compounds were synthesized using a radical alkylation reaction with naphthoquinones. One compound had a lower IC50 value against various strains of Plasmodium falciparum and assay data indicate that it binds to the Qo site of cytochrome bc1. With a low yield for the radical alkylation of the most active compound, a reductive alkylation method with used to improve reaction yields. Conclusion: Further synthetic knowledge was obtained, and the assay data indicate that there are sensitivity differences between avian and human malarial parasites for these molecules.

Biannual Account of Anti‐malarial Agents reported in 2021 and 2022: A Comprehensive Coverage

“…Berg and co-workers reported 3-alkyldiaryether containing 1,4-naphthoquinone (99) against various drug-resistant P. falciparum strains such as PfD6, PfDd2, Pf7G8, PfD1 and Tm90-C2B. [113] These compounds were predicted to bind with the Q o site of cytochrome bc 1 like atovaquone, an anti-malarial drug. The compound 100 with IC 50 of 3.18 μM against Pf3D7 was reported by Moorthy and co-workers with moderate binding affinity (K d of 18.2 M) with PLP synthase sub-unit Pdx1.…”

“…Berg and co‐workers reported 3‐alkyldiaryether containing 1,4‐naphthoquinone ( 99 ) against various drug‐resistant P. falciparum strains such as Pf D6, Pf Dd2, Pf 7G8, Pf D1 and Tm90‐C2B [113] . These compounds were predicted to bind with the Q o site of cytochrome bc 1 like atovaquone, an anti‐malarial drug.…”