Synthesis of Substituted 1H-Phenalen-1-ones and Nitrogen-Containing Heterocyclic Analogues as Potential Anti-Plasmodial Agents

Abstract

Given the known biological activity of both natural and synthetic substituted 1<i>H</i>-phenalen-1-ones, the generation of a small chemically and structurally diverse 1<i>H</i>-phenalen-1-one-based library of compounds was warranted. Herein, we have synthesized several groups of compounds to broaden and improve the chemical diversity of our 1<i>H</i>-phenalen-1-one collection. Additionally, we have also introduced hydroxyl, amides or carboxylic groups onto the core, or nitrogen atoms into the core, to increase the chemical diversity while also lowering the ClogP values to aid their water solubility. Notably, we have also improved the synthetic routes to several compounds of interest and have observed the unexpected formation of phenoxazine and acridin-7-one systems during cross-coupling reactions with polyfunctional anilines. Combining the compounds generated in this work with previous ones has enabled us to create a library of chemically diverse 1<i>H</i>-phenalen-1-one available for screening assays. Evaluation of anti-plasmodial activity against the chloroquine-resistant <i>Plasmodium falciparum</i> strain FCR3 revealed four compounds with notable activity, three of which exhibited IC₅₀ values below 1 µM, while none displayed significant cytotoxicity at 10 µM.