Synthesis and Biological Evaluation of Natural-Product-Inspired, Aminoalkyl-Substituted 1‑Benzopyrans as Novel Antiplasmodial Agents

Herein,
relationships between the structures of 1-aminoethyl-substituted
chromenes and their antimalarial activities were thoroughly investigated.
At first, the methyl moiety in the side chain was removed to eliminate
chirality. The hydrogenation state of the benzopyran system, the position
of the phenolic OH moiety, and the distance of the basic amino moiety
toward both aromatic rings were varied systematically. 1-Benzopyran-5-ol 8b (IC50 = 10 nM), 1-benzopyran-7-ol 9c (IC50 = 38 nM), and the aminoalcohol 19c (IC50 = 17 nM) displayed antiplasmodial activity with
IC50 values below 50 nM. To identify the mechanism of action,
inhibition of three key enzymes by 9c was investigated. 9c was not able to reduce the number of Plasmodia in erythrocytes of mice. This low in vivo activity was explained
by fast clearance from blood plasma combined with rapid biotransformation
of 9c. Three main metabolites of 9c were
identified by liquid chromatography–mass spectrometry (LC–MS)
methods.