Fungal indole alkaloid (–)-paraherquamide A is a known anthelmintic agent, and its semi-synthetic derivative (–)-2-deoxoparaherquamide (Derquantel©) is a commercial veterinary drug with a novel mode of action, targeting nematode nicotinic acetylcholine receptors (nAChRs). However, the use of Derquantel© is currently limited to the treatment of nematode infections in sheep due to lack of specificity for parasitic nAChRs over those of humans. Synthetic modification and diversification of the (–)-paraherquamide scaffold would enable the development of more selective lead compounds, but exploration of structure activity relationships (SAR) has been severely hindered by the structural complexity of the natural product. We have recently identified and characterized a series of indole alkaloid biosynthetic enzymes, and have developed a cascade biocatalytic platform for the generation of (–)-paraherquamide derivatives. Additionally, we have installed functional handles for late-stage functionalization using a halogenase. With this biocatalytic cascade assembly approach, we have generated a diverse panel of (–)-paraherquamide derivatives and screened their activity in a high throughput worm motility assay.<br/>

Biocatalytic synthesis of anthelmintics using a cascade assembly approach

2019 Fall National Meeting

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