Lymphatic filariasis (LF) caused by the parasitic nematodes B. malayi, represents a worldwide health crisis with over 200 million people infected and another 20% of the global population at risk for infection. Thus, a top priority of the WHO is to search for new antihelminthic drugs that kill adult parasites, have new mechanisms of action and exhibit fewer side effects than the current medications available. Tirandamycins A-D (TAMs A-D) derivatives have attracted much attention as potential antihelminthic agents for the treatment of LF, as they inhibit asparagyl-tRNA synthase (AsnRS), an excellent filarial target for B. malayi. Due to their pharmacological properties and their intriguing molecular architectures, a handful of total syntheses have been documented in the literature. However, common for all these achievements are lengthy synthetic routs not amenable late stage derivatization and thus, they are not applicable to drug development programs. Two different synthetic protocols that are able to produce advanced intermediates in 2–3 steps have been pursued, providing a short, robust and scalable route to access key intermediates suitable for library synthesis.

Synthesis of truncated tirandamycin A-D derivatives as new antihelminthic agents

253rd National Meeting (2017)

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