STTDAA · Synthesis of Truncated Tirandamycin A-D Derivatives as new Antihelminthic Agents

Synthesis of Truncated Tirandamycin A-D Derivatives as new Antihelminthic Agents

The aim of the project entitled “Synthesis of Truncated tirandamycin A-D derivatives as new Antihelminthic Agents” (STTDAA) was to develop novel asparaginyl tRNA synthetase (AsnRS) inhibitors as potential antihelminthic agents for the treatment of lymphatic filariasis (LF). LF is one of the World Health Organization’s (WHO) top 10 neglected tropical diseases (NTDs), is a vector-borne helminth disease caused by filarial (thread like) nematodes. This incapacitating disease has infected over 200 million people in 73 tropical and subtropical countries, while more than 1.4 billion people remain at the risk of infection. No vaccines are available, vector control programs have ended or are facing insect resistance, and ivermectin and albendazole (current treatment) are largely ineffective against the worm’s adult stage. Thus a top priority of the WHO is to search for new antihelminthic drugs that kill adult worms (macrofilaricides), have new mechanisms of action, and exhibit fewer side effects than currently available medications such as albendazole and ivermectin to which parasite resistance has already been confirmed. It is reported that tirandamycin B, a natural product, inhibits asparagine-tRNA synthetase (AsnRS) from B. malayi (one out of three types of roundworm casing LF), kills the adult B. malayi parasite, and does not exhibit significant general cytotoxicity to human hepatic cells. The project has resulted in development of efficient synthetic strategies for the preparation of truncated tirandamycin derivatives with a scaffold that retains the structural integrity of the natural product.

Data: CORDIS, © European Union