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

Periodic Reporting for period 1 - STTDAA (Synthesis of Truncated Tirandamycin A-D Derivatives as new Antihelminthic Agents)

Reporting period: 2015-06-01 to 2017-05-31

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.
The main result from the project is the development of a short and efficient synthetic route for the generation of truncated tirandamycin derivatives (Fig 1). The development of the synthetic strategy turned out to be extremely challenging and time consuming due to e.g. instability of initial key intermediates and the need to develop entirely new reaction sequences, and have generated a short and highly efficient synthetic protocol for the prepapration of truncated tiranadmycin derivatives on gram scale (month 0-24).
The synthetic developments have been guided by computational chemistry (docking; month 12-20) and in part biological testing (still ongoing; month 20-24).
A manuscript based on the results generated by the researcher Dr. Tania Jiménez throughout the project will be submitted (manuscript in preparation) to a high impact journal (e.g. Angewant Chemie) as soon as the biological evaluation of the truncated tirandamycin derivatives are completed.
Parts of the results have been presented at international research conferences: Bienal de quimica organica in Huelva, Spain (14-17 June 2016), The SISOC XI in Basque Country (13-15 July 2016) and ACS international conference in San Francisco, USA (3-6 April 2017).
In addition the researcher has completed a training program, that included learning new techniques (e.g. how to run enzymatic assays and carry out docking), project management, leadership training (being responsible for two graduate students) and gaining skills such as motivating others, communication, reviewing progress, applying practical strategies to get the best from a research team, getting and managing finances, writing papers, projects and grant proposals, and presenting scientific results. The researcher has been involved in the organization and implementation of the annual ¨day of open door¨ aiming at closing the gap between academia and the broad public and at demonstrating the impact of research on innovation, prosperity and public welfare. She had also given science master-classes during the Annual High School Days and had participated in the organization of the faculty´s job fair.
The researcher has developed new strategies for the synthesis of truncated tirandamycin derivatives. The chemistry developed will be useful for preparing other natural product derivatives. Furthermore, the chemistry developed allows exploring tirandamycin derivatives as potential antifilarial drugs. Such drug will have a huge socio-economic impact in those parts of the world where LF is a serious health problem.
The researcher had gained a strong scientific independency and general academic maturity, and thereby had enhanced and maximized her contribution to the European knowledge-based economy and society.
short-truncated tirandamycin derivative
synthesis of short-truncated tirandamycin derivative
tirandamycin family