Natural Product-Inspired Therapies for Leishmaniasis and Chagas Disease

Project Information

NPsVLCD

Grant agreement ID: 832700

DOI

10.3030/832700

Project terminated on 31 August 2020

EC signature date 10 April 2019

Start date 1 August 2019

End date 31 July 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 212 933,76

EU contribution

€ 212 933,76

Coordinated by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom

Periodic Reporting for period 1 - NPsVLCD (Natural Product-Inspired Therapies for Leishmaniasis and Chagas Disease)

Reporting period: 2019-08-01 to 2021-07-31

Summary of the context and overall objectives of the project

This MSC Action is titled “Natural Product-Inspired Therapies for Leishmaniasis and Chagas Disease”. This project aims to: (1) explore the potential of natural products, selected based on promising bioactivities, to serve as new templates for the development of potential therapies against Leishmania and Trypanosoma parasites. (2) develop a concise and modular synthetic strategy, to access the natural products targets from cheap starting materials and allowing scaffold diversification to facilitate SAR studies. This work is important because Visceral Leishmaniasis (VL) affects ~12 million people worldwide and is the second biggest parasitic killer after malaria (20-30000 deaths/year). Chagas disease (CD) affects ~6-7 million people worldwide and is also fatal if untreated (10000 deaths/year). In this project, we aim to show that natural products can serve as an alternative, viable source of candidates for future development as antiparasitic therapies. Throughout medicine, natural products are proven sources of drugs, either in their natural form, as semi-synthetic derivatives, or as analogues which retain the core framework of the natural molecule; it is well-recognized that some two-thirds of small molecule drugs originate from natural bioactive leads. Parasitic diseases are no exception: the frontline treatments for both malaria (artemisinin), and VL (amphotericin B) are natural products, while natural product-inspired therapies are of equal proven utility (such as the quinine analogues chloroquine and mefloquine).

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Formal objectives of this Marie Skłodowska Curie Action (MSCA) have been to (1) Develop concise, modular routes to the 'benzyltetrahydroisoquinoline' (BI) and aporphine natural products. Building on preliminary work, we established stereoselective approaches to these natural products from simple, cheap starting materials and we have initiated SAR studies with promising hits. (2) Develop synthetic strategy to form bioactive 'bis-benzyltetrahydroisoquinoline' (BBI) natural products. We established an efficient synthetic route toward a 'head-to-head' Northalrugosidine natural product, as example BBI target (which have known antiparasitic properties) and resolved the key step of our strategy. Unfortunately, we couldn’t finish the total synthesis. (3) Bioactivity evaluation/natural product modification informed by phamacokinetics. We evaluated antiparasitic bioactivity of the natural products/derivatives with André Temponé (Sao Paulo Brazil). Another goal of the MSCA Individual Fellowship is to foster the development of the individual researcher by researcher training and transfer-of-knowledge and project management activities. The first objective, a part of the second objective were to be met with success and the third objective is executed successfully for most of our Nps/analogues. The project has achieved most of its objectives and milestones for the period.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The work undertaken by the researcher was done with constant support from the supervisor – through day-to-day contact, and a series of professional development and training exercises, which include: weekly group meetings where two group members present their work over the previous 2-3 months to the whole group (PowerPoint presentation, develops presentation skills); weekly group meetings alternating literature discussion. The daily supervision of several PhD students in the laboratory offered her the chance to be involved in various projects including the aforementioned work (Natural product synthesis) and to develop team-management and organisation skills. Overall, the researcher benefited from a thorough training in modern organic chemistry – from theoretical knowledge to practical aspects – in a university of excellence. This was only possible thanks to the comfort provided by this fellowship, which facilitated the daily work of the researcher in the laboratory – by giving her enough funds to order consumables and chemicals. Overall, this postdoctoral position greatly enhanced the career prospects of the researcher and helped her to find a permanent position as scientist in process chemistry R&D at Minakem industry (in France).Discovering such new chemical entities (BI/ Aporphines/BBI) are therefore clearly be of high benefit to the research field. Further, the interaction with researchers in Brazil will bring significant impact to their activities, by moving beyond simple evaluation of natural product bioactivity, to providing these researchers with opportunities to evolve and develop hit compounds through collaborative synthetic chemistry. This work also helped to develop the syntheses of other BBI thus giving the opportunity to another phD student to work on this project within the group. Two publications were published in one year, the first on the enantioselective synthesis and anti-parasitic properties of aporphine natural products; and a second paper is under revision and report the work on the synthesis and Structure-Activity Relationship of dehydrodieugenol B Neolignans against Trypanosoma cruzi. A review is also being written up on Marine Alkaloids in Drug Discovery Studies for Protozoal Neglected Tropical Diseases and Malaria.

Individual Work packages