A game of ‘chemical croquet’: From Rio to Durham in search of the perfect compound

By on

Category: Uncategorized

The last four months have ‘flown by’ for Arielly Barreto, from Professor Bartira Rossi Bergmann’s lab the Federal University of Rio de Janeiro (UFRJ), in Brazil. Her secondment to Durham’s Department of Chemistry, supported by an NTD Network research bursary, has enabled her to progress her PhD studies – although not every learning has been directly about her work.  Arielly (front left), with supervisor Professor Patrick Steel (front right) and other lab colleagues, also shared a lab outing to Whitby (featured in Bram Stoker’s ‘Dracula), and Scarborough – for croquet; a team game, involving navigating a course of narrow hoops, using wooden balls and a mallet, (and featured in Lewis Carroll’s tale, ‘Alice in Wonderland’).  No surprise then, that this, Arielly’s first visit to the UK has been “… like walking into a story book!”.

Researching new solutions for a deadly disease
Arielly’s aim is to identify new biomolecular targets in Leishmania parasites, a potentially lethal neglected tropical disease (NTD) affecting millions worldwide.  Our current treatment options are inadequate, and with toxic side effects which are lethal for some patients.  An in-parasite target would enable us to develop drugs to combat the parasites specifically, without harming patients.  This could inform the development of new treatments, improving the lives of the many millions at risk worldwide.
Arielly is based in Bartira’s lab at UFRJ, along with fellow PhD student Douglas Escrivani.   Both students are co-supervised by Bartira and Patrick, as part of a joint programme between UFRJ and Durham University, running since 2018.  Their respective research projects, both into the potential of chalcone compounds as novel anti-leishmanial agents, are supported by a cross-disciplinary combination of expertise.  Bartira’s specialism in immunology and drug release systems here compliments Patrick’s know-how in compound modification and chemical probe synthesis.  Douglas has visited Patrick’s lab in Durham several times during his PhD studies to gain experience in chemical synthesis this year it was Arielly’s turn.
Potential inspiration from plant remedies
Chalcones are flavonoids, found in many plant species, including many South American traditional plant medicines with a history of use against Leishmania parasites and other NTDs.  These pharmacologically active compounds show a range of antimicrobial and immune-modulating properties.  Bartira’s earlier studies on certain types of chalcones suggested that these compounds have greater efficacy as anti-parasitic agents when tested in vivo (mice) than they did in vitro (a test-tube). This suggests that metabolism of these compounds once inside the body of the mammal host, leads to the formation of more active derivatives (metabolites) – which may represent a better compound for use as a drug.  Arielly’s research aims to identify these metabolites, explore their potential as new drugs and identify their mode of action.

Chalcones have a scaffold of two aromatic structures (carbon rings) around an enone core, made from a ketone (double-bonded oxygen atom =O) conjugated with an alkene (alpha to beta). Naturally occurring chalcones can have complex structures, adding additional chemical groups to the carbon atoms in each ring (1 to 6 and 1’ to 6’). Image: Wikimedia Commons

‘Chemical croquet’ – games around the compound scaffold
Earlier at UFRJ, Arielly used an ‘in-vitro liver’ system (a suspension of vesicles extracted from mouse liver tissue, and containing active enzymes) to obtain chalcone metabolites.  She then screened these compounds against lab cultures of L. amazoniensis; her work has identified a range of chalcone metabolites with anti-leishmanial activity.
In Durham, Arielly’s task has been a kind of ‘chemical croquet’.  She has made modified versions of the chalcone metabolites, navigating around the chalcone scaffold (chemical backbone) to add or remove moieties (small chemical groups).  This approach reveals which portion of the metabolite compound is responsible for its anti-leishmanial activity.  Back at UFRJ, Arielly and Douglas will now assess this latest batch of chalcones for their anti-leishmanial activity and use this information to further the design of their next chalcone analogues.
The ‘perfect’ compound would be toxic for L. amazonensis along with other species of Leishmania, but have no effect on the patient, and be cheap and easy to produce.  Chalcones may provide routes to develop such a drug, but at this stage, modifying the scaffold helps us to understand which part of the compound is active, informing how to create chemical probes that could highlight the biomolecular target of these compounds in the parasite.

This child is suffering from cutaneous leishmaniasis, caused by a South American species of the parasite, Leishmania amazonensis. and spread by biting sandflies (Phlebotomus spp). This form of leishmaniasis can occur as a skin-based infection as here, or can be muco-cutaneous, destroying the patient’s mouth and nasal passages.

Towards new solutions for NTDs: A team effort
Finding new solutions for NTDs requires a large team and a long-term vision.  The NTD Network’s ‘chemical croquet’ experts are therefore keen to share their experience, and enthuse the next generation of researchers to pick up and carry on this vital work.  We are delivering this via secondments (e.g. Arielly’s visit), along with bespoke skills training leveraged with networking opportunities:
  • Professor Patrick Steel (Durham University) along with Network partner Prof Guilllermo Labadie (University of Rosario, UNR; Argentina) and other colleagues from UNR are offering a medicinal chemistry student training workshop, “Techniques and technologies in drug discovery” (2-4 November 2019; Mendoza, Argentina). The workshop concludes with an open symposium on drug discovery case studes, delivered by representatives from Novartis, GSK and DNDi.  This event precedes the XXII SIMPOSIO NACIONAL DE QUÍMICA ORGÁNICA (22nd National Symposium for Organic Chemistry), 5th-8th November 2019, also at the Mendoza Conference centre
  • Professor Iqbal Choudhary and Dr Sammer Yousuf from the University of Karachi, along with Professor Bartira Rossi-Bergmann (UFRJ), Dr Paul Denny (Durham University) and Dr Ehmke Pohl (Durham University) are delivering a natural products training workshop in Karachi, Pakistan. The workshop, “New anti-leishmanial leads from natural sources: concepts and approaches”, 8-9 November 2019; follows the 7th International Symposium-cum-Training Course on Molecular Medicine and Drug Research (MMDR-7), from 4th-7th November.  The University of Karachi has extended support to workshop attendees to also attend the conference

Mags Leighton.