Group leader
Neglected tropical diseases (NTDs) comprise more than 17 parasitic diseases that
currently afflict an estimated one billion people worldwide. Of these NTDs,
visceral leishmaniasis (VL, caused by the parasite Leishmania donovani), Chagas
disease (caused by Trypanosoma cruzi), and human African Trypanosomiasis (HAT or
sleeping sickness, caused by Trypanosoma brucei) are considered the most
challenging (World Health Organization) since these have the highest mortality
rates and predominate in impoverished regions, where economic returns for new
drugs are minimal. VL, occurring mainly on the Indian subcontinent or in east
Africa, is transmitted via a female sandfly bite, and manifests as a chronic
(fatal) disease in the liver and spleen, while Chagas disease (predominant in
South America and spread by blood-sucking bugs) in its chronic phase causes
digestive problems, abnormal heart rhythms, heart failure, and sudden death.
HAT, carried by the tsetse fly, involves migration of parasites from the blood
to the brain, resulting in body wasting, drowsiness, coma, and death. With
current treatments mostly relying on drugs that date back more than 50 years and
suffer from poor efficacy, high toxicity, and increasing resistance, the need
for new, more effective agents is both considerable and urgent. The Geneva-based
Drugs for Neglected Diseases initiative (DNDi) is an independent, not-for-profit
product development partnership (PDP), established in 2003 to research and
develop new and improved treatments for these most challenging NTDs.
An agreement between DNDi and the Global Alliance for TB Drug Development (GATB)
facilitated anti-parasitic screening (2007-2009) of selected
nitroimidazole-based compounds prepared here for tuberculosis. Several classes
showed markedly potent activity against Leishmania donovani, leading eventually
to the joint development and selection of DNDI-VL-2098 as a new clinical
candidate for VL. Further screening of our nitroimidazole library (ca. 900
analogues) also revealed compounds that displayed promising growth inhibition of
other parasites (T. brucei, T. cruzi), suggesting the potential to develop new
drugs against Chagas disease and sleeping sickness from these hits.
Drugs for Neglected Diseases initiative
Global Alliance for TB Drug Development
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Current research
- In mid-2010, our group was awarded funding from DNDi to undertake
stereoselective syntheses of the enantiomers of several promising VL lead
candidates (this work led to the selection and development of DNDI-VL-2098, as
well as to design and synthesise new compounds with an improved drug profile
(e.g. higher aqueous solubility, better selectivity) from other structural
classes, aiming for a second-generation back-up candidate for VL. So far, the
team has prepared more than 140 analogues that have been tested in a cell-based
luciferase assay, conducted by Dr Sunil Puri’s team at Central Drug Research
Institute (CDRI), Lucknow, India. This assay determines activity against the
intracellular amastigote stage of the parasite, using mouse macrophages infected
with L. donovani that expresses a luciferase reporter gene (providing improved
sensitivity). With many compounds showing excellent potency, additional in vitro
and in vivo assessments are being employed to identify the best candidates for
further development. Compounds with high microsomal stability (Advinus
Therapeutics), good aqueous solubility, and minimal hERG inhibition, are being
evaluated in a mouse VL infection model by Dr Vanessa Yardley at the London
School of Hygiene and Tropical Medicine (LSHTM), University of London; active
compounds may then be further assessed in a chronic VL infection model (using
Syrian golden hamsters) at CDRI, India.
Central Drug Research Institute
Advinus Therapeutics
Dr Vanessa Yardley
London School of Hygiene and Tropical Medicine
- Additional funding from DNDi in mid-2011 was provided for extension of our work
to Chagas disease. Following resynthesis of 5 screening hits, initial DMPK
evaluation by Professor Susan Charman’s team at the Centre for Drug Candidate
Optimisation, Monash University, Australia, and in vitro testing at Murdoch
University, two compounds are being tested in a proof of concept in vivo
efficacy study in Trypanosoma cruzi-infected mice. Positive results will trigger
the commencement of a chemistry program aimed at further development of the
class, seeking new drugs against Chagas disease.
Professor Susan
Charman
Murdoch University
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Other
research interests
Medicinal chemistry related to the development of new antitubercular agents.
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Publications
- Thompson, A.M.; Sutherland, H.S.; Palmer, B.D.; Kmentova, I.; Blaser, A.;
Franzblau, S.G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W.A. Synthesis and
structure-activity relationships of varied ether linker analogues of the
antitubercular drug
(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
(PA-824). J. Med. Chem. 2011, 54, 6563-6585.
- Kmentova, I.; Sutherland, H.S.; Palmer, B.D.; Blaser, A.; Franzblau, S.G.; Wan,
B.; Wang, Y.; Ma, Z.; Denny, W.A.; Thompson, A.M. Synthesis and
structure-activity relationships of aza- and diazabiphenyl analogues of the
antitubercular drug
(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
(PA-824). J. Med. Chem. 2010, 53, 8421-8439.
- Sutherland, H.S.; Blaser, A.; Kmentova, I.; Franzblau, S.G.; Wan, B.; Wang, Y.;
Ma, Z.; Palmer, B.D.; Denny, W.A.; Thompson, A.M. Synthesis and
structure-activity relationships of antitubercular 2-nitroimidazooxazines
bearing heterocyclic side chains. J. Med. Chem. 2010, 53, 855-866.
- Palmer, B.D.; Thompson, A.M.; Sutherland, H.S.; Blaser, A.; Kmentova, I.;
Franzblau, S.G.; Wan, B.; Wang, Y.; Ma, Z.; Denny, W.A. Synthesis and
structure-activity studies of biphenyl analogues of the tuberculosis drug
(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
(PA-824). J. Med. Chem. 2010, 53, 282-294.
- Thompson, A.M.; Blaser, A.; Anderson, R.F.; Shinde, S.S.; Franzblau, S.G.; Ma,
Z.; Denny, W.A.; Palmer, B.D. Synthesis, reduction potentials, and
antitubercular activity of ring A/B analogues of the bioreductive drug
(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
(PA-824). J. Med. Chem. 2009, 52, 637-645.
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Group members
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