School of Medical Sciences


Medicinal Chemistry - Development of new drugs targeting neglected tropical diseases

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.

Figure_1

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.
  • 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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