Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

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The authors acknowledge the Wellcome Trust for funding (grants 092340, 105021, 100476, 101842, 079838 and 098051).

Reviewer information

Nature thanks R. Guy, J. Mottram and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

Author notes

    • Thomas D. Otto

    Present address: Centre of Immunobiology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK


  1. Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, UK

    • Susan Wyllie
    • , Michael Thomas
    • , Stephen Patterson
    • , Manu De Rycker
    • , Michael D. Urbaniak
    • , Laste Stojanovski
    • , Frederick R. C. Simeons
    • , Sujatha Manthri
    • , Lorna M. MacLean
    • , Fabio Zuccotto
    • , Nadine Homeyer
    • , Lalitha Sastry
    • , Sebastian Albrecht
    • , David W. Gray
    • , Paul G. Wyatt
    • , Michael A. J. Ferguson
    • , Alan H. Fairlamb
    • , Kevin D. Read
    •  & Ian H. Gilbert
  2. Global Health R&D, GlaxoSmithKline, Tres Cantos, Spain

    • Sabrinia Crouch
    • , Jose M. Fiandor
    •  & Timothy J. Miles
  3. David Jack Centre for R&D, GlaxoSmithKline, Ware, UK

    • Rhiannon Lowe
    •  & Stephanie Gresham
  4. Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK

    • Michael D. Urbaniak
  5. Wellcome Sanger Institute, Cambridge, UK

    • Thomas D. Otto
    •  & Matt Berriman
  6. Cellzome GmbH, A GlaxoSmithKline Company, Heidelberg, Germany

    • Hannah Pflaumer
    • , Markus Boesche
    • , Gerard Drewes
    •  & Sonja Ghidelli-Disse
  7. GlaxoSmithKline, New Frontiers Science Park, Harlow, UK

    • Paul Connolly
  8. Global Health R&D, GlaxoSmithKline, Stockley Park West, Uxbridge, UK

    • Susan Dixon


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In brief, S.W., M.D.U., T.D.O, H.P., M.Bo. and S.M. carried out the mode of action, genomic and proteomic studies. M.T., S.P. and S.A. carried out the chemistry studies. M.D.R., S.M., L.M.M. and L.Sa. carried out the parasite screening. S.C., L.S., F.R.C.S. and P.C. carried out the drug metabolism and pharmacokinetic studies. F.Z. and N.H. carried out the molecular modelling. R.L. and S.G. carried out the safety studies. S.W., M.T., S.P., M.D.R., R.L., S.G., M.D.U., L.M.M., F.Z., M.Be., G.D., D.W.G., S.G.-D., S.D., J.M.F., P.W.G., M.A.J.F., A.H.F., T.J.M., K.D.R. and I.H.G. designed experiments, managed parts of the project and contributed to the writing. See Supplementary Information for further details.

Competing interests

These authors have shares in GlaxoSmithKline: P.G.W., S.D., T.J.M., K.D.R., S.C., R.L., S.G., M.Bo., H.P., P.C., G.D., D.G., S.G.-D. and J.M.F. The other authors declare no competing interests.

Corresponding authors

Correspondence to Timothy J. Miles or Kevin D. Read or Ian H. Gilbert.

Extended data figures and tables

  1. Extended Data Fig. 1 Rate-of-kill of L. donovani axenic amastigotes by compound 7.

    Chart shows relative luminescence units (RLU) versus time from axenic amastigote rate-of-kill experiment with compound 7 (representative results for one of two independent experiments are shown; data are mean and s.d. of three technical replicates). Concentrations are as follows (µM): 50, open circles; 16.7, closed circles; 5.6, open squares; 1.85, closed squares; 0.62, open triangles; 0.21, closed triangles; 0.069, open inverted triangles; 0.023, closed inverted triangles, 0.0076, open diamonds and 0.0025, closed diamonds.

  2. Extended Data Fig. 2 Linker-containing target molecules synthesized for chemical proteomic experiments and their corresponding EC50 values.

    Potencies of the compounds in the cidal axenic and intra-macrophage assays are shown; data are from at least three independent replicates.

  3. Extended Data Table 1 Activity of compound 7 and miltefosine against a panel of Leishmania clinical isolates
  4. Extended Data Table 2 Solubility of compound 7 in simulated physiological media
  5. Extended Data Table 3 In vitro metabolic stability data for compound 7
  6. Extended Data Table 4 Drug metabolism and pharmacokinetics data for compound 7
  7. Extended Data Table 5 Sensitivity of wild-type and drug-resistant promastigotes to compounds within the series
  8. Extended Data Table 6 Sensitivity of wild-type and compound 5-resistant intra-macrophage amastigotes to the compound series

Supplementary information

  1. Supplementary Information

    This file contains author contributions, methods, characterisation of compounds and ethical statements. It also contains supplementary figures S1-S74 and supplementary tables S1-S9.

  2. Reporting Summary

  3. Supplementary Data

    This file contains Proteomic data from the work at Cellzome.

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