Atilio Anzellotti -   Searching for New Chemotherapies for Tropical Diseases: Ruthenium–Clotrimazole Complexes Display High in Vitro Activity against Leishmania major and Trypanosoma cruzi and Low Toxicity toward Normal Mammalian Cells

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      Publication Details (including relevant citation   information):

    J. Med. Chem., Article ASAP
      DOI: 10.1021/jm300070h
      Publication Date (Web): March 26, 2012

      Eight new ruthenium complexes of clotrimazole (CTZ) with high   antiparasitic activity have been synthesized,

      cis,fac-[Ru

      IICl

      2(DMSO)

      3(CTZ)]   (

      1),

      cis,cis,trans-[Ru

      IICl

      2(DMSO)

      2(CTZ)

      2]   (

      2), Na[Ru

      IIICl

      4(DMSO)(CTZ)]   (

      3), Na[

      trans-Ru

      IIICl

      4(CTZ)

      2]   (

      4), [Ru

      II

      6-

      p-cymene)Cl

      2(CTZ)]   (

      5), [Ru

      II

      6-

      p-cymene)(bipy)(CTZ)][BF

      4]

      2

      (6

      ), [RuII

      (η6

      -p

      -cymene)(en)(CTZ)][BF4

      ]2

      (7

      ), and [RuII

      (η6

      -p

      -cymene)(acac)(CTZ)][BF4

      ] (8

      ) (bipy = bipyridine; en = ethlylenediamine; acac =   acetylacetonate). The crystal structures of compounds

      4

      8

      are described. Complexes

      1

      8

      are active against promastigotes of

      Leishmania major

      and epimastigotes of

      Trypanosoma cruzi. Most notably, complex

      5

      increases the activity of CTZ by factors of 110 and 58 against

      L. major

      and

      T. cruzi, with no appreciable toxicity to human   osteoblasts, resulting in nanomolar and low micromolar lethal   doses and therapeutic indexes of 500 and 75, respectively. In a   high-content imaging assay on

      L. major-infected intraperitoneal mice macrophages,   complex

      5

      showed significant inhibition on the proliferation of   intracellular amastigotes (IC70

      = 29 nM), while complex

      8

      displayed some effect at a higher concentration (IC40

      = 1 μM).

      Abstract:

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