Synthesis, DNA binding and antileishmanial activity of low molecular weight bis-arylimidamides

The effects of reducing the molecular weight of the antileishmanial compound DB766 on DNA binding affinity, antileishmanial activity and cytotoxicity are reported. The bis-arylimidamides were prepared by the coupling of aryl S-(2-naphthylmethyl)thioimidates with the corresponding amines. Specifically, we have prepared new series of bis-arylimidamides which include 3a, 3b, 6, 9a, 9b, 9c, 13, and 18. Three compounds 9a, 9c, and 18 bind to DNA with similar or moderately lower affinity to that of DB766, the rest of these compounds either show quite weak binding or no binding at all to DNA. Compounds 9a, 9c, and 13 were the most active against Leishmania amazonensis showing IC50 values of less than 1 μM, so they were screened against intracellular Leishmania donovani, showing outstanding activity with IC50 values of 25–79 nM. Despite exhibiting little in vitro cytotoxicity these three compounds were quite toxic to mice.

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► Low MW arylimidamides as analogues of DB766 were prepared.
► Arylimidamides are synthesized from aryl thioimidates and corresponding diamines.
► New arylimidamides showed L. d. IC50 values of 25–79 nM and acceptable cytotoxicity.
► DNA binding affinities and in vivo toxicity reported.