Late-stage diversification of pyrazoles as antileishmanial agents.

T. Winge, B. Perry, A. Matheeussen, G. Caljon, B. Wünsch

Zusammenfassung

N-Pyrazolylcarboxamides and N-pyrazolylureas represent promising lead compounds for the development of novel antileishmanial drugs. Herein, we report the late-stage diversification of 3-bromopyrazoles 10A/B and 14A by Pd-catalyzed Sonogashira and Suzuki-Miyaura cross coupling reactions. The electronwithdrawing properties of the cyano moiety in 4-position of the pyrazole ring limited the acylation of the primary amino moiety in 5-position. A large set of pyrazoles bearing diverse aryl and alkynyl substituents in 3-position was prepared and the antileishmanial and antitrypanosomal activity was recorded. The urea 38 lacking the electron withdrawing cyano moiety in 4-position and containing the large 4-benzylpiperidinoo moiety exhibited a modest antileishmanial (IC50=19 μM) and antitrypanosomal activity (IC50=7.9 μM)). However, its considerable toxicity against the PMM and MRC-5 cells indicates low selectivity, i. e. a small gap between the desired antiparasitic activity and undesired cytotoxicity of <2- to 4-fold.