Late‐Stage Diversification of Pyrazoles as Antileishmanial Agents

Within the framework of “drugs for neglected disease initiative (DNDi)”, Pd-catalyzed Sonogashira and Suzuki-Miyaura cross-coupling reactions were used to introduce diverse substituents in 3-position of pyrazoles. The 5-position of pyrazoles was supplied with amino, acylamino and ureido moieties. The pyrazole with p-methoxybenzyl moiety in 3-position and 4-benzylpiperidino urea in 5-position showed modest antileishmanial and antitrypanosomal activity, but also considerable unspecific cytotoxicity.

Abstract

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 10 A/B and 14 A by Pd-catalyzed Sonogashira and Suzuki-Miyaura cross coupling reactions. The electron-withdrawing 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 (IC ₅₀=19 μM) and antitrypanosomal activity (IC ₅₀=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.

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