Late-Stage Diversification of Pyrazoles as Antileishmanial Agents

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 (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.

Keywords: 3-arylpyrazoles; Drugs for Neglected Diseases initiative (DNDi); Sonogashira cross coupling; Suzuki-Miyaura cross coupling; antileishmanial activity; antitrypanosomal activity; bromopyrazoles; late stage diversification; open synthesis network (OSN).