Late‐Stage Diversification of Pyrazoles as Antileishmanial Agents

Author:

Winge Tobias1,Perry Ben23,Matheeussen An4,Caljon Guy1,Wünsch Bernhard15ORCID

Affiliation:

1. Universität Münster Institut für Pharmazeutische und Medizinische Chemie Corrensstraße 48 D-48149 Münster Germany

2. Drugs for Neglected Diseases initiative 15 chemin Camille-Vidart 1202 Geneva Switzerland

3. current Address: Medicxi Ventures 10 Cours de Rive 1204 Geneva Switzerland

4. University of Antwerpen Laboratory of Microbiology, Parasitology and Hygiene (LMPH), Infla-Med Centre of Excellence, Campus CDE, S7.24 Universiteitsplein 1 B 2610 Wilrijk- Antwerpen

5. GRK 2515 Chemical biology of ion channels (Chembion) Universität Münster Corrensstr. 48 D-48149 Münster Germany

Abstract

AbstractN‐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.

Publisher

Wiley

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