New Acyl Derivatives of 3-Aminofurazanes and Their Antiplasmodial Activities.

Theresa Hermann,Patrick Hochegger,Johanna Dolensky,Robert Weis,Robert Saf,Pascal Mäser,Werner Seebacher,Marcel Kaiser

doi:10.3390/ph14050412

Abstract

An N-acylated furazan-3-amine of a Medicines for Malaria Venture (MMV) project has shown activity against different strains of Plasmodium falciparum. Seventeen new derivatives were prepared and tested in vitro for their activities against blood stages of two strains of Plasmodium falciparum. Several structure–activity relationships were revealed. The activity strongly depended on the nature of the acyl moiety. Only benzamides showed promising activity. The substitution pattern of their phenyl ring affected the activity and the cytotoxicity of compounds. In addition, physicochemical parameters were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability) via a PAMPA. The N-(4-(3,4-diethoxyphenyl)-1,2,5-oxadiazol-3-yl)-3-(trifluoromethyl)benzamide possessed good physicochemical properties and showed high antiplasmodial activity against a chloroquine-sensitive strain (IC50(NF54) = 0.019 µM) and even higher antiplasmodial activity against a multiresistant strain (IC50(K1) = 0.007 µM). Compared to the MMV compound, the permeability and the activity against the multiresistant strain were improved.

Highlights

Malaria is, to this day, one of the most dangerous infectious diseases worldwide.It is caused by protozoa of the genus Plasmodium
An ice-cooled suspension of NaH (60% dispersion in mineral oil; 2.00 mmol) in dry DMF (14 mL) was mixed with aminofurazan 9 (1.00 mmol) and stirred for 20 min
The substitution of the phenyl ring in ring position 4 of the furazan ring has a remarkable impact on the antiplasmodial activity

Summary

Introduction

To this day, one of the most dangerous infectious diseases worldwide. It is caused by protozoa of the genus Plasmodium. An estimated number of 229 million cases occurred in 2019, resulting in more than 400,000 deaths. The burden of this infection is mostly carried by children under the age of five located in sub-Saharan Africa. The first-line treatment for malaria infections is an artemisinin-based combination therapy (ACT). A new strategy to impede the increasing resistance development temporarily is the application of triple artemisinin-based combination therapy (TACT) [7,8]. Due to the threat of potentially untreatable P. falciparum malaria, the development of drugs with new modes of action is of utmost importance [9,10,11]

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