Screening of Agelasine D and Analogs for Inhibitory Activity against Pathogenic Protozoa; Identification of Hits for Visceral Leishmaniasis and Chagas Disease

Anders Vik,Marieke Vermeersch,Lise-Lotte Gundersen,Louis Maes,Ágnes Proszenyák,Paul Cos

doi:10.3390/molecules14010279

Abstract

There is an urgent need for novel and improved drugs against several tropical diseases caused by protozoa. The marine sponge (Agelas sp.) metabolite agelasine D, as well as other agelasine analogs and related structures were screened for inhibitory activity against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei and T. cruzi, as well as for toxicity against MRC-5 fibroblast cells. Many compounds displayed high general toxicity towards both the protozoa and MRC-5 cells. However, two compounds exhibited more selective inhibitory activity against L. infantum (IC50 <0.5 μg/mL) while two others displayed IC50 <1 μg/mL against T. cruzi in combination with relatively low toxicity against MRC-5 cells. According to criteria set up by the WHO Special Programme for Research & Training in Tropical Diseases (TDR), these compounds could be classified as hits for leishmaniasis and for Chagas disease, respectively. Identification of the hits as well as other SAR data from this initial screening will be valuable for design of more potent and selective potential drugs against these neglected tropical diseases.

Highlights

Several so-called neglected diseases, e.g. illnesses that disproportionally affect poor and marginalized populations and for which satisfactory treatment is not available, partly due to lack of interest in drug development, are due to protozoal infections
Current drugs used to treat Trypanosoma infections are unsatisfactory with respect to safety [6] and an increasing number of malaria cases are caused by Plasmodium falciparum resistant to first-line drugs [1,2]
A higher activity was found for agelasine D (2c; IC50 0.29 μg/mL = 0.63 μM) against P

Summary

Introduction

Several so-called neglected diseases, e.g. illnesses that disproportionally affect poor and marginalized populations and for which satisfactory treatment is not available, partly due to lack of interest in drug development, are due to protozoal infections. We chose to screen agelasine D and some agelasine analogs and structurally related compounds for activity against pathogenic protozoa causing the above mentioned tropical neglected diseases. The marine sponge metabolite agelasine D (2c) was screened for in vitro activity against the pathogenic protozoa P. falciparum, Leishmania infantum, Trypanosoma cruzi, and Trypanosoma brucei (Table 1). These results encouraged us to examine the antiprotozoal activities of a number of agelasine analogs 1 – 9 in search for more potent and selective compounds.

Results

Conclusion