Organoarsenic Compounds with In Vitro Activity against the Malaria Parasite Plasmodium falciparum.

Sofia Basova,Aram Prokop,Gabriele Pradel,Che Julius Ngwa,Albrecht Berkessel,Jan Christoph Koch,Nathalie Wilke

doi:10.3390/biomedicines8080260

Abstract

The rapid development of parasite drug resistance as well as the lack of medications targeting both the asexual and the sexual blood stages of the malaria parasite necessitate the search for novel antimalarial compounds. Eleven organoarsenic compounds were synthesized and tested for their effect on the asexual blood stages and sexual transmission stages of the malaria parasite Plasmodium falciparum using in vitro assays. The inhibitory potential of the compounds on blood stage viability was tested on the chloroquine (CQ)-sensitive 3D7 and the CQ-resistant Dd2 strain using the Malstat assay. The most effective compounds were subsequently investigated for their effect on impairing gametocyte development and gametogenesis, using the gametocyte-producing NF54 strain in respective cell-based assays. Their potential toxicity was investigated on leukemia cell line Nalm-6 and non-infected erythrocytes. Five out of the 11 compounds showed antiplasmodial activities against 3D7, with half-maximal inhibitory concentration (IC50) values ranging between 1.52 and 8.64 µM. Three of the compounds also acted against Dd2, with the most active compound As-8 exhibiting an IC50 of 0.35 µM. The five compounds also showed significant inhibitory effects on the parasite sexual stages at both IC50 and IC90 concentrations with As-8 displaying the best gametocytocidal activity. No hemolytic and cytotoxic effect was observed for any of the compounds. The organoarsenic compound As-8 may represent a good lead for the design of novel organoarsenic drugs with combined antimalarial and transmission blocking activities.

Highlights

The tropical disease malaria is a major health threat with an estimated 228 million cases and405,000 deaths in 2018 [1]
Most antimalarials are active mainly on the asexual blood stages, which are responsible for the clinical manifestation of the disease, but not on the gametocyte stages, which are important for disease transmission from the Biomedicines 2020, 8, 260; doi:10.3390/biomedicines8080260
The results show a significant reduction in the numbers of exflagellation centers by approximately 50 and 80%, when the gametocytes were treated with the compounds at IC50 and IC90 concentrations, respectively (Figure 4b)

Summary

Introduction

The tropical disease malaria is a major health threat with an estimated 228 million cases and405,000 deaths in 2018 [1]. Chemotherapeutic measures are increasingly encountering resistance of the Plasmodium parasites to current antimalarial regimes, including the artemisinin-based combination therapies, which serve as first line drugs for the treatment of malaria tropica. There is the need to search for new drugs with combined activities against the blood and transmission stages. Inorganic arsenic compounds are highly toxic and comprise numerous valence states including arsenic trioxide (As2 O3 ) and realgar [5]. Arsenic compounds have been shown to display good therapeutic potentials and have been used in traditional medicine for the treatment of diseases such as skin cancer and fevers [5]. Studies have shown that compounds which inhibit cancer growth often exhibit an inhibitory effect against the malaria parasite and vice versa [7,8]

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Conclusion