Chloroquine analogs as antimalarial candidates with potent in vitro and in vivo activity

Anna C.C Aguiar,Erika Murce,Wilian A Cortopassi,Andre S Pimentel,Maria M.F.S Almeida,Daniele C.S Barros,Jéssica S Guedes,Mario R Meneghetti,Antoniana U Krettli

doi:10.1016/j.ijpddr.2018.10.002

Abstract

In spite of recent efforts to eradicate malaria in the world, this parasitic disease is still considered a major public health problem, with a total of 216 million cases of malaria and 445,000 deaths in 2016. Artemisinin-based combination therapies remain effective in most parts of the world, but recent cases of resistance in Southeast Asia have urged for novel approaches to treat malaria caused by Plasmodium falciparum. In this work, we present chloroquine analogs that exhibited high activity against sensitive and chloroquine-resistant P. falciparum blood parasites and were also active against P. berghei infected mice. Among the compounds tested, DAQ, a chloroquine analog with a more linear side chain, was shown to be the most active in vitro and in vivo, with low cytotoxicity, and therefore may serve as the basis for the development of more effective chloroquine analogs to aid malaria eradication.

Highlights

Malaria remains a major public health problem and approximately 40% of the world population lives in areas of malarial endemicity distributed in 91 countries
A recent rise in the artemisinin-based combination therapies (ACT) resistance against Plasmodium falciparum in Southeast Asia poses a serious threat to malaria control and its elimination globally, making the search for new antimalarial drugs urgent (Ariey et al, 2014; Talundzic et al, 2015)
We investigate the relationship between chemical structure and the antimalarial activity of CQ-analogs bearing different side chains

Summary

Introduction

Malaria remains a major public health problem and approximately 40% of the world population lives in areas of malarial endemicity distributed in 91 countries. The World Health Organization (WHO) reported a total of 216 million cases of malaria and 445,000 deaths in 2016, which represents an increase of 5 million cases over the previous year (WHO, 2017). A recent rise in the artemisinin-based combination therapies (ACT) resistance against Plasmodium falciparum in Southeast Asia poses a serious threat to malaria control and its elimination globally, making the search for new antimalarial drugs urgent (Ariey et al, 2014; Talundzic et al, 2015). Chloroquine (CQ), a 4-aminoquinoline drug, was extensively used worldwide in countries where malaria is endemic, being the most effective and the least expensive antimalarial for many decades, and is still recommended for treating P. vivax infections. CQ has a rapid onset of action, low toxicity and is well tolerated

Methods

Results

Conclusion