1  Introduction
Chloroquine is an amine acidotropic form of quinine that was synthesised in Germany by Bayer in 1934 and emerged approximately 70 years ago as an effective substitute for natural quinine [1,2]. Quinine is a compound found in the bark of Cinchona trees native to Peru and was the previous drug of choice against malaria [3]. For decades, chloroquine was a front-line drug for the treatment and prophylaxis of malaria and is one of the most prescribed drugs worldwide [4]. Chloroquine and the 4-aminoquinoline drug hydroxychloroquine belong to the same molecular family. Hydroxychloroquine differs from chloroquine by the presence of a hydroxyl group at the end of the side chain: the N-ethyl substituent is β-hydroxylated. This molecule is available for oral administration in the form of hydroxychloroquine sulfate. Hydroxychloroquine has pharmacokinetics similar to that of chloroquine, with rapid gastrointestinal absorption and renal elimination. However, the clinical indications and toxic doses of these drugs slightly differ. In malaria, the indication for chloroquine was a high dose for a short period of time (due to its toxicity at high doses) or a low dose for a long period of time. Hydroxychloroquine was reported to be as active as chloroquine against Plasmodium falciparum malaria and less toxic, but it is much less active than chloroquine against chloroquine-resistant P. falciparum owing to its physicochemical properties. What is advantageous with hydroxychloroquine is that it can be used in high doses for long periods with very good tolerance. Unfortunately, the efficacy of chloroquine gradually declined due to the continuous emergence of chloroquine-resistant P. falciparum strains [5]. Chloroquine is also utilised in the treatment of autoimmune diseases [6]. Yet the activity of the molecule is not limited to malaria and the control of inflammatory processes, as illustrated by its broad-spectrum activity against a range of bacterial, fungal and viral infections [7], [8], [9], [10]. Indeed, in the mid-1990s, due to its tolerability, rare toxicity reports, inexpensive cost and immunomodulatory properties [11], chloroquine repurposing was explored against human immunodeficiency virus (HIV) and other viruses associated with inflammation and was found to be efficient in inhibiting their replication cycle [12].
Recently, a novel coronavirus emerged in the Chinese city of Wuhan in December 2019. After human coronavirus 229E (HCoV-229E) (classified in the genus Alphacoronavirus) and HCoV-OC43 (Betacoronavirus lineage 2a member) described in the 1960s, SARS-CoV-1 (Betacoronavirus lineage 2b member) that emerged in March 2003, HCoV-NL63 (Alphacoronavirus lineage 1b member) described in 2004, HCoV-HKU1 (Betacoronavirus lineage 2a member) discovered in 2005, and finally MERS-CoV that emerged in 2012 (classified in Betacoronavirus lineage 2c), the novel coronavirus is the seventh human coronavirus described to date as being responsible for respiratory infection. Evidence was rapidly reported that patients were suffering from an infection with a novel Betacoronavirus tentatively named 2019 novel coronavirus (2019-nCoV) [13,14]. Despite drastic containment measures, the spread of 2019-nCoV, now officially known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is ongoing. Phylogenetic analysis of this virus indicated that it is different (~80% nucleotide identity) but related to SARS-CoV-1 [15]. Because the world is threatened by the possibility of a SARS-CoV-2 pandemic, the broad-spectrum antiviral effects of chloroquine warranted particular attention for repurposing this drug in the therapy of the disease caused by SARS-CoV-2, named coronavirus disease 2019 (COVID-19).