**3.3 Aminoquinoline antimalarials**

Chloroquine was discovered in 1934, by Hans Andersag and co-workers at the Bayer laboratories. Research by German scientists to discover a substitute for quinine led to the synthesis in 1934 of Resochin (chloroquine) and Sontochin (3-methyl-chloroquine). After the war, chloroquine have for decades been the mainstays for malaria treatment and prevention during the global malaria eradication campaign by WHO in 1950s. This safe and inexpensive 4-aminoquinoline compound is believed to exert its antimalarial property through accumulation in the food vacuole [50]. The mechanisms by which chloroquine selectively accumulates may include protonation and ion trapping of the chloroquine due to the low pH of the food vacuole, active uptake of chloroquine by a parasite transporter(s), and/or binding of chloroquine to a specific receptor in the food vacuole [51–55].

After a decade of its use, chloroquine resistant *P. falciparum* arose in four separate locations, starting with the Thai-Cambodian border around 1957; in Venezuela and parts of Colombia around 1960; in Papua New Guinea in the mid-1970s and in Africa in 1978 in Kenya and Tanzania [56]. Resistance of *P. falciparum* to chloroquine changed the treatment policy to use several drugs such as halofantrine, lumefantrine, pyronaridine, mefloquine, and sulfadoxine-pyrimethamine (SP), while chloroquine and primaquine remain effective to treat *P. vivax* until few decades.

Resistance by *P. vivax* to chloroquine was unknown until 1989, when Australians repatriated from Papua New Guinea failed routine treatment [57]. Subsequent reports affirmed that finding and CQ-resistant *P. vivax* (CRPV) was reported from Indonesia [58] and Guyana [59]. A review and meta-analytic study evaluating chloroquine clinical trials performed during the period of 1960 to 2014 found out a contrasting evidence, indicating chloroquine sensitivity as shown by elimination of the asexual parasite by day 3 [60]. Although in some studies, a high degree of resistance was confirmed, the trials exhibited heterogeneity in study design and the presence of confounding factors such as interpretation of a recurrent parasites to distinguish relapse or recrudescence. In addition, technical issues on the quality and the dose of chloroquine used may also play role as the chloroquine possesses a wide therapeutic windows that enable to increase the dose. A therapeutic efficacy study to determine the efficacy of chloroquine in uncomplicated vivax malaria was conducted in Papua, Indonesia in 2007 isolated few recurrent parasites that survive chloroquine at blood concentration ranged from 100 ng/ml to 516 ng/ml [61]. Other study performed *in vitro* chloroquine sensitivity assay on either freshly

collected or cryopreserved *P. vivax* isolates collected from Papua and Thailand [62]. The global spread of chlroquine-resistant *P. vivax* was later summarised in 2016 [63], as shown in **Figure 2**.

The absence of reliable, robust, sensitive methods for detection and monitoring of antimalarial drug efficacy in *P. vivax* has almost certainly contributed to the delayed recognition of this emerging problem [57]. Other factors include the relatively small parasite biomass in *P. vivax* infections, concomitant medication, such as primaquine to kill hypnozoites, early transmission due to the early presence of gametocytes, and high genetic diversity in natural population of *P. vivax* [64]. This delay has had important public health implications in areas where high-grade chloroquine-resistant *P. vivax* is prevalent (such as Indonesia and Oceania), partly effective drug treatments and consequent recurrent infections are an important contributing factor to severe anaemia from *P. vivax* malaria [65].
