**1. Introduction**

#### **1.1. History**

The chronicle of malaria predating humanity is as ancient as mankind.[1] Malaria continues to be a persistent menace wreaking havoc especially in tropical and subtropical regions despite tremendous efforts toward its control and eradication. The unavailability of the vaccine and the emergence of resistance in the parasite against nearly all existing antimalarial drugs have attracted attention of researchers to modify the existing antimalarial drugs with improved efficacy over older therapies and identify new compounds as appropriate clinical candidate. Mortality from malaria is increasing at an alarming rate despite various renewed efforts and

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eradication campaigns[2] because the parasites (*Plasmodium* strains) responsible for the majority of fatal infections have become resistant to the existing drugs. Malaria is also the cause of poverty and a major hindrance to economic development, especially in sub-Saharan countries.[3] Mostly, malaria is spread due to local transmission through female anopheles mosquitoes. Occasionally, it can also be transmitted by exposure to infected blood products (transfusion malaria) and also through congenital transmission. The major species of *Plasmo‐ dium* strains that infect humans are *P*. *falciparum, P. vivax, P. ovale, P. malariae*, and *P. knowlesi*. Among these, *P. falciparum* causes the most severe form of infection, which could be fatal.

The original picture of the parasitic existence and passage of malaria through historic times remains blurred. It is uncertain whether the human population settlements preceded the arrival of malaria within them.[3] The versions may vary from tentative to widely accepted or even controversial based on the general scientific evidence. However, the effect of malaria wreaking havoc to the human species is prominent, clear, and unmistakable. There was no specific treatment for malaria until the 17th century.[4] The discovery of quinine from the bark of *Cinchona calisaya* began effective treatment of malaria. Further, the synthesis of chloroquine by Hans Andersag in 1934 introduced a cheap antimalarial drug and a substitute for quinine. [5] Until the widespread resistance in 1960, quinoline-related antimalarial drugs played an important role in the treatment of malaria. Fortunately, in 1972, the Chinese discovered artemisinin from sweet wormwood plant *Artemisia annua*.[6] Artemisinin along with its derivatives artemether, arteether (artemotil), and artesunate are the main treatment for malaria that is resistant to conventional therapies.

Recent advances in the molecular genetics and biochemical technologies available for the investigation of malaria parasites within the last half century have enabled us to gain a unique perspective on the human health and health services in relation to malaria.[7]

#### **1.2. Life cycle of malaria parasite**

The life cycle of malaria parasites is very complex. It is completed inside two hosts, including the humans (asexual) and the mosquitoes (sexual) (Figure 1).[8, 9] Malaria infection begins when an infected female anopheles mosquito feeding on human blood bites and injects sporozoites into the bloodstream. The parasites then quickly reach liver to form merozoites by asexual multiplication. Subsequently, merozoites exit liver with the rupture of hepatic tissues and enter the bloodstream where they invade and disintegrate red blood cells. Some mero‐ zoites transform into gametocytes, which are then circulated in the bloodstream. When the second mosquito bites an infected human, it gets infected and intakes gametocytes. The sexual transformation of gametocytes into ookinetes and ookinetes into oocyst takes place inside the midgut of mosquito. Finally, sporozoites are developed from oocysts, which eventually burst, releasing sporozoites into the salivary gland. Continued infection in humans and mosquitoes alternatively propagates and spreads malaria.

A comparative study with human and rodent parasites revealed the activities of current antimalarial drugs on the life cycle stages of plasmodium.[10] 8-Aminoquinolones are known to be active for liver stage. The most currently available antimalarial drugs primarily target the human blood cell stage. In addition to the asexual blood stage, some drugs (viz., pyronar‐ Recent Advances in Antimalarial Drug Discovery — Challenges and Opportunities http://dx.doi.org/10.5772/61191 41

**Figure 1.** Life cycle of malaria parasite.[9]

idine and atovaquone) can also target both liver and sexual stage. Further, new stable synthetic endoperoxides can inhibit gamete formation and gametocyte maturation.[10] Furthermore, it is important to profile the currently available drugs for specific stage in parasite's life cycle to combat malaria by eradication and circumventing resistance.

#### **1.3. Status quo**

eradication campaigns[2] because the parasites (*Plasmodium* strains) responsible for the majority of fatal infections have become resistant to the existing drugs. Malaria is also the cause of poverty and a major hindrance to economic development, especially in sub-Saharan countries.[3] Mostly, malaria is spread due to local transmission through female anopheles mosquitoes. Occasionally, it can also be transmitted by exposure to infected blood products (transfusion malaria) and also through congenital transmission. The major species of *Plasmo‐ dium* strains that infect humans are *P*. *falciparum, P. vivax, P. ovale, P. malariae*, and *P. knowlesi*. Among these, *P. falciparum* causes the most severe form of infection, which could be fatal. The original picture of the parasitic existence and passage of malaria through historic times remains blurred. It is uncertain whether the human population settlements preceded the arrival of malaria within them.[3] The versions may vary from tentative to widely accepted or even controversial based on the general scientific evidence. However, the effect of malaria wreaking havoc to the human species is prominent, clear, and unmistakable. There was no specific treatment for malaria until the 17th century.[4] The discovery of quinine from the bark of *Cinchona calisaya* began effective treatment of malaria. Further, the synthesis of chloroquine by Hans Andersag in 1934 introduced a cheap antimalarial drug and a substitute for quinine. [5] Until the widespread resistance in 1960, quinoline-related antimalarial drugs played an important role in the treatment of malaria. Fortunately, in 1972, the Chinese discovered artemisinin from sweet wormwood plant *Artemisia annua*.[6] Artemisinin along with its derivatives artemether, arteether (artemotil), and artesunate are the main treatment for malaria

Recent advances in the molecular genetics and biochemical technologies available for the investigation of malaria parasites within the last half century have enabled us to gain a unique

The life cycle of malaria parasites is very complex. It is completed inside two hosts, including the humans (asexual) and the mosquitoes (sexual) (Figure 1).[8, 9] Malaria infection begins when an infected female anopheles mosquito feeding on human blood bites and injects sporozoites into the bloodstream. The parasites then quickly reach liver to form merozoites by asexual multiplication. Subsequently, merozoites exit liver with the rupture of hepatic tissues and enter the bloodstream where they invade and disintegrate red blood cells. Some mero‐ zoites transform into gametocytes, which are then circulated in the bloodstream. When the second mosquito bites an infected human, it gets infected and intakes gametocytes. The sexual transformation of gametocytes into ookinetes and ookinetes into oocyst takes place inside the midgut of mosquito. Finally, sporozoites are developed from oocysts, which eventually burst, releasing sporozoites into the salivary gland. Continued infection in humans and mosquitoes

A comparative study with human and rodent parasites revealed the activities of current antimalarial drugs on the life cycle stages of plasmodium.[10] 8-Aminoquinolones are known to be active for liver stage. The most currently available antimalarial drugs primarily target the human blood cell stage. In addition to the asexual blood stage, some drugs (viz., pyronar‐

perspective on the human health and health services in relation to malaria.[7]

that is resistant to conventional therapies.

alternatively propagates and spreads malaria.

**1.2. Life cycle of malaria parasite**

40 An Overview of Tropical Diseases

WHO has recommended artemisinin combination therapy (ACT) for the treatment of malaria. [11] Since 2006, artemisinin-based combination therapies remain as the first-line treatment for *P. falciparum* malaria replacing chloroquine and sulfadoxine/pyrimethamine. Combined with other drugs, its derivatives, such as artesunate and artemether, can clear symptoms of malaria in three days. However, a rise in demand has led to a shortage of artemisinin. Artemisininbased drugs are also more expensive than conventional treatments, in part because large doses are required. Further, with recent reports on the emergence of resistance to artemisinin,[12] it can be foreseen that in the near future, new armamentarium will be required to fight against malaria. Thus, to overcome this problem, there is an urgent need to identify new chemotypes or reexamining old molecules to transform them into an appropriate clinical candidate.
