**3. Mechanism of action**

it was eradicated and spread of malaria to new areas is a major threat. The World Health Organization defined antimalarial drug resistance as the "ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject."[14] It was modified later to specify that the drug in question must "gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action."[15] Antimalarial drug resistance occurs through spontaneous mutations that reduces the sensi‐ tivity to a given class of drug(s).[16] Only a single point mutation is sufficient to confer

resistance to some drugs, while multiple mutations appear to be required for others.

2. Amodiaquine Yes

7. Lumefantrine No

9. Trimethoprim Yes 10. Proguanil Since 2000 11. Sulfonamides Yes

16. Artemether Since 2001

3. Piperaquine Since 1980s

1.

42 An Overview of Tropical Diseases

5.

8.

13.

15.

4-Aminoquinoline

Aryl-amino alcohol

Antifolates

Antibiotic

Artemisinin

**Table 1.** Status of resistance in antimalarial drugs.

17. Dihydroartemisinin

**Sl. no Drug class Drug Resistance Mechanism of action**

4. 8-Aminoquinoline Primaquine - Unknown

6. Mefloquine Since 1985 Unknown

12. Napthoquinone Atovaquone Since 2000 Inhibition cytochrome

synthesis and apicoplast 14. Clindamycin

The malaria parasite has developed some level of resistance against nearly all previous generation antimalarial drugs (Table 1). Recent research has confirmed evidence of artemisinin resistance.[10] Although it is under investigation, immediate actions are needed to restrict resistance to artemisinin from spreading to new areas. It is high time that we should fight this

Artesunate Yes

Doxycycline

Chloroquine Since 1945

Quinine Yes

Pyrimethamine Since 1967

Inhibition of hemozoin formation

Inhibition of DHFR

Free radical mechanism Heme alkylation

No Inhibition of protein

The mechanism of action of antimalarial drugs is based on the extensive studies of selected drugs. Most drugs available for the treatment were discovered based on the serendipitous identification of active compounds (natural, synthetic, and semisynthetic).[17] The progress in the understanding of the biochemistry of malarial parasite has shed light on the mechanism of action of new as well as older drugs.

It is believed that artemisinin and related drugs are transported to the food vacuole of the parasite, where they generate free radicals upon interaction with Fe(II)-heme. These free radical's interaction with heme generates oxidative stress and kills the parasite.[18] The mechanism of action of quinoline and related drugs is also well established.[19] It is shown that the drugs enter the RBC and inhabit the digestive vacuole of parasite by simple diffusion. The subsequent inhibition of hemozoin biocrystallization leads to the aggregation and accumulation of cytotoxic heme in food vacuoles resulting in parasite's death. The commer‐ cially available quinolone antimalarials target the gyrase and inhibit DNA replication. It results in the delayed death of treated parasites by formation of abnormal apicoplasts.[20]

Based on the mechanism of action, different groups of antimalarials can be classified as follows:

