Recent Advances in Antimalarial Drug Discovery: Challenges and Opportunities

Abstract

Malaria is a global health problem that needs attention from drug discovery scientists to investigate novel compounds with high drug efficacy, safety and low cost to encounter the malaria parasites that are resistant to existing drug molecules. Antimalarial drug development follows several approaches, ranging from modifications of existing agents to the design of novel agents that act against novel targets. Most of market and clinical drugs act on blood schizonticide are in current therapy for malaria reduction. This chapter will intend to highlight the currently available drugs including various novel agents. In addition, emphasis has been given on the prospective pharmacophores that are likely to emerge as effective clinical candidates in the treatment of malaria. Besides all aspects, some alternative approaches will also be highlight.

Antimalarial Drugs with Quinoline Nucleus and Analogs

“…• Enhancing efficacy: Many natural antimalarial compounds, such as quinine from the cinchona tree, exhibited therapeutic properties but had limitations in terms of their efficacy. Hemisynthesis and synthesis of derivatives allowed modifications of the chemical structure to enhance the potency and effectiveness against malaria parasites [12][13][14].…”

“…This includes factors such as bioavailability, distribution in the body, metabolism, and elimination. Optimization of these properties can enhance the drug's efficacy and patient compliance [4,14].…”

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

“…Certain gametocyte stages have also shown sensitivity to the AM activity of its derivatives. In the ART derivatives their endoperoxide linkage is critical for AM activity; for example, deoxyartemisinin, which lacks the endoperoxide bridge, is ineffective 65–68 . During the hemoglobin digestion in parasites heme iron [Fe(II)] is produced, in the presence of which endoperoxides typically undergo reductive activation.…”

“…In 2005, Singh 130 and co-workers studied the chemistry of keto-functionalized 1,2,4-trioxanes 55-70, which can be efficiently converted in a variety of spiro-derivatives. Several of these compounds (55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70) show promising activity and were initially screened against MDR P. yoelii using the 96 mg/kg in Swiss mice given orally and via IM routes.…”

“…In the ART derivatives their endoperoxide linkage is critical for AM activity; for example, deoxyartemisinin, which lacks the endoperoxide bridge, is ineffective. [65][66][67][68] During the hemoglobin digestion in parasites heme iron [Fe(II)] is produced, in the presence of which endoperoxides typically undergo reductive activation. This triggers hemolytic breakdown of the peroxide linkage and result in a radical formation which is O-centered and later converted to a stable carbon-centered radical which is known for its cytotoxicity.…”