Antimalarial Agents

Abstract

Malaria continues to be a major global health problem and seems to be increasing in some parts of the world. By way of an introduction, relevant aspects of the disease, including incidence and resistance, and of the parasite and its biochemistry and genetics are presented. The chemotherapeutic agents now available to prevent and treat malaria are discussed individually. Some of these drugs have been in use for decades or even centuries, such as quinine, chloroquine, and primaquine. Other agents are of more recent origin including mefloquine, halofantrine, atovaquone, and the artemisinins. Chloroquine had been the drug of first resort for many years. It is inexpensive, well‐tolerated, and extremely effective where parasites remain sensitive. But the development of resistance to chloroquine has emphasized the need for new agents and strategies to treat malaria. New information on the genetic basis of chloroquine resistance and on the overall mechanism of action of chloroquine holds promise for advances in therapy. Another important tactic in dealing with infection by resistant parasites is the use of drug combinations. The combination of pyrimethamine and sulfadoxine has been very successful, but resistance is developing. Newer, highly effective combinations include atovaquone with proguanil, lumefantrine with artemether, and chlorproguanil with dapsone. The artemisinin group of compounds has made a powerful positive impact on malaria chemotherapy although their use in monotherapy is not recommended. Details of the mechanism of action of these drugs are becoming clearer. Knowledge about action should assist in addressing issues of possible toxicity. Great progress has been made in sequencing the genome of Plasmodium falciparum . New molecular targets have been identified as a result and efforts are underway to develop antimalarial agents based on these targets. Researchers around the world are also exploring natural products for yet another lead in antimalarial chemotherapy. “If we take as our standard of importance the greatest harm to the greatest number, then there is no question that malaria is the most important of all infectious diseases 1 .” “Ah, poor heart! he is so shaked of a burning quotidian tertian, that it is most lamentable to behold [2].”

The Invasive Anemone Condylactis sp. of the Coral Reef as a Source of Sulfur- and Nitrogen-Containing Metabolites and Cytotoxic 5,8-Epidioxy Steroids

“…Terpenoid and steroid peroxides isolated from terrestrial and marine organisms represent an interesting bioactive group of natural products [ 57 , 58 , 59 , 60 ]. These natural peroxides have been reported to exhibit a variety of biological activities, which may be linked to their ability to release oxygen, such as antiprotozoal (e.g., antimalarial) [ 61 , 62 ], anthelmintic, antiviral [ 63 , 64 ], and cytotoxic [ 33 , 58 , 65 , 66 ] activities. Moreover, the 5α,8α-epidioxy sterol 8 , which was also isolated from edible mushrooms, has also been reported to possess anti-tumor activity against breast cancer (MCF-7) [ 65 , 66 ] and carcinosarcoma (Walker 256) cells [ 65 ] and to act as an inhibitor against 12- O -tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in mouse skin [ 67 ], immunosuppressant [ 68 ], and anti-inflammatory [ 69 ].…”

Synthesis and Characterization of Phenylenediamine Side‐Chain‐Modified 4‐Aminoquinoline Mannich Bases and Evaluation of their in vitro Antimalarial Activity

“…The presence of a substituted phenyl ring and a heteroaromatic ring system caused the peaks in the lower wavelengths. The Infra-Red spectra showed the C=C stretching bands for aromatic rings were visible between 1600 and 1450 cm 1 . In the range of 1300-1000 cm À 1 denoted to the presence of in-plane CÀ H bending vibrations and in the range of 900-690 cm À 1 out-ofplane CÀ H bending vibrations occurred.…”

“…Malaria in macaques is caused by the Southeast Asian zoonotic species P. knowlesi, which can also cause life-threatening infections in people. [1][2][3][4] Studies on the structure activity relationship of antimalarial compounds that contain 4-aminoquinoline indicate to the 7chloro-4-aminoquinoline nucleus as being essential for antimalarial activity, notably for the capacity of drugto accumulate at the target location and block the synthesis of beta-haematin. [5][6][7][8][9] According to studies, the antimalarial activity is decreased when the 7-chloro group is substituted by an electron donor group, such as À NH 2 , À OCH 3 , and so on, or an electronwithdrawing group, such as À NO 2 , either because pKa of quinoline nitrogen atom is raised or lowered.…”

“…P. falciparum is the primary killer in the overwhelming majority of cases. Malaria in macaques is caused by the Southeast Asian zoonotic species P. knowlesi , which can also cause life‐threatening infections in people [1–4] …”

Direct Access of the Chiral Quinolinyl Core of Cinchona Alkaloids via a Brønsted Acid and Chiral Amine Co-catalyzed Chemo- and Enantioselective α-Alkylation of Quinolinylmethanols with Enals

“…Cinchona alkaloids such as quinine and quinidine occupy a unique position in natural products and medicinal and organic chemistry due to their interesting structures, important biological properties, and “privileged” ligands widely used in catalysis and synthesis (Scheme , eq 1) . Their broad utilities make them long-sought targets in organic synthesis over 150 years .…”