1,4-Naphthoquinone antimalarials

Quinones and naphthoquinones were explored during the World War 11 Antimalarial Dmg Program. Now that chloroquine resistance is a serious problem, compounds of this group such as menoctone (76) are being reinvestigated. 

As hydroxyl or hydroxyl-like radicals are produced by the superoxide-driven Fenton reaction, superoxide overproduction must also occur in thalassemic cells. First, it has been shown by Grinberg et al. [382], who demonstrated that thalassemic erythrocytes produced the enhanced amount of superoxide in comparison with normal cells in the presence of prooxidant antimalarial drug primaquine. Later on, it has been found that the production of superoxide and free radical-mediated damage (measured through the MetHb/Hb ratio) was much higher in thalassemic erythrocytes even in the absence of prooxidants, although quinones (menadione, l,4-naphthoquinone-2-methyl-3-sulfonate) and primaquine further increased oxidative stress [383]. Overproduction of superoxide was also observed in thalassemic leukocytes [384]. 

With the advent of World War II Fieser was obliged to suspend all previous research and teaching to work on problems for the National Defense Research Committee. Thus for three and one-half years he was involved with the development of new incendiaries (e.g., Napalm), antimalarials, and syntheses of cortisone. He became especially interested in the antimalarial program, which included a large number of collaborators, and which yielded some extremely potent new substances in the naphthoquinone series. 

In 1993, the effects of selected topoisomerase II inhibitors, antimalarial agents, DNA binders, naphthoquinones, and various other agents on integrase activity in vitro were investigated [46]. 

It should be pointed out, however, that the pharmacological effects of ada-mantyl moieties are not general. The adamantyl substituted naphthoquinones, 111, for example, are found to be slightly less effective antimalarials than the... 

Foumet and Munoz published a review on natural products as trypanocidal, antileishmanial and antimalarial drugs. Among the active natural products, they include some naphthoquinones related to lapachol [194]. 

Su ate esters. Baumgarten showed that the reagent sulfates substances such as hydrazine, diethylamine, phenol, and naphthalene. It has been used in preparation of carbohydrate sulfate esters, sterol sulfate esters, phenol sulfate esters. 2-Hydroxy-3-alkyl-l,4-naphthoquinone antimalarials can be separated from metabolites hydroxylated in the side chain by conversion of the hydroxylated metabolites into water-soluble sulfate esters and extraction with water. Hydroxy-hydrolapachol (1), which was identified as a metabolite of hydrolapachol and which... 

The importance of naphthoquinones, particularly 2-hydroxy-3-alkyl-l,4-naphthoquinones, in chemotherapy of malaria came to light when a naphthoquinone, hydrolapachol (9), was found to possess activity against P. lophurai in ducks [8]. This observation prompted Fieser and coworkers [9-13] to synthesize a series of substituted naphthoquinones, of which lapinone (10) and menoctone (11) emerged as promising antimalarials. 

The fact that naphthoquinones are potent inhibitors of respiration in parasitized RBCs, characterised by an abnormal content of coenzyme Q (ubiquinone, 18) [16], a variety of heterocyclic quinones have been tested for their antimalarial activity [19-26]. Of these compounds 19-21 exhibited promising prophylactic activity. At a dose of 10 mg/kg given subcutaneously, 20 gave complete protection to ducks against sporozoite-induced P. gallinaceum infection [27], while 21 suppressed para-sitaemia in monkeys infected with P. cynomolgi at an intravenous dose of 3.16 mg/kg [8]. 

Fry, M., and Pudney, M. (1992). Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4 -chlorophenyl) cyclohexyl]-3-hydroxy-l,4-naphthoquinone (566C80). Biochem. Pharmacol. 43,1545-1553. 

Six naphthoquinone derivatives, including two new compounds, 4-O-methyl erythrostominone (46) and compound (47), were isolated as antimalarial and cytotoxic constituents of Cordyceps unilateralis BCC 1869 (Kittakoop et al., 1999). Compound (46) and four known erythrostominones exhibited in-vitro antimalarial activity against Plasmodium falciparum K1 (IC50 4.0—10 p,g/mL),... 

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