Dihydroartemisinin, antimalarial

Dihydroartemisinin, antimalarial, 1281 Dihydrogen dioxide see Hydrogen peroxide Dihydrogen trioxide... 

Newton PN et al. Comparison of oral artesunate and dihydroartemisinin antimalarial bioavailabilities in acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 2002, 46 1125-1127. 

A high level of activity continues in connection with the synthesis of antimalarial artemisinin analogues and congeners, in which the 1,2-dioxepane moiety is embedded. Recent examples include the syntheses of various 10-substituted deoxoartemisinins of type 123 (eg. R1 = Cl COMe) from dihydroartemisinin acetate, and of type 124 (eg. R2 = a-OH, R3 = Me), from Grignard reagent addition to 10-(2-oxoethyl)deoxoartemisinin . 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

N. Truong Thi Thanh, C. Menage, J.P. Begue, D. Bonnet-Delpon, J.C. Gantier, B. Pradines, J.C. Doury, T. Truong Dinh, Synthesis and antimalarial activities of fluoroalkyl derivatives of dihydroartemisinin, J. Med. Chem. 41 (1998) 4101-4108. 

Artemisia annua L. A. apiacea Hance ex Walpers Qing Guo (Stinking artemisia) (aerial part) Dihydroartemisinin, artesunate, artemisinin, chloroquine, flavonoids, sesquiterpene.33-269-476 This herb is mildly toxic. A schizonticidal agent, antimalarial, treat infections of multidrug-resistant strains of Plasmodium falciparum, the cause of human malignant cerebral malaria. 

Artemisia annua L. China Dihydroartemisinin, artesunate, artemisinin, chloroquine.33 This herb is mildly toxic. A schizonticidal agent, antimalarial. 

With the Chinese claims validated in 1984 by Klayman and coworkers,94 studies in the early 1980s rapidly addressed two key issues with the advancement of artemisinin as an antimalarial drug. One, how could it be made commercially and if so, what is its mode of action Although the former question was addressed,95,96 the lack in understanding its activity was reported by Gu.97 Here, evidence from prior studies indicated that, while active analogues could be prepared, including dihydroartemisinin and artemether (Figure 3.8), the endoperoxide function was key to this activity.98 In their work, Gu and co-workers postulated that the activity arose from modification of protein synthesis within the malaria parasite, Plasmodium falciparum 1 This was followed by a series of studies that indicated that the activity of artemisinin was attenuated by addition... 

Oil-soluble artemether and water-soluble sodium artesunate were developed and approved as new antimalarial drugs by the Chinese authorities in 1987. After 1992, dihydroartemisinin, Coartem (a combination of artemether and benflumetol), and Artekin (a combination of dihydroartemisinin and piperaquine) were also marketed as new antimalarial dmgs. Since then, over 10 million malaria patients on a global scale have been cured after administration of these drugs. As a result, artemether, artesunate, and Coartem were added by the World Health Organization to the ninth, eleventh, and twelfth Essential Medicine List respectively. 

Another type of (9-glycosides (127), 12-(3 aryl ethers of dihydroartemisinin, was synthesized by a reaction of acetyl dihydroartemisinin or trifluoroacetyl dihydroartemisinin with various substituted phenols in the presence of trifluoroacetic acid. Most of these compounds were proved to have better antimalarial activity against P. berghei in mice than qinghaosu, but less activity than artemether. Unexpectedly,... 

To search for stable, water-soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunate and artelinic acid, deoxoarteli-nic acid 134 was prepared (Scheme 5-18) and tested in vitro and in vivo. It was reported that 134 showed superior antimalarial activity and was more stable in simulated stomach acid than arteether. In 1992, Haynes et al. already reported on the synthesis of 5-carba-4-deoxoartesunic acid (135) from artemisinic acid (20) in a similar way, but they did not mention its activity at that time. ... 

It was found that dihydroartemisinin can selectively kill cancer cells in the presence of holotransferrin, which can increase intracellular iron concentrations, and normal breast cells (HTB 125) and lymphocytes had nonsignificant changes. It seems the mechanisms of anticancer action and of antimalarial activity are similar.2 -" ... 

Reduction of (162) with sodium borohy-dride occurs at the lactone carbonyl, leaving the peroxide intact (196, 197). The resulting cyclic hemiacetal, dihydroartemisinin (155), which is a more potent antimalarial than the parent compound, shows typical acetal reac-... 

Artemisinin is an antimalarial constituent isolated from Qinghao. It is a sesquiterpene lactone with an endoper-oxide bridge, structurally distinct from other classes of antimalarial agents. Several derivatives of the original compound have proved effective in the treatment of Plasmodium falciparum malaria and are currently available in a variety of formulations artesunate (intravenous, rectal, oral), artelinate (oral), artemisinin (intravenous, rectal, oral), dihydroartemisinin (oral), artemether (intravenous, oral, rectal), and artemotil (intravenous). Artemisinic acid (qinghao acid), the precursor of artemisin, is present in the plant in a concentration up to 10 times that of artemisinin. Several semisjmthetic derivatives have been developed from dihydroartemisinin (1). 

All three Artemisia derivatives are quickly hydrolysed to the active substance dihydroartemisinin. They produce a more rapid clinical and parasitological response than other antimalarial drugs. There are no reports of significant toxicity, and as late as 1994 there was no convincing evidence of specific resistance, but chloroquine-resistant Plasmodium berghei is resistant to artemisinin as well. The recrudescence rate is fairly high (1). 

Pinheiro, J.C., Ferreira, M.M.C. and Romero, O.A.S. (2001) Antimalarial activity of dihydroartemisinin derivatives against P. falciparum resistant to mefloquine a quantum chemical and multivariate study. J. Mol. Struct. (Theochem), 572, 35—44. 

Another quite fascinating use of intramolecular carbenoid C-H insertion was demonstrated in the synthesis of analogs of artemisinin, which exhibits antimalarial properties (Scheme 10) [63], Beginning from 10-dihydroartemisinin, diazo ester 48 was constructed. Intramolecular C-H insertion into the adjacent methyl group (Cl6) occurred in 90% yield with 5% Rh2(pfb)4 (25f) to provide lactone 49. Importantly, the labile endoperoxide moiety was left untouched throughout the sequence. 

Esters (32 4, R = C(=0)-alkyl or -aryl), of which a-epimers were mainly obtained, were more active than the ethers. Sodium artesunate (32 5, R = C(=0)-CH2CH2C00Na), the half succinic acid half-ester of dihydroartemisinin is water-soluble and shows potent antimalarial activity. Therefore, this can be administered intravenously. However it is uncertain whether this derivative is pharmacologically effective because of its sensitivity to hydrolysis. In considering this result new ether derivatives of dihydroartemisinin, which are stable and water soluble derivatives have been prepared [46]. Dihydroartemisinin was condensed with esters of aliphatic or aromatic carboxylic acids with hydroxy groups to produce mainly ethers with the P-configuration. Ethyl 2-( 10-dihydroartemisininoxy) acetate (31 4, R = CH2COOCH2CH3) and methyl... 

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