Structure-activity relationships of the antimalarial agent artemisinin. 8. design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria.
21 Aug 2003-Journal of Medicinal Chemistry (American Chemical Society)-Vol. 46, Iss: 20, pp 4244-4258
TL;DR: The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.
Abstract: Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.
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TL;DR: Propargylamines have been synthesized by a gold(III) salen complex-catalyzed three-component coupling reaction of aldehydes, amines, and alkynes in water in excellent yields at 40 degrees C with excellent diastereoselectivities.
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TL;DR: Evidence for each mechanism of action attributed to artemisinin includes interference with parasite transport proteins, disruption of parasite mitochondrial function, modulation of host immune function and inhibition of angiogenesis, and the evidence for each is reviewed.
298 citations
TL;DR: Data indicate that artemisinin has promising anti-leishmanial activity that is mediated by programmed cell death and, accordingly, merits consideration and further investigation as a therapeutic option for the treatment of leishmaniasis.
Abstract: A major impediment to effective anti-leishmanial chemotherapy is the emergence of drug resistance, especially to sodium antimony gluconate, the first-line treatment for leishmaniasis. Artemisinin, a sesquiterpene lactone isolated from Artemisia annua, is an established anti-malarial compound that showed anti-leishmanial activity in both promastigotes and amastigotes, with IC(50) values of 160 and 22 microM, respectively, and, importantly, was accompanied by a high safety index (>22-fold). The leishmanicidal activity of artemisinin was mediated via apoptosis as evidenced by externalization of phosphatidylserine, loss of mitochondrial membrane potential, in situ labelling of DNA fragments by terminal deoxyribonucleotidyltransferase-mediated dUTP nick end labelling (TUNEL) and cell-cycle arrest at the sub-G(0)/G(1) phase. Taken together, these data indicate that artemisinin has promising anti-leishmanial activity that is mediated by programmed cell death and, accordingly, merits consideration and further investigation as a therapeutic option for the treatment of leishmaniasis.
210 citations
Cites background or result from "Structure-activity relationships of..."
...Studies of the efficacy of artemisinin against Leishmania donovani, the causative organism of visceral leishmaniasis, have been restricted to promastigotes (Avery et al., 2003), and studies of its efficacy in amastigotes, the biologically relevant form, are notably absent....
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...The IC50 value of artemisinin agreed with previous reports using L. donovani promastigotes (Avery et al., 2003) in which artemisinin and over 70 of its derivatives were studied....
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TL;DR: A series of dihydropyrido[2,3-d]pyrimidines have been synthesized and screened for its in vitro antileishmanial activity profile in promastigote and amastigotes models.
136 citations
TL;DR: Artemisinin compounds have been shown to inhibit the growth of cultured Trypanosoma cruzi and Brucei rhodesiense at concentrations in the low micromolar range as mentioned in this paper.
Abstract: Artemisinin compounds inhibit in vitro growth of cultured Trypanosoma cruzi and Trypanosoma brucei rhodesiense at concentrations in the low micromolar range. Artemisinin also inhibits calcium-dependent ATPase activity in T. cruzi membranes, suggesting a mode of action via membrane pumps. Artemisinins merit further investigation as chemotherapeutic options for these pathogens.
132 citations
References
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TL;DR: In this article, a method for the rapid calculation of atomic charges in σ-bonded and nonconjugated π-systems is presented, where only the connectivities of the atoms are considered.
3,640 citations
TL;DR: Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself, and offer promise as a totally new class of antimalarials.
Abstract: The herb Artemisia annua has been used for many centuries in Chinese traditional medicine as a treatment for fever and malaria. In 1971, Chinese chemists isolated from the leafy portions of the plant the substance responsible for its reputed medicinal action. This compound, called qinghaosu (QHS, artemisinin), is a sesquiterpene lactone that bears a peroxide grouping and, unlike most other antimalarials, lacks a nitrogen-containing heterocyclic ring system. The compound has been used successfully in several thousand malaria patients in China, including those with both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Derivatives of QHS, such as dihydroqinghaosu, artemether, and the water-soluble sodium artesunate, appear to be more potent than QHS itself. Sodium artesunate acts rapidly in restoring to consciousness comatose patients with cerebral malaria. Thus QHS and its derivatives offer promise as a totally new class of antimalarials.
2,025 citations
TL;DR: To better evaluate, in the context of QSAR studies, new validation techniques such as bootstrapping and crossvalidation and the new analytic technique of partial least squares, seventeenQSAR results taken from nine recent publications were reexamined using these techniques.
Abstract: To better evaluate, in the context of QSAR studies, new validation techniques such as bootstrapping and crossvalidation and the new analytic technique of partial least squares (PLS), seventeen QSAR results taken from nine recent publications were reexamined using these techniques. The results indicate that bootstrapping and crossvalidation are more powerful indicators of possible chance correlation than are the classical tests based on assumed normal independent distribution of variables. Although PLS will not detect all correlations existing within a set of data, its conservative behavior is particularly valuable when the candidate physicochemical descriptors are numerous and non-orthogonal.
820 citations
TL;DR: It is reported here that after incubation with holotransferrin, which increases the concentration of ferrous iron in cancer cells, dihydroartemisinin, an analog of artemis inin, effectively killed a type of radiation-resistant human breast cancer cell in vitro.
331 citations
TL;DR: Iron probably catalyzes the generation of free radicals from artemisinin since alpha-tocopherol antagonizes the thiol-oxidizing activity of art Artemisinin and since a spin-trapped free radical signal can be seen by electron paramagnetic resonance only when artemis inin is incubated in the presence of iron.
Abstract: Artemisinin is an important new antimalarial agent containing a bridged endoperoxide. The in vitro antimalarial activity of an artemisinin derivative, arteether, is antagonized by two iron chelators, pyridoxal benzoylhydrazone and 1,2-dimethyl-3-hydroxypyrid-4-one. Similarly, the acute toxicity of artemisinin in mice is antagonized by another chelator, deferoxamine-hydroxyethylstarch. A combination of artemisinin and hemin oxidizes erythrocyte membrane thiols in vitro, and this oxidation is also inhibited by an iron chelator. Thus, iron plays a role in the mechanisms of action and toxicity of artemisinin. The combination of artemisinin and hemin also decreases erythrocyte deformability. Iron probably catalyzes the generation of free radicals from artemisinin since alpha-tocopherol antagonizes the thiol-oxidizing activity of artemisinin and since a spin-trapped free radical signal can be seen by electron paramagnetic resonance only when artemisinin is incubated in the presence of iron.
317 citations