Antimalarial activities

The first 25 compounds (in oil solution) were tested in the mice-infected chloroquine-resistant P. berghei by administration of intramuscular injection. Most of these derivatives showed more activity than qinghaosu and dihydroartemisinin. 

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. 

When artemether and sodium artesunate were successfully used by intramuscular or intravenous administration for treatment of severe malarial patients, their shortcomings, such as short half-life and instability of aqueous solution of sodium artesunate, were cognized. Hence, qinghaosu derivatives and analogs numbering in the thousands were synthesized and evaluated by many research groups worldwide. 

An extensive series of thiosemicarbazones obtained from 2-acetylpyridine was tested by Klayman et al. [4, 85] for antimalarial activity against Plasmodium berghei in mice. The molecular features essential for activity were found to be a 2-pyridylethylidene moiety, the presence of the thiocarbonyl sulfur, and certain, bulky or cyclic substituents at the terminal AT-atom. The most active 2-acetylpyridine thiosemicarbazones were N-phenyl- and those with azacycUc substituents. For example, iV-substituents of 4-methylpiperidine, piperazine, and azabicyclo[3.2.2.]nonyl-, 4, were curative at a dose level as low as 20 mg/kg. 

against Neisseria gonorrhoeae the 2-acetylpyridine JV-dialkylthiosemi-carbazones were the most active [86], Recently, it has been shown that 

2- formylpyridine thiosemicarbazone inhibited adenosine uptake in rodent erythrocytes and reticulocytes parasitized with Plasmodium berghei [87]. This suggests that potential interaction with the adenosine receptor may be an additional mode of action of these drugs besides chelation. Further studies are needed to substantiate these conclusions. Thiosemicarbazones of 3-formyl- and 

3- acetyl-B-carboline effectively inhibit the promastigote form of Leishmania donavani 2-formylpyridine thiosemicarbazone was considerably less active [88]. 

The activity of manzamine Y against both the D 6 clone and W2 clone of the malarial parasite P. falciparum (IC50 420 and850 ng/mL, respectively) is significantly lower than that of 8-hydroxymanzamine A (IC50 6.0 and 8.0 ng/mL, respectively). This difference indicates that the change of the hydroxyl substitution from the C-8 position of the (3-carboline moiety to the C-6 position decreases the antimalarial activity dramatically. 

The growth of the chloroquine resistant blood parasite Plasmodium falciparum (responsible for malaria) was markedly inhibited in vitro by certain quassinoids 103). The most active compound simalikalactone D (83) gave complete inhibition at 0.002 pg/ml. Glaucarubinone (36a) and soularubinone (35) were equally effective at 0.006 pg/ml, whereas chapar-rinone (40a) and simarolide (77) had little effect even at 0.01 pg/ml. These relative activities parallel the antineoplastic activities of these compounds. Indeed, the two last mentioned quassinoids (40 a) and (77) do not possess the structural requirements for antileukemic activity. 

The 3-, 15-esters and 3,15-diesters of bruceolide (48), including brucean-tin (53) as well as brusatol (55 a) and bruceolide (48), were reported to be effective inhibitors of chloroquine resistant strains of P. falciparum 49). 

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Many quinazolines possessing a wide variety of biological activities are known. The antimalarial activity of febrifugine spurred the preparation and testing of a number of quinazolines, and several... 

The pioneering work carried out in Germany in the 1920s showed that appropriately substituted aminoquinolines and amino-acridines afforded a series of synthetic compounds that exhibited antimalarial activity.The exigencies of the Second World War led to a massive program aimed at the same goal in this country. This work led to the development of two distinct structural classes of quinoline antimalarials the 4-amino-7-chloroquino-... 

An acridine with a radically different substitution pattern, interestingly, still exhibits antimalarial activity. Condensation of acetone with diphenylamine in the presence of strong acid affords the partly reduced acridine, 20. Alkylation with 3-chloro-dimethylaminopropane (via the sodium salt of 20) affords dimethacrine (21). ... 

Tetracycline and its derivative doxycycline are antibiotics widely used in the treatment of bacterial infections. They also exert an antimalarial activity. Tetracyclines inhibit the binding of aminoacyl-tRNA to the ribosome during protein synthesis. 

Proguanil appears to have a dual activity. Part of it is metabolized to cycloguanil, which subsequently inhibits the protozaon dihydrofolate reduc-tase/thymidylate synthase (DHFR/TS) (Fig. 4). In addition, the native form, proguanil itself, exerts a potent antimalarial activity, especially in combination with other antimalarial drugs. The target of proguanil is unknown. 

Navarro, M., Vasquez, F., Sanchez-Delgado, R.A., Perez, H., Sinou, V. and Schrevel, J. (2004) Toward a Novel Metal-Based Chemotherapy against Tropical Diseases. 7. Synthesis and in Vitro Antimalarial Activity of New Gold-Chloroquine Complexes. Journal of Medicinal Chemistry, 47, 5204. 

These complexes were tested for in vitro antimalarial activity showing that the coordination to the Au increases the potency of chloroquine. The ferrocenyl ligands... 

Blackie, M.A.L., Beagley, P., Chibale, K., Clarkson, C., Moss, J.R. and Smith, P.J. (2003) Synthesis and antimalarial activity in vitro of new heterobimetallic complexes Rh and Au derivatives of chloroquine and a series of ferrocenyl-4-amino-7-chloroquinolines. Journal of Organometallic Chemistry, 688(1-2), 144-152. 

An iron(III) complex of 2-acetylpyridine 3-azabicyclononylthiosemi-carbazone, 4, the thiosemicarbazone that was found to have the most potent antimalarial activity of a large number of 2-acetylpyridine thiosemicarbazones tested [88], was originally formulated as 5-coordinate [Fe(4-H)Cl2], [135], but more recent studies have shown it to be [Fe(4-H)2] [FeCl4] [117]. This complex has similar antimalarial activity to that of the uncomplexed ligand, but possesses enhanced antitumor activity [136]. 

Figueiredo, J. N. Raz, B. Sequin, U. Novel quinone methides fromSalacia kraussiiwith in vitro antimalarial activity. J. Nat. Prod. 1998, 61, 718-723. 

Acedapsone (127), which is conveniently prepared by acetylation of dapsone, was intended to be a prodrug. Leprous patients being treated with dapsone were observed to have a lower incidence of malaria and acedapsone was made to capitalize on this observation. It, indeed, has both antileprotic and antimalarial activity. 

Nkunya MH, Weenen H, Bray DH, Mgani QA, Mwasumbi LB. Antimalarial activity of Tanzanian plants and their active constituents the genus UvariaPlanta Med 1991 57 341-343. 

A series of pyrrolopyridopyrazines have been prepared from 3-amino-2-(iV-pyrrolyl)pyridines (Scheme 58) and evaluated for their properties as 5-HT3 receptor ligands and for antimalarial activity <1997JME1808, 1999JME4362, 2004JME1997>. 

Titanium tetrachloride-catalysed Michael additions of trimethylsilyl enol ethers to artemisitene afforded a neat route to 14-substituted artemisinin derivatives of type 125 (eg. R = allyl) and to 9-epiartemisinin derivatives 126 some of these compounds were more active against Plasmodium falciparum than artemisinin <00BMCL1601>. A series of 11-azaartemisinins also have better activity than artemisinin <00BMC1111>. On the other hand, epiartemisinin, prepared by base-catalysed epimerisation of artemisinin, has been shown to have poor antimalarial activity <00HCA1239>. 

The dimeric carbazole alkaloids often occur along with the corresponding monomeric carbazoles in terrestrial plants [7,62] (Scheme 7). Clausenamine-A was obtained by Wu from the stem bark of Clausena excavata [63]. Clausen-amine-A and its synthetic analogs, like bis(O-demethylmurrayafoline-A), show cytotoxic activities against diverse human cancer cell lines [64] and exhibit moderate antimalarial activity [65,66]. Furukawa isolated l,r-bis(2-hy-droxy-3-methylcarbazole) and bismurrayaquinone-A, the first dimeric car-bazolequinone alkaloid found in nature, from Murraya koenigii [67]. 

All the material world is formed of mixtures, aggregates or more complex combinations of pure substances. For example, it is well known that the bark of the Cinchona tree Cinchona calisaya) shows a remarkable antimalarial activity, which is due, not to the bark as such, but to some "pure substance" which forms an integral part of it. In 1820, the French pharmacists Pelletier and Caventou isolated the active principle of the Cinchona bark, which they called quinine, as a pure, crystalline substance, m.p. 177 °C (dec), -169°, and assigned an elemental... 

It must not be forgotten that the concept of pure substance, referred to earlier, is very rigorous and must take into account, not just the constitution and relative configuration of a molecule, but also the absolute configuration of each chiral center that may present. For example, again in relation to quinine (i), quinidine (2) is also known and the only difference between the two molecules is the disposition in space of the groups bonded to C(8). Nevertheless 2 is a different molecule and shows no antimalarial activity. In addition, only one enantiomer of quinine (1), the laevorotatory, corresponds to the natural compound and manifests the specific physiological properties associated with this substance. 

Hormaomycin - peptide with antimicrobial 65, 101, and antimalarial activity 102... 

R. Modeling antimalarial activity application of kinetic energy density quantum similarity measures as descriptors in QSAR./. Chem. Inf. Comput. Sci. 2000, 40, 1400—1407. 

Following the discovery of the antimalarial activity [148) of biguanides and quinoline derivatives, a variety of substituted quinolyl-b anides were synthesised [9, 42, 101, 188, 298, 303, 306, 428, 558, 583, 585) by these procedures. The production of a series of m.m-hexamethylenebi-guanides [724) illustrates the use of secondary amines in this synthesis. 

Several excellent accounts have described the need which arose in World War II for new antimalarial drugs, and the chemical reasoning which led to the synthesis of Paludrine (l-p-chlorophenyl-5-isopropylbiguanide) (742, 746, 545). Curd, Davey and Rose (142) found that both Paludrine and its 5-methyl-homologue showed antimalarial activity in chicks and birds chnical trials demonstrated their activity in man. Paludrine presently proved (2) to be of considerable therapeutic value in the prevention and cure of acute human malaria (475). Animal experiments (ducks) indicated (178, 421) that Paludrine was most effectively administered in the diet in order to maintain a suitable concentration in the blood. 

Malaria parasite has developed resistance to many of these so-called quinoline antimalarials rendering them completely obsolete. This situation has forced the use of combination regimens that consists of a mixture of two or more antimalarial active ingredients this approach has proven to work better than monotherapies, but often is only a temporary soulu-tion. Nevertheless, quinine remains a very effective drug, with only few treatment failures or resistance reported around the globe. 

Nevertheless, in order to improve their effectiveness, a second generation of artemisinin analogs, obtained by the derivatization of artemisinin, has been prepared. Figure 4 shows some selected second-generation artemisinin analogs that have displayed strong antimalarial activity although none of them has ever been clinically used. 

One of the most important developments in the biochemistry and biology of xanthones is surely the recent discovery of their antimalarial activity, and attempts to understand their mode of action. In the last few years, a large number of polyoxygenated, prenylated and non-prenylated xanthones have been reported for their antimalarial activity, and the advance in the understanding of their mode of action has progressed quicker than any other known antimalarials (cf. 14 for a review). 

The structural diversity of natural products with antimalarial activity from marine and freshwater sources are stunning, ranging from isonitrile-containing derivatives to depsipeptides through peroxides and alkaloids. 

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