Antimalarial derivatives

Malaria IGnome Much of the promise of kinase inhibitor antimalarials derives from... 

One sometimes observes alternating (serrated) variations of activity (zig-zag curves) according to whether the number of atoms of carbon is even or odd. Such an example is found for antimalarials derived from methoxy-6-amino-8-quinoline (Figure 14.14). 

Qinghaosu is a sesquiterpene 1,2,4-trioxane simulating the peroxide linkage, which is an important structural requirement for antimalarial activity. Further, qinghaosu and its synthetic derivatives suffer from various limitations such as high rate of recrudescence, poor oral absorption, short half-life and embiyo-toxicity [65]. These facts led to an intense search for better antimalarials derived from simple 1,2,4-triox-anes (38). This class of compounds have been extensively studied by Jefford et al. [66-69] and others [70-75] some of them show marked in vitro and in vivo antimalarial activities [62,65]. 

Artemisinin and its antimalarial derivatives belong to the chemical class of unusual 1,2,4-trioxanes. Artemisinin is poorly soluble in water and decomposes in other protic solvents, probably by opening of the lactone ring. It is soluble in most aprotic solvents and is unaffected by them at temperatures up to 150 °C and shows a remarkable thermal stability. This section will focus on biological and pharmaceutical aspects synthetic routes to improve antimalarial activity and to synthesize artemisinin derivatives with differ-... 

Further isonitrile-containing antimalarial derivatives have been later isolated from the Japanese sponge Acanthella sp. [e.g. 22-25, Fig. (4)]... 

Name three important antimalarials derived from 8-amino-6-methoxy quinoline nucleus. Give their structure, chemical name, uses and the synthesis of any one drug. 

Fascinating plant folklore and ethnopharmacology leads to medicinal potential. Examples are the muscle relaxants based on the arrow poison, curare, from species of Chondrodendron, and the antimalarials derived from species of Cinchona and Artemisia. The methods of detection of pharmacological activity have become increasingly reliable and specific, frequently involving enzymes in bioassays and avoiding the use of laboratory animals. By using bioassay linked fractionation of crude plant juices or extracts, compounds can be specifically... 

A series of artemisinin-based semisynthetic antimalarial derivatives, with all of them maintaining the key endoperoxide bridge, such as arteether (18), artemether (19), artesunate (20), and dihydroartemisinin (21), have been designed to improve the water solubility and the metabolic stability of artemisinin [53, 54], Among them, dihydroartemisinin (artenimol), is considered as a common active metaboUte of artemisinin derivatives [53, 54]. Currently, artemisinin-based therapies eombined with standard antimalarials such as amodiaquine, sulfadoxine-pyrimethamine, mefloquine, and lumefantrine are recommended by the World Health Organization (WHO) as first-line therapies for malaria [55, 56]. 

By similar means, it was foimd that the gametocidal antimalarials derived from 8-amino-6-methoxyquinoline, such as primaquine (i.27), act only after demethylation and oxidation to the corresponding 5,6-quinone (3.28) (cf. Smith, 1956). 

Aminoquinazolines have been the subject of considerable investigation and a large number of derivatives have been prepared as potential antimalarials. The secondary and tertiary amino compounds can be prepared from the corresponding chloroquinazolines and the required primary or secondary amines. The reaction depends on the reactivity of the halogen atom, e.g, the 4-chloro atom reacts more readily than the 2-chloro atom in quinazolines and also on the basic strength of the amine used (see 6a). The reaction is... 

Amino- and hydrazino-quinazolines exhibited antibacterial ac-tivity and a patent claim on the in vitro action of 2,4-diamino-quinazolines was rnade. The preparation of thiopegan derivatives as potential antimalarials and antibacterials deserves mention. Complete inhibition of influenza virus in vitro but not in vivo was shown by. 6,8-dichloro-2,4-dihydroxyquinazoline and other cyclic ureas. Activity against trachoma virus was also displayed by several 2-trichloromethylquinazolines. ... 

Interaction of biomolecules with ginghaosu (artemisinin) and its derivatives in the presence of Fe(II) ion—an exploration of antimalarial mechanism 99PAC1139. 

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. 

Pinworm is a helminHi infection that is universally common most oHier helminth infections are predomi-lianHy found in countries or areas of the world that lack proper sanitary facilities. Malaria is rare in the United States, but it is sometimes seen in individuals who have traveled to or lived in areas where this disease is a healtii problem. The first antimalarial drug, quinine, is derived from the bark of the cinchona tree. Amebiasis is seen Hiroughout the world, but it is less common in developed countries where sanitary facilities prevent Hie spread of the causative organism. 

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. 

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>. 

Erratic availability and high costs of the natural compound make further investigations for cheaper natural or synthetic endoperoxide-based antimalarials necessary. Meanwhile, a Belgian company, Dafra Pharma, Turnhout, is bringing the natural product and its derivatives onto the market [44]. 

---