Antimalarial Properties

Some antibiotics, such as the tetracyclines, tetracycline (7), doxycycline (78), and minocycline (17), chloramphenicol (79), and clindamycin (23) have modest antimalarial properties, but are slow-acting. 

The antimalarial properties attributed to preparations from Dichroa febrifuga by the Chinese were confirmed about 1944 and two alkaloids, febrifugine (999) and isofebrifugine (1000), were isolated eventually. After difficult structural elucidations, syntheses of ( )-febrifugine followed it proved to be half as active as the natural material, itself far better than quinine, but the therapeutic index was disappointingly low (67HC(24-l)490). 

The oldest effective drug for the treatment of this disease is indisputably quinine. Although the antipyretic activity of cinchona bark was known to the Incas, it remained for the Jesuit missionaries to uncover its antimalarial properties in the early seventeenth century. The advance of organic chemistry led to the isolation and identification of the alkaloid, quinine, as the active compound at the turn of this century. The emerging clinical importance of this drug led up to the establishment of cinchona plantations in the Dutch East Indies. This very circum-... 

Following the discovery of the antimalarial properties of Paludrine iJ48), an obvious step in the search for active compounds was the synthesis of the comparable triguanides (LVII). Several attempts by Indian investigators with this object in view appear to have been unsuccessful 304). 

CXXVI) may be rejected. Structure CXXVI is also inadmissible because the product cannot be reduced to l-p-chlorophenyl-5-isopropylbiguanide, and has no antimalarial properties. 

Fr6d6rich, M., Tits, M., Golffin, E., Philippe, G., Grellier, P., Mol, P. D., Hayette, M.-P. and Angenot, L. 2004. In vitro and in vivo antimalarial properties of isostrychnopentamine, an indolomonoterpenic alkaloid from Strychnos usambaren-sis. Planta Medica, 70 520-525. 

The ozonide (176) was prepared as part of a synthetic study towards the antimalarial natural product artemisinin (177) <92JCS(Pl)325l>. It proved stable enough to allow x-ray crystal structure determination (see Section 4.16.3.1). Other, more complex, polycyclic ozonides were prepared in order to investigate possible antimalarial properties. Compounds were evaluated in vitro for antimalarial activity using a multiresistant strain of Plasmodium falciparum. Most were found to be weakly active although a thousand times less active than artemisinin. 

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

Table 1 summarizes the synthetic and antimalarial profiles of selected endoperoxides. Clearly, synthetic organic chemistry has enabled several excellent potential drng candidates to be prepared, some of which have outstanding antimalarial properties. At the forefront of these efforts are the trioxolanes prepared by Vennerstrom and colleagnes. The challenge in this field in future years will be to construct additional endoperoxide templates that can be prepared in a few steps using scalable synthesis and have similar pharmacological profiles to lead semi-synthetic artemisinins and trioxolanes (e.g. 6). 

A number of naturally occurring pharmacologically active alkaloids possess quinoline and isoquinoline skeleton. For examples, papaverine from Papa-ver somniferum is an isoquinoline alkaloid and quinine from Cinchona barks is a quinoline alkaloid that has antimalarial properties. 

Quinidine, cinchonine, and cinchonidine also have antimalarial properties, but these alkaloids are not as effective as quinine. The cardiac effect makes quinidine unsuitable as an antimalarial. However, mixtures of total Cinchona alkaloids, even though low in quinine content, are acceptable antimalarial agents. This mixture, termed totaquine, has served as a substitute for quinine during shortages. Quinine-related alkaloids, especially quinidine, are also found in the bark of Remija pendunculata (Rubiaceae). 

Malaria is one of the most prevalent diseases in the world. Although there are numerous drugs on the market for both the treatment and prevention of the disease, multiple drug resistance by parasites is now ubiquitous in all parts of the world where malaria is endemic.55 Therefore, there is an increasing need for the development of new antimalarial drugs, especially ones that possess novel modes of action. The antimalarial properties of nonalkaloidal compounds such as artemisinin (54) and yingzhaosu A (55) have attracted considerable attention because of the limited availability of the natural product by extraction from the Chinese Artemisia annua plant.56 58... 

Attention continues to be focused on 1,2,4-trioxanes because of their antimalarial properties, with much of the work being devoted to interconversions within the artemisinins. 

In common with many other tropical and subtropical plant extracts used locally for their alleged antimalarial properties, the reputation of... 

Little of value has come out of pharmacological studies on these alkaloids (34) local anesthetic properties (35) have been reported, and none of the alkaloids have shown antimalarial properties (36). 

An enantioselective aryloxylation of aldehydes is based on their prior conversion to an enamine through reaction with a chiral secondary amine catalyst. A subsequent inverse HDA reaction with o-quinones leads to 3-alkyl-2-hydroxy-l,4-benzodioxins with ee ca. 80% (Scheme 47). Manipulation allows the synthesis of (S)-2-alkyl-2,3-dihydro-l,4-benzodioxins <07TL1605>. In like manner, racemic nitidanin, which possesses antimalarial properties, has been synthesised through a regioselective cycloaddition of an o-quinone with a protected 3-arylpropen-l-ol <07TL771>. 

The antimalarial properties of the traditional Chinese medicine, Quinghaosu (artemisinin)... 

Aromoline was screened for in vitro antimalarial properties using a multi-drug resistant (Kl) strain of Plasmodium falciparum. The screen detected the inhibition of incorporation of [3H]-hypoxanthine into P. falciparum, and aromoline was characterized by IC 0.67 pg/ml (with 95% confidence intervals of 0.53 - 0.85). The standard antimalarial drug chloroquine diphosphate exhibits IC 0.14 pg/ml (with 95% confidence intervals of 0.12 - 0.16)[177]. 

Maytenus senegalensis (Lam.) Excell, [sibhubhu, red spike thorn] (Celastraceae) stem bark decoction is taken by women for iirfertility. The stem bark contains flavonoids, polyphenols, steroids and tarmins (15). Leaves of the plant are also nsed for treating nansea (11). The plant also has antidiabetic and antimalarial properties (41,42). 

This review has shown that many plants from Africa and other continents have been reported to be used to treat malaria in traditional medicine. Modem in vitro screens against the P. falciparum has confirmed the antimalarial properties for many of these plants and their extracts and clearly given the magnitude of the problem and the national costs due to malaria illness, death and suffering, the use of medicinal plants either in traditional manners and/or as leads for new compounds that may serve in the future for new anti-malarial drags presents scientific opportunities. 

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