Antimalarial lead compounds

ANTIMALARIAL LEAD COMPOUNDS FROM MARINE ORGANISMS... 

Under conditions of in vitro testing, compounds which inhibit the growth and survival of a variety of cell types can legitimately be called "antiplasmodial" however, the meaning of the term is obscured due to the promiscuous nature of the toxicity. The inclusion of a selectivity parameter along with "antimalarial" data rejxrrted in the literature, is suggested here to facilitate a more qualitative evaluation of compounds with genuine potential as antimalarial lead compounds. 

The ten membered N-heterocycles have also attracted a lot of interest due to their structural appearance with various biologically interesting molecules like the alkaloid Dysazecine (Aladesanmi et al., 1983), Protopine (Xiao et al., 2008) (a potent antimalarial lead compound) as well as the nanomolar dopamine receptor antagonist LE300 (Mohr et al., 2006). Dunkel et al. (2010) reported a straight forward, microwave-assisted synthesis of tribenzo[b,d,f]- and pyridazino[d]dibenzo[b,f] azecines, employing the tert-amino effect. The desired compounds were furnished via an open-vessel microwave-assisted cyclization of corresponding triphenyl intermediates at 100-200 °C for 2-150 min. 

Natural sources are still important sources of lead compounds and new drugs. However, the large diversity of potential natural sources in the world makes the technique of random screening a rather hit or miss process. The screening of local folk remedies (ethnopharmacology) offers the basis of a more systematic approach. In the past this has led to the discovery of many important therapeutic agents, for example, the antimalarial quinine from cinchona bark, the... 

We believe there is a need for a new approach to foster intergroup collaboration to speed up drug discovery. The impact of accelerating the identification and advancement of promising anti-malarial and Mtb lead compounds through the efforts of a collaborative network of top antimalarial and Mtb or other neglected disease researchers, very simply, can be measured in terms of the potential number of lives saved. Malaria infects ca. 200 million people and causes over 1 million deaths per year, disproportionately claiming African children under the age of 5 years. Similarly Mtb kills over 1 million people per year. 

A lead compound bearing a ferrocenyl moiety at position N(l) was identified. This derivative is more active than Ciprofloxacin and Doxycycline. The activity is remarkably constant regardless of the level of resistance to CQ of the strains. Contrary to other antibiotics, no delayed-death effect was noted. Isobologram analysis showed that this compound exerts an antagonist effect with the main quinoline-containing antimalarials. In vitro results have to be confirmed in vivo to check the bioavailability of the molecule and its potential interest as a new antimalarial [113],... 

The presence of the ferrocene moiety within the lateral chain of CQ is the main condition required to retain a strong antimalarial activity on CQ-resistant P. falciparum. FQ was rapidly identified as a lead compound with sufficiently potent in vitro and in vivo activities to meet candidate nomination requirements. 

However, in this section, the total synthesis of yingzhaosu A, the lead compound of a particular class of antimalarial 1,2-dioxocins, is reported. The synthesis involves eight steps and a 7.3% overall yield starting from (A)-limonene (Scheme 64). Besides the TOCO procedure that allowed the formation of five bonds in one step, the most intriguing steps involved the selective hydrogenation of a C-C double bond in the presence of a peroxide and an aldehyde functionalities (step vi) and the stereoselective reduction of the side-chain carbonyl with (R)-CBS catalyst (step viii). Last but not least, the old classical fractional recrystallization allowed the separation of yingzhaosu A from its C-14 epimer and saved two synthetic steps <2005JOC3618>. 

The uncommon structural artemisinin framework, and the well-known difficulty in selectively introducing a fluorinated motif into a molecule, faced us with numerous chemical challenges. The evaluation of the effects of fluorine on physicochemical and antima-larial properties is reported. These data and preclinical data of lead compounds are encouraging, with strong and prolonged antimalarial activity of fluoro-artemisinins. 

Synthetic antimalarials developed fiom herbals include chloroquine, primaquine, proguanil, pyrimethamine and mefloquine. Botanicals represent a diverse arsenal of molecules that could constitute lead compounds for new antimalarial dmgs, such as artemisinin, isolated from Artemisia annuaSeveral studies have been undertaken to evaluate the inhibitory effects of various plants extracts on P. falciparum in culture. The in vivo antiplasmodial effects of several plant extracts have been studied on Plasmodium berghei and P. yoelii The majority of the plants that we screened for antimalarial activities had similar ethnopharmacological use among different Kenyan ethnic groups. ... 

The study of natural products, or Nature s Combinatorial Library , has had a long history as a source of drugs, and plants have historically been at the forefront of natural product drug discovery. In the anticancer area, for example, vinblastine and vincristine, etoposide, paclitaxel (Taxol), docetaxel, topotecan, and irinotecan, among others, are all plant-derived natural products or modified versions of plant compounds, while antimalarial therapy would be much poorer without quinine and artemisinin and the drugs derived from these plant products. This chapter provides an overview of the major medicinal agents that are themselves natural products isolated from plants or are chemical modifications of such lead compounds. It covers the therapeutic areas of cancer, HIV, malaria, cardiovascular, and central nervous system (CNS) diseases. Natural plant products have also made contributions in areas such as immunomodulatory and antibiotic activities," and the reader is referred to the cited reviews for information on these areas. 

Keough, D. T., Skinner-Adams, T., Jones, M. K., Ng, A. L., Brereton, I. M., Guddat, L. W., and de Jersey, J. (2006). Lead compounds for antimalarial chemotherapy purine base analogs discriminate between human and P. falciparum 6-oxopurine phosphoribosyltransferases. J. Med. Chem. 49, 7479-7486. 

Remijia purdieana (Rubiaceae), but is devoid of antimalarial activity. Thus, the 5-vinyl-2-quinuclidyl group is not necessary for antimalarial activity. Quinine has been the lead compound for the development of a large number of antimalarial compounds. 

ABSTRACT A series of about 70 secondary metabolites produced by marine organisms have been grouped into three structural types and discussed in terms of their reported antimalarial activities. The major groups of metabolites include isonitrile derivatives, alkaloids and cycloperoxide derivatives. Structure-activity relationships and, when applicable, mechanisms of action of the isolated molecules, have been discussed. The following discussion evidences that antimalarial marine molecules can efficiently integrate the panel of lead compounds isolated from terrestrial sources with new chemical backbones and, sometimes, with typically marine functional groups (as isonitriles). 

After preliminary disclosure of promising antimalarial leads, there is an ongoing requirement for the evaluation of selectivity in more advanced phases of the development process. By monitoring the effects of natural and chemical derivatization of lead compounds upon potency and selectivity in an in vitro bioassay system such as that described here, the safest and most effective candidates can be promoted for further study in in vivo models. 

The SI value that is used as a cut-off parameter for prioritizing those samples that possess the most potent and selective antimalarial activity is somewhat subjective due to the nature of the work involved. In the preliminary stages of the work, a cutoff is established such that the volume of samples that are subjected to bioassay-directed fractionation and further analysis is limited to a practical number. Ideally, the SI cut-off should be as high as possible and in our laboratory it is presently around 100 however, we are limited by the activities of the samples at hand. It is also meaningful to consider that if the cut-off is set too high, many potentially important lead compounds may be discarded for the sake of pursuing the ideal drug. 

In addition, we have not intended that the selectivity index be the only criterion applied in the decision to subject pure compounds with significant antimalarial activity to further study. The discovery of compounds of novel structure possessing potent antimalarial activity but with relatively low (i.e., <100) SI values, such may represent lead compounds which could be synthetically modified to yield drugs with higher selectivity, and may also provide valuable insight into potential mechanisms of antimalarial action or structure-activity relationships, and thus, such compounds may also be included in mechanistic studies to a limited extent. 

This topic will be only briefly highlighted here as synthetic biology (SB) is the topic of the previous chapter (Chapter 14) in this edition. Amyris and Sanofi have commercialised a semi-synthetic artemisinic acid process to enable the cost-effective production of artemisinin, a key API for antimalarial combination therapies, by inserting the artemisininic acid pathway into S. cerevisiae For discovery research, SB is starting to provide exciting new pathways into unique and novel secondary metabolites as possible new drugs or lead compounds for semi-synthetics. Walker et al. have demonstrated the ability of two polyketide synthase systems to accept fluoroacetate in place of acetate leading to the production of a number of novel... 

Artemisia annua and (—)-o -bisabolol from Matricaria recutita (German chamomile). Addition of IPP to GPP produces 2 , 6 -famesylpyropho-sphate (FPP), the precursor for all sesquiterpenes. Farnesylpyrophosphate can cyclize by various cyclase enzymes in various ways, leading to the production of a variety of sesquiterpenes. Some of these sesquiterpenes are medicinally important hioactive compounds. For example, (—)-o -bisabolol and its derivatives have potent anti-inflammatory and spasmolytic properties, and artemisinin is an antimalarial drug. 

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