No description available.

The in vitro antimalarial activity of clofazimine and seven of its analogues, all TMP(tetramethyl-piperidyl group)-derivatives except 8669, against the R8-1 and pfUP-1 laboratory strains of Plasmodium falciparum was investigated using a flow cytometric procedure. The flow cytometric method was compared with microscopy and radiometry for efficiency in quantitating the level of parasitemia in malaria cultures. The flow cytometric method compared well, as determined by the 81and and Altman measure of agreement, with both microscopy and radiometry and was chosen for use in this study due to its speed, precision and convenience (includes a fixing step that allows samples to be evaluated at anyone time). The riminophenazine agents were found to exhibit antimalarial action of varying degrees: B669, B4100, B4103, B4112 and B4158 showed the best activity followed by B4121 and B4169. Clofazimine did not exhibit any activity at concentrations up to 2µg/ml in this system. Their effective concentrations in vitro were comparable to that of standard antimalarial agents such as chloroquine. The agents B4103 and B4112 exhibited additive antimalarial activities when combined with chloroquine. The inclusion of the TMP group and extent of halogenation of six of the riminophenazines tested indicate that it is these structural properties which are the major determinants of the antiplasmodial activity. This is the first study to establish an antiplasmodial activity of riminophenazines and further tests are necessary to establish their antiparasitic mode of action and therapeutic potential in animal models of experimental chemotherapy. / Dissertation (MSc)--University of Pretoria, 2010. / Pharmacology / unrestricted

Relief of the global malaria burden relies on the management and application of effective therapies. Unfortunately, the continuous development of resistance to therapies by the deadliest parasite strain, Plasmodium falciparum, has made the treatment and control of malaria much more difficult. Derivatives of the Chinese peroxidic antimalarial drug artemisinin primarily used in first-line combination therapy for treatment of P. falciparum malaria have proved to be highly effective. However, their use also is now compromised by the development of resistance by the parasite to the artemisinin derivative in the drug combination. This event emphasizes the need for ongoing development of new and effective drug combinations. This research aimed to identify efficacious combinations selected from a group of compounds known to induce oxidative stress by redox cycling combined with an artemisinin, which as an oxidant drug also induces oxidative stress but is unable to undergo redox cycling. Combination of the artemisinin with a redox-active compound is expected to both enhance and maintain oxidative stress within the parasite's proliferative environment. These combinations should be used together with a third drug with a completely different mode of action, such as a quinolone. Selected amino artemisinins and redox active phenothiazines, phenoxazines, thiosemicarbazones, and quinolone derivatives were screened for antimalarial activity and mammalian toxicity. These were found to be potently active (11 μM) to Chinese Hamster ovarian (CHO) cells. The compounds are thus highly selective for P. falciparum, as revealed by the selectivity indices (SI) of >270. The in vitro absorption, distribution, metabolism, and elimination (ADME) properties of the compounds were also determined through the application of specific assays. In vivo pharmacokinetic (PK) profiling was also carried out by intravenous and oral administration of the individual compounds to healthy C57BL/6 mice. Biological samples were analysed via liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical methods, which were validated according to the fit-for purpose recommendations by the FDA. Evaluation of the in vitro and in vivo profiles thereby facilitated the identification of suitable combination candidates. The phenoxazine and phenothiazine derivatives were identified as the best potential redox partners and were each investigated in combination with the amino-artemisinin artemisone through fixed ratio isobole analysis. A substantial synergistic interaction was observed. Overall, the investigation enabled the identification of drug combinations that are potently active in vitro. This synergistic interaction strongly supports the redox cycling rationale for identifying new antimalarial therapies and further suggests that such combinations in chemotherapy may delay the onset of resistance to the new agents. The results strongly encourage further investigation of the in vivo pharmacokinetic and pharmacodynamic (PK/PD) relationships of these combinations in the humanized murine model of P. falciparum

No description available.

no / New antimalarial drugs are urgently needed to combat emerging multidrug resistant strains of malaria parasites. This Highlight focuses on plant-derived natural products that are of interest as potential leads towards new antimalarial drugs including synthetic analogues of natural compounds, with the exception of artemisinin derivatives, which are not included due to limited space. Since effective antimalarial treatment is often unavailable or unaffordable to many of those who need it, there is increasing interest in the development of locally produced herbal medicines; recent progress in this area will also be reviewed in this Highlight.

The Kingston group's engagement in an International Cooperative Biodiversity Group (ICBG) program and a collaborative research project established between Virginia Tech and the Institute for Hepatitis and Virus Research (IHVR) has focused on the search for bioactive natural products from tropical forests in both Madagascar and South Africa. As a part of this research, a total of four antiproliferative extracts were studied, leading to the isolation of fourteen novel compounds with antiproliferative activity against the A2780 human ovarian cancer line. One extract with antimalarial activity was studied, which led to the isolation of two new natural products with antiplasmodial activity against a drug-resistant Dd2 strain of Plasmodium falciparum. The plants and their secondary metabolites are discussed in the following order: two new antiproliferative acetogenins from a Uvaria sp. (Annonaceae); two new antiproliferative calamenene-type sesquiterpenoids from Sterculia tavia (Malvaceae); two new antiproliferative triterpene saponins from Nematostylis anthophylla (Rubiaceae); six new antiproliferative homoisoflavonoids and two new bufatrienolides from Urginea depressa (Asparagaceae); and two new antiplasmodial anthraquinones from Kniphofia ensifolia (Asphodelaceae). The structures of all these compounds were determined by analysis of their mass spectrometric, 1D and 2D NMR, UV and IR spectroscopic and optical rotation data. Other than structural elucidation, this work also involved bioactivity evaluations of all the isolates, as well as total synthesis of the two antiproliferative sesquiterpenoids, and a structure-activity relationship (SAR) studies on the antiplasmodial anthroquinones. / Ph. D.

Ces travaux de thèse décrivent la synthèse d'une série de dérivés du noyau 7-chloroquinoléine substitués en position 4. Ces nouveaux composés résultent de l’introduction de motifs thio- et amino-alcool, suivie d’une réaction de couplage avec des acides benzoïques ou des indanones diversement substitués. Les composés soufrés ont également fait l’objet d’oxydation en sulfones. Cent sept (107) dérivés de la 7-chloroquinoléine ont ainsi été synthétisés, puis soigneusement purifiés et complètement caractérisés en vue de leur évaluation biologique en tant qu’agents cytotoxiques-antitumoraux et antimalariques. Parmi les principaux résultats : i) plus le degré d’oxydation du soufre est élevé, plus l’effet cytotoxique est important, ii) la longueur de la chaîne alkyle et la nature des substituants ont aussi leur importance, et iii)aucune amélioration de l’activité antimalarique n’a été observée avec le bioisostérisme classique basé sur le remplacement de l’azote par le soufre en position 4 du noyau quinoléinique. / This thesis work describes the chemical synthesis of a series of 7-chloroquinoline derivatives substituted at their position 4. These newcompounds resulted from the introduction of thio- and amino-alcohol motifs,followed by a coupling reaction with diversely substituted benzoic acidsorindanones. The sulfur-containing compounds were also oxidized intosulfones. One hundred seven (107) compounds were thus synthesized, andthen carefully purified and fully characterized in the aim of their biologicalevaluation as cytotoxic-antitumoral and antimalarial agents. Among the mainresults: i) the greater the oxidation state of sulfur, the greater the cytotoxic effecton the cell lines studied, ii) the lenght of the alkyl chain and the substitutionpattern are of importance, and iii) no improvement of the antimalarial activitywas observed with classical bioisosterism based on replacement of nitrogen bysulfur in position 4 of the quinolinic ring.

Malaria still remains one of the world’s biggest killers with more than two million people dying from the disease each year. Present drugs have become ineffective because parasites are developing resistance to most of them. Efforts are now being directed in obtaining drugs with different structural features. Plants have provided most of the antimalarial drugs so far and efforts now concentrate on screening plants for new antimalarial drugs. South Africa with its rich floral resources and ethnobotanical history is an ideal place to screen plants for antimalarial activity. The antimalarial activity of 20 extracts from 14 ethnobotanically selected South African plants was screened for antimalarial activity in vitro. Results obtained showed that most of the plants had strong antimalarial activity. IC50 values obtained with the flow cytometric method were between 0.9 and 2 µg/ml for 9 of the 10 selected extracts. This represents a very high number of extracts with very good antimalarial activity. Cytotoxicity of the most active extracts were determined against monkey kidney cells as well as a luminescent bacteria method. Results obtained had a ID50 between 35 and 100 µg/ml with the monkey kidney cell test and between 100 and 2000 µg/ml with the bacteria test. Therapeutic values ranged between 35 and 100. Extracts therefore have a poor selectivity towards Plasmodium. The dichloromethane extract from Ozoroa engleri was further purified with silica gel column chromatography, Sephadex column chromatography and HPLC. Results obtained showed at least five or six compounds responsible for the antimalarial activity of the extract, all with moderate antimalarial activity and no further efforts were undertaken to identify them. The acetone extract of Croton pseudopulchellus was then selected for isolation of active principles and was purified by silica gel column chromatography, Sephadex column chromatography and PTLC. Kaurenoic acid was isolated as one of the active principles and identified by NMR and GC-MS. Kaurenoic acid was found to have an antimalarial IC50 of 38 µg/ml, while its cytotoxicity ID50 was 35 µg/ml. Kaurenoic acid was responsible for only some of the activity found in the purified fraction and other compound(s) in the extract might have much better antimalarial activity. / Dissertation (MSc (Plant Physiology))--University of Pretoria, 2008. / Plant Science / unrestricted

Artemisinin is produced in the leaves of Artemisia annua and is currently one of the most valuable antimalarial treatments. A. annua is of Asian origin but many other family members have been identified worldwide. A. annua however, is the only one that produces artemisinin. Synthetic production of artemisinin is not yet feasible, not to mention very expensive and the product yields are relatively low. The aims of this study were threefold: 1) To regenerate callus, cell cultures and plants from genetically modified root cultures of A. afra into which an artemisinin biosynthetic gene was inserted from A. annua 2) To investigate the probability that fungal endophytes are responsible for the production of artemisinin and 3) To establish two fields of high yielding varieties of A. annua plants and evaluate whether artemisinin production of these two locations will remain high. Callus and cell cultures of the genetically modified A. afra root cultures were established, but no shoots have been produced as of yet and this is an on-going investigation. Fungal endophytes were sampled and none of the endophytes produced artemisinin. Five different lines of A. annua were cultivated, successfully grown and harvested. Measurements were taken at different stages of processing, these were compared and analysed using various methods such as height and mass comparisons. Comparisons revealed that the production of artemisinin is correlated to local sets of conditions rather than the variety of individual lines. The genetic potential to produce high quantities of artemisinin appears to have been lost, instead of being maintained. We confirmed that secondary compound production and specifically, artemisinin, is enhanced by certain stress factors on the plants. / Dissertation (MSc)--University of Pretoria, 2013. / gm2014 / Plant Science / unrestricted

no / Cryptolepine, a naturally occurring indoloquinoline alkaloid used as an antimalarial drug in Central and Western Africa, has been found to bind to DNA in a formerly unknown intercalation mode. Evidence from competition dialysis assays demonstrates that cryptolepine is able to bind CG-rich sequences containing nonalternating CC sites. Here we show that cryptolepine interacts with the CC sites of the DNA fragment d(CCTAGG)2 in a base-stacking intercalation mode.