Antiplasmodial, anti-trypanosomal, anti-leishmanial and cytotoxicity activity of selected Tanzanian medicinal plants.

The antiplasmodial, anti-trypanosomal and anti-leishmanial activity of 25 plant extracts obtained from seven Tanzanian medicinal plants: Annickia (Enantia) kummeriae (Annonaceae), Artemisia annua (Asteraceae), Pseudospondias microcarpa (Anacardiaceae), Drypetes natalensis (Euphorbiaceae), Acridocarpus chloropterus (Malpighiaceae), Maytenus senegalensis (Celastraceae) and Neurautanenia mitis (Papilonaceae), were evaluated in vitro against Plasmodium falciparum K1, Trypanosoma brucei rhodesiense STIB 900 and axenic Leishmania donovani MHOM-ET-67/82. Out of the 25 extracts tested, 17 showed good antiplasmodial activity (IC50 0.04-5.0 microg/ml), 7 exhibited moderate anti-trypanosomal activity (IC50 2.3-2.8 microg/ml), while 5 displayed mild anti-leishmanial activity (IC50 8.8-9.79 microg/ml). A. kummeriae, A. annua, P. microcarpa, D. natalensis, M. senegalensis and N. mitis extracts had good antiplasmodial activity (IC50 0.04-2.1 microg/ml) and selectivity indices (29.2-2,250 microg/ml). The high antiplasmodial, moderate anti-trypanosomal and mild anti-leishmanial activity make these plants good candidates for bioassay-guided isolation of anti-protozoal compounds which could serve as new lead structures for drug development.

Use of a pharmacophore model for the design of EGFR tyrosine kinase inhibitors: isoflavones and 3-phenyl-4(1H)-quinolones.

Using a pharmacophore model for ATP-competitive inhibitors interacting with the active site of the EGFR protein tyrosine kinase together with published X-ray crystal data of quercetin (2) in complex with the Hck tyrosine kinase and of deschloroflavopiridol (3b) in complex with CDK2, a putative binding mode of the isoflavone genistein (1) was proposed. Then, based on literature data suggesting that a salicylic acid function, which is represented by the 5-hydroxy-4-keto motif in 1, could serve as a pharmacophore replacement of a pyrimidine ring, superposition of 1 onto the potent EGFR tyrosine kinase inhibitor 4-(3'-chlorophenylamino)-6, 7-dimethoxyquinazoline (4) led to 3'-chloro-5,7-dihydroxyisoflavone (6) as a target structure which in fact was 10 times more potent than 1. The putative binding mode of 6 suggests a sulfur-aromatic interaction of the m-chlorophenyl moiety with Cys 773 in the "sugar pocket" of the EGFR kinase model. Replacement of the oxygen in the chromenone ring of 6 by a nitrogen atom further improved the inhibitory activity against the EGFR kinase. With IC50 values of 38 and 8 nM, respectively, the quinolones 11 and 12 were the most potent compounds of the series. N-Alkylation of 11 did not further improve enzyme inhibitory activity but led to derivatives with cellular activity in the lower micromolar range.

Novel quinone methides from Salacia kraussii with in vitro antimalarial activity.

Three novel quinone methides, i.e., 28-nor-isoiguesterin-17-carbaldehyde (1), 17-(methoxycarbonyl)-28-nor-isoiguesterin (2), and 28-hydroxyisoiguesterin (3), together with the known celastrol (5), pristimerin (6), and isoiguesterol (7), were isolated from the roots of Salacia kraussii (Celastraceae) by bioassay-guided fractionation. The structures of the compounds were determined by DEPT and 2D NMR techniques. The isolates showed antimalarial activity 30-50-fold greater than their cytotoxicity (in HT-29 cells) in vitro, and they showed an additive effect when combined with each other. In vivo, 2 was found to be inactive against blood stages of Plasmodium berghei in mice after oral and parenteral administration, and the compound was toxic with increasing concentrations.

Total synthesis and biological activities of (+)- and (-)-boscialin and their 1'-epimers.

Natural (-)-boscialin [(-)-1] has recently been described as one of the constituents of various medicinal plants. To obtain more material for investigations of its biological activities, we carried out the synthesis of (-)-1 and its isomers. Starting from the chiral building block 2, the key steps of the synthesis involved a regioselective reduction and a nucleophilic addition. The enantiomer of the natural product, (+)-boscialin [(+)-1], could be obtained via acid-catalyzed epimerization of hydroxyketone 4 to (+)-3. Starting the synthesis with (-)-3 led to (-)-boscialin [(-)-1] with the natural absolute configuration. In addition to (+)- and (-)-boscialin, the corresponding 1'-epimers (+)- and (-)-epiboscialin were also obtained. In vitro assays with (-)-boscialin [(-)-1] and its three stereoisomers were carried out to test for activity against microbes, parasites, and human fibroblasts. The investigations revealed activity against various microbes and against Trypanosoma brucei rhodesiense and also revealed cytotoxicity against human cancer cells.

New butenolides from the photoconductivity screening of Streptomyces antibioticus (Waksman and Woodruff) Waksman and Henrici 1948.

Streptomyces antibioticus strain TU 99, from which a wide variety of active compounds had been isolated previously, was reinvestigated using an HPLC photoconductivity screening system. Four new compounds were isolated, characterized and their constitutions determined. All four were alpha, beta-unsaturated gamma-lactones; the most abundant compound 3 (C10H16O4), as well as compound 1 (C9H14O4) had a hydroxy group at C(5) of the lactone ring. The four lactones showed antibiotic activity against Pseudomonas aeruginosa and also a weak inhibition of the chitinase from Serratia marcescens.

Constituents of Bidens pilosa L.: do the components found so far explain the use of this plant in traditional medicine?

The dried aerial parts of Bidens pilosa L. were extracted with petrol ether, chloroform, methanol, and methanol/water. The petrol ether and the methanol/water extracts showed some antimicrobial activity. Fractionation of the extracts yielded well known substances, most of which have, however, not yet been described as constituents of Bidens pilosa. Several of these substances have previously been shown to be biologically active. Thus, phenylheptatriyne, linolic acid and linolenic acid have antimicrobial activities. On the other hand, friedelin and friedelan-3 beta-ol, as well as several of the flavonoids found are anti-inflammatory agents. The detection of these compounds in extracts from B. pilosa may rationalize the use of this plant in traditional medicine in the treatment of wounds, against inflammations and against bacterial infections of the gastrointestinal tract.

The photodeactivation of hedamycin, an antitumor antibiotic of the pluramycin type.

The cytotoxicities of hedamycin and photohedamycin A as well as of kidamycin and isokidamycin were determined using HeLa cell cultures. Photohedamycin A proved to be 15 times less cytotoxic than hedamycin thus explaining the loss of biological activity observed for solutions of hedamycin left in daylight. The fact that photohedamycin A is less active than hedamycin, and isokidamycin less than kidamycin points to the important role the rings E and F play in the biological activity of hedamycin and kidamycin.

How to view stereoscopic pictures of crystal structures and molecular models.

Methods are presented for practicing the viewing of stereoscopic pictures of crystal structures and molecular models without optical aids.