Antigiardial activity of isoflavones from Dalbergia frutescens bark.

Several isoflavones [formononetin (1), castanin (5), odoratin (6), glycitein (7), pseudobaptogenin (8), fujikinetin (9), and cuneatin (10)] were isolated from Dalbergia frutescens, and their antiprotozoal activities were determined against Giardia intestinalis. Among these compounds, formononetin (1) was the most potent antigiardial agent, with an IC(50) value of 30 ng/mL (approximately 0.1 microM), as compared to the value for metronidazole, the current drug of choice, of 100 ng/mL (approximately 0.6 microM). Three isoflavones closely related to formononetin [daidzein (2), biochanin A (3) and genistein (4)] were also evaluated, but they were at least 100 times less active than 1. Formononetin (1) may thus be an interesting lead for development of new antigiardial agents or as a probe for a new mechanistic target.

Synthesis and biological activity of new potential antimalarial: 1H-pyrazolo[3,4-b]pyridine derivatives.

The appearance of drug resistant Plasmodium falciparum malaria necessitates the search for novel antimalarial agents. Using the classical ring-bioisosterism concept as a strategy to develop new potential drugs, 1H-pyrazolo[3,4-b]pyridine 4-aminomethanol compounds were designed and synthesized as isosteres of the classical quinoline antimalarial mefloquine. The hydrochloride form of these compounds were tested for in vitro antimalarial activity against chloroquine-sensitive (Sierra Leone D-6) and resistant (Indochina W-2) clones of P. falciparum. The results described herein indicated that 1-H-pyrazolo[3,4-b]pyridine system represents a bioisosteric framework to quinoline system in the antimalarial activity.

Structure-activity relationships of the antimalarial agent artemisinin. 4. Effect of substitution at C-3.

Novel antimalarial artemisinin analogs, 3-alkylartemisinins as well as 3-(arylalkyl)- and 3-(carboxyalkyl)artemisinins, were prepared via the synthetic intermediate 2. Formation of the N,N-dimethylhydrazones 5 and 24 and then regio- and chemoselective deprotonation followed by alkylation provided initially alkylated hydrazones that upon chromatography gave ketones 6-13 and 25-30. Direct ozonolysis of the ketones followed by in situ acidification lead directly to the formation of title compounds 14-21 and 31-36. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found to be in some cases much more active than the natural product (+)-artemisinin. The results were included in structure-activity relationship (CoMFA) studies for further analog design.

Structure-activity relationships of the antimalarial agent artemisinin. 3. Total synthesis of (+)-13-carbaartemisinin and related tetra- and tricyclic structures.

Provided by total synthesis, endoperoxides 18, 20, and 22 underwent intramolecular oxymercuration-demercuration leading respectively to formation of an isomeric tetracycle, (1aS, 3S, 5aS, 6R, 8aS, 9R, 12S)-10-deoxo-13-carbaartemisinin (19), (+)-10-deoxo-13-carbaartemisinin (21), and (+)-13-carbaartemisinin (4). Structure assignment to 19 and 21 was based on single-crystal X-ray crystallographic analysis. Tricyclic endoperoxide 20 was converted to methyl and benzyl ethers 23 and 24 and reduced to saturated analog 25 which was also converted to ethers 26 and 27. In vitro antimalarial screening of both tri- and tetracyclic analogs was conducted using the W-2 and D-6 clones of Plasmodium falciparum. Neither target 4 nor 21 displayed substantial antimalarial potency in vitro against P. falciparum, but the diastereomeric peroxide 19 possessed good antimalarial potency in vitro. Tricyclic analogs were uniformly impotent. Iron(II) bromide-promoted rearrangement of 21 gave, in 79% yield, the unique tetracyclic alcohol 35, while 19 provided ring-opened cyclohexanone 41 (39%) along with the tricyclic epoxide 42 (20%). Neither 41 nor 42 possessed in vitro antimalarial activity, suggesting that epoxide-like intermediates are not responsible for the mode of action of this subclass of antimalarials. Rearrangement of 10-deoxoartemisinin (43) with FeBr2 gave a major product (79%) not encountered in the rearrangement of artemisinin that resulted from unraveling of the tetracyclic system cyclohexanone 46. Minor amounts of 1,10-dideoxoartemisinin (49) (8%) were also produced in this reaction.

A new quassinoid from Castela texana.

A new quassinoid, 11-O-trans-p-coumaroyl amarolide (1) was isolated from Castela texana, and the structure was elucidated by spectroscopic analysis. Compound 1 is the first coumaroyl quassinoid derivative to have been isolated from nature. The known compounds amarolide (2), chaparrinone, chaparrin, glaucarubolone, holacanthone, and 15-O-beta-D-glucopyranosyl glaucarubol were also isolated. All isolated compounds were tested for their cytotoxicity and antiprotozoal activities.

Structure-activity relationships of the antimalarial agent artemisinin. 2. Effect of heteroatom substitution at O-11: synthesis and bioassay of N-alkyl-11-aza-9-desmethylartemisinins.

A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found in some cases to be more active than artemisinin. A comparison of the in vitro testing methods of Milhous and Makler was conducted and gave similar relative antimalarial activities for these artemisinin analogs. Log P values were determined for most of the compounds, but no apparent correlation between log P and in vitro activity was found.