John B. Bremner

Synthèses à l'aide de sulfones (XXIV) Synthèse stéréosélective d'oléfines par hydrogénolyse des vinylsulfones.

Abstract The now readily available E or Z vinylsulphones can be reduced stereospecifically to the corresponding olefins with sodium dithionite.

Identification of volatile compounds released by roots of an invasive plant, bitou bush (Chrysanthemoides monilifera spp. rotundata), and their inhibition of native seedling growth

Allelopathy has been suggested as a mechanism promoting the monoculture formation of some invasive exotic plants. Previous studies have shown that hydrophobic extracts of the roots and soil of exotic bitou bush (Chrysanthemoides monilifera spp. rotundata (DC.) T. Norl.) inhibited the seedling growth of five Australian native plants, including the dominant acacia (Acacia longifolia var. sophorae (Labill.) F. Muell.). Based on this finding, we compared the hydrophobic root and soil chemical profiles of bitou bush and acacia to determine whether bitou bush roots release allelopathic compounds that are novel to the invaded system. We detected three compounds that were exclusive to the bitou bush root and soil, and seven compounds that were common to the bitou bush and acacia roots but only present in the bitou bush soil. The compounds unique to the bitou bush invaded soil were all sesqui- and diterpenes. Several of these compounds were found to inhibit the seedling growth of a native sedge, Isolepis nodosa (Rott.) R. Br. Of particular interest are the sesquiterpenes: β-maaliene, α-isocomene, β-isocomene, δ-cadinene, 5-hydroxycalamenene and 5-methoxycalamenene which were found in high concentrations in the bitou bush root and soil extracts and exhibited phytotoxic activity. Therefore, we present evidence to suggest that bitou bush exudes low molecular weight volatile compounds into the soil which inhibit native plant seedling growth. The reduced establishment of native plants via allelopathy is likely to create space and contribute to the invasion of bitou bush on the eastern Australian coast.

Antibacterial activity of berberine-NorA pump inhibitor hybrids with a methylene ether linking group

Conjugation of the NorA substrate berberine and the NorA inhibitor 5-nitro-2-phenyl-1H-indole via a methylene ether linking group gave the 13-substituted berberine-NorA inhibitor hybrid, 3. A series of simpler arylmethyl ether hybrid structures were also synthesized. The hybrid 3 showed excellent antibacterial activity (MIC Staphylococcus aureus, 1.7 microM), which was over 382-fold more active than the parent antibacterial berberine, against this bacterium. This compound was also shown to block the NorA efflux pump in S. aureus.

Ligand design for α1 adrenoceptor subtype selective antagonists

Abstract α1 Adrenoceptors have three subtypes and drugs interacting selectively with these subtypes could be useful in the treatment of a variety of diseases. In order to gain an insight into the structural principles governing subtype selectivity, ligand based drug design (pharmacophore development) methods have been used to design a novel 1,2,3-thiadiazole ring d analogue of the aporphine system. Synthesis and testing of this compound as a ligand on cloned and expressed human α1 adrenoceptors is described. Low binding affinity was found, possibly due to an unfavourable electrostatic potential distribution. Pharmacophore models for antagonists at the three adrenoceptor sites (α1A, α1B, α1D) were generated from a number of different training sets and their value for the design of new selective antagonists discussed. The first preliminary antagonist pharmacophore model for the α1D adrenoceptor subtype is also reported.

Initial Studies on Alkaloids from Lombok Medicinal Plants

Initial investigation of medicinal plants from Lombok has resulted in the collection of 100 plant species predicted to have antimicrobial, including antimalarial, properties according to local medicinal uses. These plants represent 49 families and 80 genera; 23% of the plants tested positively for alkaloids. Among the plants testing positive, five have been selected for further investigation involving structure elucidation and antimicrobial testing on the extracted alkaloids. Initial work on structural elucidation of some of the alkaloids is reported briefly.

Indole derivatives from the egg masses of Muricid molluscs

A range of brominated indole derivatives were found in the egg masses of six species of muricid molluscs. Several non-brominated indoles were also present in the eggs of two Mediterranean Muricidae, although these were not found in the Australian species. Tyrindoleninone (3), was the only compound found in all six species and is likely to be responsible for the observed antimicrobial activity of these muricid egg masses [1,2]. These bioactive indoles appear to be characteristic of muricid egg masses and were not found in the egg masses from 17 species in different families of marine molluscs.

N-Phenethyl and N-naphthylmethyl isatins and analogues as in vitro cytotoxic agents

A range of N-phenethyl, N-phenacyl, and N-(1- and 2-naphthylmethyl) derivatives of 5,7-dibromoisatin 2 were prepared by N-alkylation reactions. Their activity against human monocyte-like histiocytic lymphoma (U937), leukemia (Jurkat), and breast carcinoma (MDA-MB-231) cell lines was assessed. The results allowed further development of structure-activity relationships. The compound 5,7-dibromo-N-(1-naphthylmethyl)-1H-indole-2,3-dione 5a was the most potent against U937 cells with an IC(50) value of 0.19 microM.

TYRIAN PURPLE PRECURSORS IN THE EGG MASSES OF THE AUSTRALIAN MURICID, Dicathais orbita: A POSSIBLE DEFENSIVE ROLE

We report a putative defensive role for the precursors of Tyrian purple in the egg masses of the Australian muricid, Dicathais orbita. The fresh egg masses contain a high proportion of tyrindoleninone, which reacts to form tyriverdin and subsequently Tyrian purple and 6-bromoisatin as the eggs develop and the larvae hatch. Antimicrobial testing revealed that tyrindoleninone is toxic to both marine and human pathogens at a concentration of 1 mg/ml. Tyriverdin inhibits the growth of two marine pathogens, as well as the yeast Candida albicans at 0.001 mg/ml and was effectively bacteriostatic at 0.0005 mg/ml against three human pathogenic bacteria. Tyriverdin did not appear to significantly lyse the microbial cells. 6-Bromoisatin has mild antimicrobial properties, whereas Tyrian purple exhibited no significant activity. The antimicrobial properties of these compounds and changes in their presence during egg development correlates with ripening in the egg masses of D. orbita. This is the first report of the chemical ripening of eggs in a marine environment.

Dual Action-Based Approaches to Antibacterial Agents

This review collates and analyses recent work done on dual action approaches to tackling the mounting health problem of resistance by human pathogenic bacteria to antibacterial agents. In particular the areas reviewed include the use of two drugs in combination, dual action prodrugs, and dual action drugs (or hybrid drugs).

Structure-activity relationships of 2-aryl-1H-indole inhibitors of the NorA efflux pump in Staphylococcus aureus

The synthesis of 22 2-aryl-1H-indoles, including 12 new compounds, has been achieved via Pd- or Rh-mediated methodologies, or selective electrophilic substitution. All three methods were based on elaborations from simple indole precursors. SAR studies on these indoles and 2-phenyl-1H-indole in Staphylococcus aureus as NorA efflux pump inhibitors indicated 5-nitro-2-(3-methoxycarbonyl)phenyl-1H-indole was a slightly more potent inhibitor than the lead INF55. A promising new antibacterial lead compound against S. aureus (2-phenyl-1H-indol-5-yl)-methanol, was also found.