Many different plant species synthesise triterpenoid saponins as part of their normal programme of growth and development. Examples include plants that are exploited as sources of drugs, such as liquorice and ginseng, and also crop plants such as legumes and oats. Interest in these molecules stems from their medicinal properties, antimicrobial activity, and their likely role as determinants of plant disease resistance. Triterpenoid saponins are synthesised via the isoprenoid pathway by cyclization of 2,3-oxidosqualene to give primarily oleanane (β-amyrin) or dammarane triterpenoid skeletons. The triterpenoid backbone then undergoes various modifications (oxidation, substitution and glycosylation), mediated by cytochrome P450-dependent monooxygenases, glycosyltransferases and other enzymes. In general very little is known about the enzymes and biochemical pathways involved in saponin biosynthesis. The genetic machinery required for the elaboration of this important family of plant secondary metabolites is as yet largely uncharacterised, despite the considerable commercial interest in this important group of natural products. This is likely to be due in part to the complexity of the molecules and the lack of pathway intermediates for biochemical studies. Considerable advances have recently been made, however, in the area of 2,3-oxidosqualene cyclisation, and a number of genes encoding the enzymes that give rise to the diverse array of plant triterpenoid skeletons have been cloned. Progress has also been made in the characterisation of saponin glucosyltransferases. This review outlines these developments, with particular emphasis on triterpenoid saponins.

Biosynthesis of triterpenoid saponins in plants.

Ro 63-9141 is a new member of the pyrrolidinone-3-ylidenemethyl cephem series of cephalosporins. Its antibacterial spectrum was evaluated against significant gram-positive and gram-negative pathogens in comparison with those of reference drugs, including cefotaxime, cefepime, meropenem, and ciprofloxacin. Ro 63-9141 showed high antibacterial in vitro activity against gram-positive bacteria except ampicillin-resistant enterococci, particularly vancomycin-resistant strains of Enterococcus faecium. Its MIC at which 90% of the isolates tested were inhibited (MIC(90)) for methicillin-resistant Staphylococcus aureus (MRSA) was 4 microg/ml. Ro 63-9141 was bactericidal against MRSA. Development of resistance to the new compound in MRSA was not observed. Ro 63-9141 was more potent than cefotaxime against penicillin-resistant Streptococcus pneumoniae (MIC(90) = 2 microg/ml). It was active against ceftazidime-susceptible strains of Pseudomonas aeruginosa and against Enterobacteriaceae except Proteus vulgaris and some isolates producing extended-spectrum beta-lactamases. The basis for the antibacterial spectrum of Ro 63-9141 lies in its affinity to essential penicillin-binding proteins, including PBP 2' of MRSA, and its stability towards beta-lactamases. The in vivo findings were in accordance with the in vitro susceptibilities of the pathogens. These data suggest the potential utility of Ro 63-9141 for the therapy of infections caused by susceptible pathogens, including MRSA. Since insufficient solubility of Ro 63-9141 itself precludes parenteral administration in humans, a water-soluble prodrug, Ro 65-5788, is considered for development.

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In vitro and in vivo properties of Ro 63-9141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci.

Research on the ergosterol biosynthetic pathway in fungi has focused on the identification of the specific sterol structure required for normal membrane structure and function and for completion of the cell cycle. The pathway and its end product are also the targets for a number of antifungal drugs. Identification of essential steps in ergo-sterol biosynthesis could provide new targets for the development of novel therapeutic agents. Nine of the eleven genes in the portion of the pathway committed exclusively to ergosterol biosynthesis have been cloned, and their essentiality for aerobic growth has been determined. The first three genes;ERG9 (squalene synthase),ERG1 (squalene epoxidase), andERG7 (lanosterol synthase), have been cloned and found to be essential for aerobic viability since their absence would result in the cell being unable to synthesize a sterol molecule. The remaining eight genes encode enzymes which metabolize the first sterol, lanosterol, to ultimately form ergosterol. The two earliest genes,ERG11 (lanosterol demethylase) andERG24 (C-14 reductase), have been cloned and found to be essential for aerobic growth but are suppressed by mutations in the C-5 desaturase (ERG3) gene andfen1 andfen2 mutations, respectively. The remaining cloned genes,ERG6 (C-24 methylase),ERG2 (D8AE7 isomerase),ERG3 (C-5 desaturase), andERG4 (C-24(28) reductase), have been found to be nonessential. The remaining genes not yet cloned are the C-4 demethylase and the C-22 desaturase (ERG5).

Cloning of the Late Genes in the Ergosterol Biosynthetic Pathway of Saccharomyces Cerevisiae--A Review

Ceftobiprole exhibited tight binding to PBP2a in methicillin-resistant Staphylococcus aureus, PBP2x in penicillin-resistant Streptococcus pneumoniae, and PBP3 and other essential penicillin-binding proteins in methicillin-susceptible S. aureus, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole also bound well to PBP2 in the latter organisms, contributing to the broad-spectrum antibacterial activity against gram-negative and gram-positive bacteria.

https://aac.asm.org/content/aac/51/7/2621.full.pdf

Binding of Ceftobiprole and Comparators to the Penicillin-Binding Proteins of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae

Ro 48-8.071, a new 2,3-oxidosqualene:lanosterol cyclase inhibitor lowering plasma cholesterol in hamsters, squirrel monkeys, and minipigs: comparison to simvastatin.

Inhibitors of 2,3-oxidosqualene lanosterol-cyclase as potential antifungal agents.

The synthesis and structure−activity relationships of a new class of vinylcephalosporins substituted with a lactamyl residue (1) are described. These compounds show excellent activity against enterococci and retain the broad spectrum activity of third-generation cephalosporins such as ceftriaxone.

Synthesis and Structure−Activity Relationship of (Lactamylvinyl)cephalosporins Exhibiting Activity against Staphylococci, Pneumococci, and Enterococci

Antimycotically-active compounds of the formula ##STR1## wherein R 1 and R 2 each independently are hydrogen, C 1-7 -alkyl or C 2-7 -alkenyl or together are a straight chain C 2-4 -alkylene; R 3 and R 4 each independently are hydrogen or C 1-7 -alkyl; R 5 and R 6 each independently are hydrogen, halogen, trifluoromethyl, nitro, cyano, C 1-7 -alkoxy or C 1-7 -alkyl; and Q is an unsubstituted or substituted phenyl or naphthyl group, wherein the substituents are at least one of halogen, trifluoromethyl, cyano, nitro, C 1-7 -alkyl, C 1-7 -alkoxy; C 2-10 -alkenyl; or a substituted or unsubstituted C 1-10 -alkyl group wherein said substituents are at least one hydroxy group; and pharmaceutically acceptable acid addition salts thereof.

Substituted aminoalkyl biphenyl compounds

The invention relates to substituted 5-benzyl-2,4-diaminopyrimidines of general formula (A), wherein R1 is C2-C3 alkyl and R2 is heterocyclyl, phenyl or naphthyl, bonded by one of its C-atoms and R3 is C2-C6 alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfamoyl, heterocyclylsulfonyl, heterocyclyalkylsulfonyl or dialkylsulfamoyl; wherein alkyl, cycloalkyl and alkenyl can carry up to 6 carbon atoms alone or in compositions and can carry up to 6 ring members heterocyclically, alone, or in compositions and the groups R?2 and R3? can be substituted; and to acid addition salts of compounds. The invention also relates to a method for producing the above 5-benzyl-2,4-diaminopyrimidines, to the intermediate products that are produced, to corresponding medicaments and to the use of 5-benzyl-2,4-diaminopyrimidines as medicinal preparations. The products have antibiotic properties and are useful for combating or preventing infectious diseases.

Substituted 5-benzyl-2,4-diaminopyrimidines

The invention is concerned with compounds of general formula (I), wherein R1 signifies lower-alkoxy, R2 signifies hydroxy or lower-alkoxy, R3 signifies hydrogen, cyano, alkyl, alkenyl, cycloalkyl, aryl, heterocycyl, aralkyl, aryl-Q-alkyl, heterocyclalkyl or a group of the formula -(CH?2?)n-, Q signifies -SO-; R?4, R4'? each independently signify hydrogen, alkyl, aryl or heterocyclalkyl, R?5? signifies hydrogen, alkyl, alkoxy, aryl or heterocycyl, or R?4 and R5? together can form a group -(CH?2?)n-, and n is a whole number of 2 to 5, as well as pharmaceutically usable salts thereof; the use of these compounds and their salts as therapeutically active substances; medicaments based on these substances and their production; the use of these substances as medicaments and for the production of antibacterially-active medicaments; as well as the manufacture of the compounds of formula (I) and their pharmaceutically acceptable salts and intermediates for their manufacture.

Philippe Guerry

Papers

Inhibitors of 2,3-oxidosqualene lanosterol-cyclase as potential antifungal agents.

Synthesis and Structure−Activity Relationship of (Lactamylvinyl)cephalosporins Exhibiting Activity against Staphylococci, Pneumococci, and Enterococci

Substituted aminoalkyl biphenyl compounds

Substituted 5-benzyl-2,4-diaminopyrimidines

Substituted 2,4-diaminopyrimidines