3.1. Chelation 564 3.2. Acid−Base Character 564 3.3. Photochemistry 565 4. In Vitro Antimicrobial Spectra 566 5. Structure−Activity Relationships 568 5.1. N-1 Ethyl Family 568 5.2. N-1 Cyclopropyl Family 568 5.3. N-1 to C-8 Bridged (Tricyclic) Family 568 5.4. N-1 Aryl Family 569 5.5. Positions C-2, C-3, and C-4 570 5.6. C-4a Substituted Analogues 571 5.7. C-5 Substituents 571 5.8. C-6 Substituents 571 5.9. C-7 Substituents 571 5.9.1. Piperazinyl and Related Moieties 572 5.9.2. Pyrrolidinyl and Related Moieties 572 5.9.3. Cyclobutylaminyl and Related Moieties 572 5.9.4. Bicycloaminyl Moieties 572 5.9.5. Carbon-Linked Substituents 572 5.10. Substituents at C-8 573 5.11. Resume of Structure−Activity Relationships of Quinolones 573

Bacterial topoisomerase inhibitors: quinolone and pyridone antibacterial agents.

Despite the success of genomics in identifying new essential bacterial genes, there is a lack of sustainable leads in antibacterial drug discovery to address increasing multidrug resistance. Type IIA topoisomerases cleave and religate DNA to regulate DNA topology and are a major class of antibacterial and anticancer drug targets, yet there is no well developed structural basis for understanding drug action. Here we report the 2.1 A crystal structure of a potent, new class, broad-spectrum antibacterial agent in complex with Staphylococcus aureus DNA gyrase and DNA, showing a new mode of inhibition that circumvents fluoroquinolone resistance in this clinically important drug target. The inhibitor 'bridges' the DNA and a transient non-catalytic pocket on the two-fold axis at the GyrA dimer interface, and is close to the active sites and fluoroquinolone binding sites. In the inhibitor complex the active site seems poised to cleave the DNA, with a single metal ion observed between the TOPRIM (topoisomerase/primase) domain and the scissile phosphate. This work provides new insights into the mechanism of topoisomerase action and a platform for structure-based drug design of a new class of antibacterial agents against a clinically proven, but conformationally flexible, enzyme class.

Type IIA topoisomerase inhibition by a new class of antibacterial agents.

This invention describes novel pyrazole compounds of formula (IV) wherein Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; R?x and Ry? are independently selected from T-R3, or taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen; and R2, R2', and T, and R3 are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzehimer's disease.

Pyrazole compounds useful as protein kinase inhititors

DNA gyrase is a type II topoisomerase that can introduce negative supercoils into DNA at the expense of ATP hydrolysis. It is essential in all bacteria but absent from higher eukaryotes, making it an attractive target for antibacterials. The fluoroquinolones are examples of very successful gyrase-targeted drugs, but the rise in bacterial resistance to these agents means that we not only need to seek new compounds, but also new modes of inhibition of this enzyme. We review known gyrase-specific drugs and toxins and assess the prospects for developing new antibacterials targeted to this enzyme.

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Exploiting bacterial DNA gyrase as a drug target: current state and perspectives.

The present invention provides a compound of formula I: or a pharmaceutically acceptable salt or mixtures thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK mammalian protein kinase, and more particularly inhibitors of GSK-3 mammalian protein kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

Compositions useful as inhibitors of protein kinases

Design, synthesis, and structure-activity relationship studies of ATP analogues as DNA gyrase inhibitors.

Design, synthesis, and structure-activity relationship studies of new phenolic DNA gyrase inhibitors

The sequence of the gyrase B subunit gene from Staphylococcus aureus strains resistant to the gyrase B subunit inhibitors cyclothialidine, coumermycin, and novobiocin has been determined. The residues altered in the resistant gyrase B subunits map to the ATP-binding region, suggesting that the drugs inhibit ATP binding and hydrolysis. The pattern of cross-resistances indicates that the detailed binding mode of the compounds differs.

GyrB mutations in Staphylococcus aureus strains resistant to cyclothialidine, coumermycin, and novobiocin.

We investigated how cyclothialidine (Ro 09-1437), a novel DNA gyrase inhibitor belonging to a new chemical class of compounds, acts to inhibit Escherichia coli DNA gyrase. Cyclothialidine up to 100 micrograms/ml showed no effect on DNA gyrase when linear DNA was used as a substrate. Under the same conditions, quinolones, which inhibit the resealing reaction of DNA gyrase, caused a decrease in the amount of linear DNA used. No effect of cyclothialidine was observed on the accumulation of the covalent complex of DNA and the A subunit of DNA gyrase induced by ofloxacin in the absence of ATP. The effect of cyclothialidine on the DNA supercoiling reaction was antagonized by ATP, reducing the inhibitory activity 11-fold as the ATP concentration was increased from 0.5 to 5 mM. Cyclothialidine competitively inhibited the ATPase activity of DNA gyrase (Ki = 6 nM). The binding of [14C]benzoyl-cyclothialidine to E. coli gyrase was inhibited by ATP and novobiocin, but not by ofloxacin. These results suggest that cyclothialidine acts by interfering with the ATPase activity of the B subunit of DNA gyrase. Cyclothialidine was active against a DNA gyrase resistant to novobiocin, suggesting that its precise site of action might be different from that of novobiocin.

Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA gyrase inhibitor.

The quinolones inhibit the A subunit of DNA gyrase in the presence of Mg2+ by interrupting the DNA breakage and resealing steps, and the latter step is also retarded without quinolones if Mg2+ is replaced by Ca2+. Pyrimido[1,6-a]benzimidazoles have been found to represent a new class of potent DNA gyrase inhibitors which also act at the A subunit. To determine alterations in the DNA sequence specificity of DNA gyrase for cleavage sites in the presence of inhibitors of both classes or in the presence of Ca2+, we used DNA restriction fragments of 164, 85, and 71 bp from the pBR322 plasmid as model substrates. Each contained, at a different position, the 20-bp pBR322 sequence around position 990, where DNA gyrase preferentially cleaves in the presence of quinolones. Our results show that pyrimido[1,6-a]benzimidazoles have a mode of action similar to that of quinolones; they inhibit the resealing step and influence the DNA sequence specificity of DNA gyrase in the same way. Differences between inhibitors of both classes could be observed only in the preferences of DNA gyrase for these cleavage sites. The 20-bp sequence appeared to have some properties that induced DNA gyrase to cleave all three DNA fragments in the presence of inhibitors within this sequence, whereas cleavage in the presence of Ca2+ was in addition dependent on the length of the DNA fragments.

Hans Gmünder

Papers

Design, synthesis, and structure-activity relationship studies of ATP analogues as DNA gyrase inhibitors.

Design, synthesis, and structure-activity relationship studies of new phenolic DNA gyrase inhibitors

GyrB mutations in Staphylococcus aureus strains resistant to cyclothialidine, coumermycin, and novobiocin.

Mechanism of inhibition of DNA gyrase by cyclothialidine, a novel DNA gyrase inhibitor.

Effect of pyrimido[1,6-a]benzimidazoles, quinolones, and Ca2+ on the DNA gyrase-mediated cleavage reaction.