Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: Synthesis and preliminary SAR analysis

Gomez, Laurent; Hack, Michael D.; Wu, Jiejun; Wiener, John J. M.; Venkatesan, Hariharan; Santillán, Alejandro; Pippel, Daniel J.; Mani, Neelakandha S.; Morrow, Brian J.; Motley, S. Timothy; Shaw, Karen Joy; Wolin, Ronald; Grice, Cheryl A.; Jones, Todd K.

doi:10.1016/j.bmcl.2007.03.003

Cited by 91 publications

(47 citation statements)

References 10 publications

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“…Johnson & Johnson has reported on tetrahydroindazole analogs (135,385), some of which have good activity against S. aureus, S. pneumoniae, and E. coli (Fig. 5E shows compound I from reference 135).…”

Section: Single Pharmacophore Multiple Targetsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,135

961

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SUMMARY The discovery of novel small-molecule antibacterial drugs has been stalled for many years. The purpose of this review is to underscore and illustrate those scientific problems unique to the discovery and optimization of novel antibacterial agents that have adversely affected the output of the effort. The major challenges fall into two areas: (i) proper target selection, particularly the necessity of pursuing molecular targets that are not prone to rapid resistance development, and (ii) improvement of chemical libraries to overcome limitations of diversity, especially that which is necessary to overcome barriers to bacterial entry and proclivity to be effluxed, especially in Gram-negative organisms. Failure to address these problems has led to a great deal of misdirected effort.

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Section: Single Pharmacophore Multiple Targetsmentioning

confidence: 99%

Challenges of Antibacterial Discovery

Silver¹

2011

Clin Microbiol Rev

1,135

961

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“…Bioisosteric substitutions as well as modifications in the ring structures were additionally performed. Recent studies suggest the potential usefulness of gatifloxacin and ofloxacin derivatives, quinolines, pyrazoles, isothiazolopyridones, and aminoquinazolinediones, some of which are especially suited to counteract the onset of resistance [141][142][143][144][145][146][147][148].…”

Section: New Inhibitorsmentioning

confidence: 99%

In front of and behind the replication fork: bacterial type IIA topoisomerases

Sissi

Palumbo

2010

Cell. Mol. Life Sci.

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Topoisomerases are vital enzymes specialized in controlling DNA topology, in particular supercoiling and decatenation, to properly handle nucleic acid packing and cell dynamics. The type IIA enzymes act by cleaving both strands of a double helix and having another strand from the same or another molecule cross the DNA gate before a re-sealing event completes the catalytic cycle. Here, we will consider the two types of IIA prokaryotic topoisomerases, DNA Gyrase and Topoisomerase IV, as crucial regulators of bacterial cell cycle progression. Their synergistic action allows control of chromosome packing and grants occurrence of functional transcription and replication processes. In addition to displaying a fascinating molecular mechanism of action, which transduces chemical energy into mechanical energy by means of large conformational changes, these enzymes represent attractive pharmacological targets for antibacterial chemotherapy.

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“…ovel bacterial type II topoisomerase inhibitors (NBTIs) represent a new class of antimicrobial agents that display potent broad-spectrum antibacterial activity (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). NBTIs bind to and inhibit the essential bacterial enzymes DNA gyrase and topoisomerase IV at sites distinct from the fluoroquinolone-binding site; therefore, they retain activity against clinically relevant pathogens resistant to quinolones and other antibiotic agents.…”

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confidence: 99%

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

Tan

Gill

Jin

et al. 2016

Antimicrob Agents Chemother

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dOxabicyclooctane-linked novel bacterial topoisomerase inhibitors (NBTIs) represent a new class of recently described antibacterial agents with broad-spectrum activity. NBTIs dually inhibit the clinically validated bacterial targets DNA gyrase and topoisomerase IV and have been shown to bind distinctly from known classes of antibacterial agents directed against these targets. Herein we report the molecular, cellular, and in vivo characterization of AM-8722 as a representative N-alkylated-1,5-naphthyridone left-hand-side-substituted NBTI. Consistent with its mode of action, macromolecular labeling studies revealed a specific effect of AM-8722 to dose dependently inhibit bacterial DNA synthesis. AM-8722 displayed greater intrinsic enzymatic potency than levofloxacin versus both DNA gyrase and topoisomerase IV from Staphylococcus aureus and Escherichia coli and displayed selectivity against human topoisomerase II. AM-8722 was rapidly bactericidal and exhibited whole-cell activity versus a range of Gram-negative and Gram-positive organisms, with no whole-cell potency shift due to the presence of DNA or human serum. Frequency-of-resistance studies demonstrated an acceptable rate of resistance emergence in vitro at concentrations 16-to 32-fold the MIC. AM-8722 displayed acceptable pharmacokinetic properties and was shown to be efficacious in mouse models of bacterial septicemia. Overall, AM-8722 is a selective and potent NBTI that displays broad-spectrum antimicrobial activity in vitro and in vivo.

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Novel pyrazole derivatives as potent inhibitors of type II topoisomerases. Part 1: Synthesis and preliminary SAR analysis

Cited by 91 publications

References 10 publications

Challenges of Antibacterial Discovery

Challenges of Antibacterial Discovery

In front of and behind the replication fork: bacterial type IIA topoisomerases

In Vitro and In Vivo Characterization of the Novel Oxabicyclooctane-Linked Bacterial Topoisomerase Inhibitor AM-8722, a Selective, Potent Inhibitor of Bacterial DNA Gyrase

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