6-Aminoquinolones as New Potential Anti-HIV Agents

Cecchetti, Violetta; Parolin, Cristina; Moro, Stefano; Pecere, Teresa; Filipponi, Enrica; Calistri, Arianna; Tabarrini, Oriana; Gatto, Barbara; Palumbo, Manlio; Fravolini, Arnaldo; Palù, Giorgio

doi:10.1021/jm9903390

Cited by 104 publications

(105 citation statements)

References 10 publications

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“…This is in contrast to the findings presented in a previous report, which noted higher mutation rates for other fluorinated quinolones (15). Previous reports have shown that changes at position 6, such as in the NFQs studied here, may lead to an enhancement of in vitro activity but not an enhancement of in vivo activity (2,17). While the NFQs demonstrated good in vitro activities, future pharmacokinetic and pharmacodynamic studies are necessary to show whether a sufficient area under the concentration-time curve/MIC ratio (assuming that this is the parameter most predictive of clinical outcome, as demonstrated for levofloxacin and another NFQ, BMS-284756 [5,18]) can be obtained to predict whether NFQs will have sufficient potencies against isolates of S. aureus and S. pneumoniae, especially those harboring significant mutations in QRDRs.…”

Section: Discussioncontrasting

confidence: 99%

In Vitro Activities of Novel Nonfluorinated Quinolones PGE 9262932 and PGE 9509924 against Clinical Isolates of Staphylococcus aureus and Streptococcus pneumoniae with Defined Mutations in DNA Gyrase and Topoisomerase IV

Jones

Critchley

Karlowsky

et al. 2002

Antimicrob Agents Chemother

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Two 8-methoxy nonfluorinated quinolones (NFQs), PGE 9262932 and PGE 9509924, were tested against contemporary clinical isolates of Staphylococcus aureus (n ‫؍‬ 122) and Streptococcus pneumoniae (n ‫؍‬ 69) with genetically defined quinolone resistance-determining regions (QRDRs). For S. aureus isolates with wild-type (WT) sequences at the QRDRs, the NFQs demonstrated activities 4-to 32-fold more potent (MICs at which 90% of isolates are inhibited [MIC 90 s], 0.03 g/ml) than those of moxifloxacin (MIC 90 , 0.12 g/ml), gatifloxacin (MIC 90 , 0.25 g/ml), levofloxacin (MIC 90 , 0.25 g/ml), and ciprofloxacin (MIC 90 , 1 g/ml). Against S. pneumoniae isolates with WT sequences at gyrA and parC, the NFQs PGE 9262932 (MIC 90 , 0.03 g/ml) and PGE 9509924 (MIC 90 , 0.12 g/ml) were 8-to 64-fold and 2-to 16-fold more potent, respectively, than moxifloxacin (MIC 90 , 0.25 g/ml), gatifloxacin (MIC 90 , 0.5 g/ml), levofloxacin (MIC 90 , 2 g/ml), and ciprofloxacin (MIC 90 , 2 g/ml). The MICs of all agents were elevated for S. aureus isolates with alterations in GyrA (Glu88Lys or Ser84Leu) and GrlA (Ser80Phe) and S. pneumoniae isolates with alterations in GyrA (Ser81Phe or Ser81Tyr) and ParC (Ser79Phe or Lys137Asn). Fluoroquinolone MICs for S. aureus strains with double alterations in GyrA combined with double alterations in GrlA were >32 g/ml, whereas the MICs of the NFQs for strains with these double alterations were 4 to 8 g/ml. The PGE 9262932 and PGE 9509924 MICs for the S. pneumoniae isolates did not exceed 0.5 and 1 g/ml, respectively, even for isolates with GyrA (Ser81Phe) and ParC (Ser79Phe) alterations, for which levofloxacin MICs were >16 g/ml. No difference in the frequency of selection of mutations (<10 ؊8 at four times the MIC) in wild-type or first-step mutant isolates of S. aureus or S. pneumoniae was detected for the two NFQs. On the basis of their in vitro activities, these NFQ agents show potential for the treatment of infections caused by isolates resistant to currently available fluoroquinolones.

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Section: Discussioncontrasting

confidence: 99%

In Vitro Activities of Novel Nonfluorinated Quinolones PGE 9262932 and PGE 9509924 against Clinical Isolates of Staphylococcus aureus and Streptococcus pneumoniae with Defined Mutations in DNA Gyrase and Topoisomerase IV

Jones

Critchley

Karlowsky

et al. 2002

Antimicrob Agents Chemother

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“…A few examples of 6-nitro (12c, 12t, 12u) (19), 6-methylamino (13h) (19), and 6-hydroxy (14q) (22) derivatives were also tested. Moreover, the library also included two anti-HIV 6-aminoquinolones, 1o (27) and 4s (28), selected within our inhouse library of antiviral quinolones (29).…”

Section: Mycobacterium Tuberculosis Inhibitory Activitymentioning

confidence: 99%

6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

et al. 2012

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The screening of an in-house quinolones library against Mycobacterium tuberculosis (Mtb) H 37 Rv, followed by a first cycle of optimization, yielded 6-hydrogen-8-methyl derivatives endowed with good potency. The antitubercular activity also encompassed the bacteria in a non-replicating state (NRP-TB) with minimum inhibitory concentration values lower than those of the reference agent, moxifloxacin. Among the best compounds, 11w and 11ai, characterized by a properly substituted piperidine at the C-7 position, were active against single-drug-resistant (SDR-TB) Mtb strains, maintaining overall good potency also against ciprofloxacin-resistant Mtb. This study expands the body of SAR around antitubercular quinolones leading to reconsider the role played by the usual fluorine atom at the C-6 position. Further elaboration of the 6-hydrogen-8-methylquinolone scaffold, with a particular focus on the C-7 position, is expected to give even more potent congeners holding promise for shortening the current anti-TB regimen.Key words: 6-desfluoroquinolones, antitubercular agents, multidrug resistance, non-replicating bacteria, quinolone SAR Abbreviations: 6-DFQs, 6-desfluoroquinolones; CipR, ciprofloxacinresistant; DOTS, Directly Observed Therapy Short-course; EMB, ethambutol; FQs, fluoroquinolones; INH, isoniazid; LORA, low oxygen recovery assay; MABA, microplate Alamar Blue assay; MBC, minimum bactericidal concentration; MDR-TB, multidrug-resistant Mtb; MIC, minimum inhibitory concentration; Mtb, Mycobacterium tuberculosis; NCEs, new chemical entities; NRP-TB, non-replicating persistent Mtb; PZA, pyrazinamide; RMP, rifampin; SAR, structure-activity relationships; SDR-TB, single-drugresistant Mtb; TB, tuberculosis; XDR-TB, extensively drug-resistant Mtb.Received 3 May 2012, revised 31 July 2012 and accepted for publication 2 August 2012 Tuberculosis (TB) is an old and re-emerging disease that spreads at alarming rate. Mycobacterium tuberculosis (Mtb) is responsible for 8.8 million new active cases and 1.5 million deaths in 2010, and one-third of the world's population is estimated to be latently infected with TB. About 95% of the tuberculosis cases and deaths occur in the developing countries, but there has also been a recent, highly publicized, resurgence of TB also in developed ones.a This pandemic is complicated by the co-infection with HIV (15% of new cases worldwide are HIV positive) and the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) Mtb strains.b The current recommended therapeutic strategy, namely Directly Observed Therapy, Short-course (DOTS) is based on the co-administration of four drugs, namely rifampin (RMP), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for 2 months, followed by a prolonged treatment with INH and RMP for an additional 4-7 months.c The cause of the long-period treatment is the peculiar ability of Mtb to survive in a non-replicating persistent (NRP-TB) state while withstanding chemotherapy. These features highlight the need to develop well-tolerated...

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“…It is important to note that the related 6-aminoquinolone antibiotic WM-5 ( Fig. 1D), which likewise inhibits IN in vitro, can inhibit Tat-dependent transcription from the HIV-1 promoter (4,23).…”

mentioning

confidence: 99%

Characterization of a Replication-Competent, Integrase-Defective Human Immunodeficiency Virus (HIV)/Simian Virus 40 Chimera as a Powerful Tool for the Discovery and Validation of HIV Integrase Inhibitors

Daelemans

Clercq

et al. 2007

J Virol

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Integrase is actively studied as an antiviral target, but many inhibitors selected from biochemical screens fail to inhibit human immunodeficiency virus (HIV) replication or primarily affect off-site targets. Here we develop and validate a replication-competent, simian virus 40-HIV integrase mutant chimera as a novel tool to classify the mechanism of action of potential integrase inhibitors. Whereas the mutant was more susceptible than the wild type to entry, reverse transcriptase, and protease inhibitors, it specifically resisted the action of integrase inhibitor L-870,810. We furthermore demonstrate inhibition of integration by GS-9137 and GS-9160 and off-site targeting by the 6-aminoquinolone antibiotic WM-5.

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6-Aminoquinolones as New Potential Anti-HIV Agents

Cited by 104 publications

References 10 publications

In Vitro Activities of Novel Nonfluorinated Quinolones PGE 9262932 and PGE 9509924 against Clinical Isolates of Staphylococcus aureus and Streptococcus pneumoniae with Defined Mutations in DNA Gyrase and Topoisomerase IV

In Vitro Activities of Novel Nonfluorinated Quinolones PGE 9262932 and PGE 9509924 against Clinical Isolates of Staphylococcus aureus and Streptococcus pneumoniae with Defined Mutations in DNA Gyrase and Topoisomerase IV

6‐Hydrogen‐8‐Methylquinolones Active Against Replicating and Non‐replicating Mycobacterium tuberculosis

Characterization of a Replication-Competent, Integrase-Defective Human Immunodeficiency Virus (HIV)/Simian Virus 40 Chimera as a Powerful Tool for the Discovery and Validation of HIV Integrase Inhibitors

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