Structure−Activity Relationship Study on Anti-HIV 6-Desfluoroquinolones

Tabarrini, Oriana; Massari, Serena; Daelemans, Dirk; Stevens, Miguel; Manfroni, Giuseppe; Sabatini, Stefano; Balzarini, Jan; Cecchetti, Violetta; Pannecouque, Christophe; Fravolini, Arnaldo

doi:10.1021/jm701585h

Cited by 55 publications

(50 citation statements)

References 22 publications

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“…The 6-hydrogen derivative maintained low cytotoxicity but exhibited a 6-fold decrease in antiviral activity ( Table 1), indicating that the amino group in the C-6 position is important for preserving potent anti-HCMV activity. This is in agreement with recent reports on other 6-hydrogen-1-methylquinolones, which were found to be inactive against HCMV (39). To explore the importance of the carboxylic substituent at the C-3 position, the anti-HCMV activity of WC5E, the ethyl ester analogue of the lead compound, WC5 (9), was also tested.…”

Section: Resultssupporting

confidence: 88%

The 6-Aminoquinolone WC5 Inhibits Human Cytomegalovirus Replication at an Early Stage by Interfering with the Transactivating Activity of Viral Immediate-Early 2 Protein

Loregian

Mercorelli

Muratore

et al. 2010

Antimicrob Agents Chemother

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WC5 is a 6-aminoquinolone that potently inhibits the replication of human cytomegalovirus (HCMV) but has no activity, or significantly less activity, against other herpesviruses. Here we investigated the nature of its specific anti-HCMV activity. Structure-activity relationship studies on a small series of analogues showed that WC5 possesses the most suitable pattern of substitutions around the quinolone scaffold to give potent and selective anti-HCMV activity. Studies performed to identify the possible target of WC5 indicated that it prevents viral DNA synthesis but does not significantly affect DNA polymerase activity. In yield reduction experiments with different multiplicities of infection, the anti-HCMV activity of WC5 appeared to be highly dependent on the viral inoculum, suggesting that WC5 may act at an initial stage of virus replication. Consistently, time-of-addition and time-of-removal studies demonstrated that WC5 affects a phase of the HCMV replicative cycle that precedes viral DNA synthesis. Experiments to monitor the effects of the compound on virus attachment and entry showed that it does not inhibit either process. Evaluation of viral mRNA and protein expression revealed that WC5 targets an event of the HCMV replicative cycle that follows the transcription and translation of immediate-early genes and precedes those of early and late genes. In cell-based assays to test the effects of WC5 on the transactivating activity of the HCMV immediate-early 2 (IE2) protein, WC5 markedly interfered with IE2-mediated transactivation of viral early promoters. Finally, WC5 combined with ganciclovir in checkerboard experiments exhibited highly synergistic activity. These findings suggest that WC5 deserves further investigation as a candidate anti-HCMV drug with a novel mechanism of action.

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Section: Resultssupporting

confidence: 88%

The 6-Aminoquinolone WC5 Inhibits Human Cytomegalovirus Replication at an Early Stage by Interfering with the Transactivating Activity of Viral Immediate-Early 2 Protein

Loregian

Mercorelli

Muratore

et al. 2010

Antimicrob Agents Chemother

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“…Subsequent structural investigations on a number of analogues of the lead compound WM5 allowed us to obtain insights into their structure-activity relationships (44). We successfully eliminated the amino group from the C-6 position and positioned a suitable 4-arylpiperazine at the C-7 position, resulting in the development of a new series of potent 6-DFQs (45). Indeed, we found that substitution at the N-4 piperazine core of m-trifluoromethylphenyl (HM-12) or benzothiazole (HM-13) resulted in pronounced anti-HIV properties, particularly in M/M cell lineages, with EC 50 values in the ng/ml range.…”

Section: Discussionmentioning

confidence: 99%

Novel In Vivo Model for the Study of Human Immunodeficiency Virus Type 1 Transcription Inhibitors: Evaluation of New 6-Desfluoroquinolone Derivatives

Stevens

Pollicita

Pannecouque

et al. 2007

Antimicrob Agents Chemother

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Two novel 6-desfluoroquinolone derivatives, HM-12 and HM-13, were evaluated for anti-human immunodeficiency virus (anti-HIV) activity in acutely, chronically, and latently HIV type 1 (HIV-1)-infected cell cultures and were found to behave as potent HIV-1 transcription inhibitors. In order to extend this result in vivo, we developed an artificial hu-SCID mouse model for HIV-1 latency based on SCID mice engrafted with latently HIV-1-infected promyelocytic OM-10.1 cells in which HIV-1 can be reactivated in vivo by the administration of human tumor necrosis factor alpha (hTNF-␣). Treating these SCID mice with HM-12 or HM-13 prior to hTNF-␣ stimulation resulted in a pronounced suppressive effect on viral reactivation. Since both quinolone derivatives were able to inhibit the reactivation of HIV-1 from this artificial viral reservoir in vivo, we provide encouraging evidence for the use of quinolones in the control of HIV-1 infections.

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“…[1,2,5] Benzothiazolyl derivative 12 showed good anti-HIV activity which, however, was not perfectly reproducible, whereas 13, bearing the pyridinylpiperazine as a C7 substituent, showed moderate activity coupled with low cytotoxicity leading to positive SI values.…”

Section: Biological Activitymentioning

confidence: 99%

Structural Investigation of the Naphthyridone Scaffold: Identification of a 1,6‐Naphthyridone Derivative with Potent and Selective Anti‐HIV Activity

Tabarrini¹,

Massari²,

Sancineto³

et al. 2011

ChemMedChem

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Building upon a large, previously reported series of anti-HIV 6-desfluoroquinolones endowed with a peculiar mechanism of action, the inhibition of Tat-mediated transcription, replacement of the quinolone nucleus with a naphthyridone core was shown to be very productive. In this work, the naphthyridone scaffold was investigated in depth by synthesizing various analogues. This led to the identification of NM13 as the most selective derivative obtained in MT-4 cells. It is the result of the successful combination of the 1,6-naphthyridone nucleus and the C7 benzothiazolpiperazine group, which, for the first time, not only grants potent anti-HIV activity but displays very high selectivity. Further studies aimed at a more thorough investigation of the anti-HIV profile of this new derivative are in progress.

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Structure−Activity Relationship Study on Anti-HIV 6-Desfluoroquinolones

Cited by 55 publications

References 22 publications

The 6-Aminoquinolone WC5 Inhibits Human Cytomegalovirus Replication at an Early Stage by Interfering with the Transactivating Activity of Viral Immediate-Early 2 Protein

The 6-Aminoquinolone WC5 Inhibits Human Cytomegalovirus Replication at an Early Stage by Interfering with the Transactivating Activity of Viral Immediate-Early 2 Protein

Novel In Vivo Model for the Study of Human Immunodeficiency Virus Type 1 Transcription Inhibitors: Evaluation of New 6-Desfluoroquinolone Derivatives

Structural Investigation of the Naphthyridone Scaffold: Identification of a 1,6‐Naphthyridone Derivative with Potent and Selective Anti‐HIV Activity

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