Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors:  Design, Synthesis, Biological Activities, and Mechanism of Action

Santo, Roberto Di; Costi, Roberta; Roux, Alessandra; Artico, M.; Lavecchia, Antonio; Marinelli, Luciana; Novellino, Ettore; Palmisano, Lucia; Andreotti, Mauro; Amici, Roberta; Galluzzo, Clementina Maria; Nencioni, Lucia; Palamara, Anna Teresa; Pommier, ﻿Yves; Marchand, Christophe

doi:10.1021/jm0511583

Cited by 83 publications

(77 citation statements)

References 34 publications

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“…A set of INIs ( Fig. 1) with strand transfer IN-inhibitory activities (InSTIs), including RDS1624, RDS1625, RDS1996, RDS1997, RDS2196, and RDS2197 (all quinolinonebased diketo acid derivatives) (5,7,14,15,45), L-731,988 (a styrylquinoline diketo acid derivative) (6,16,18,24,44), and L-870812 (a naphthyridine carboxamide) (18,25,45), was evaluated in a single-cycle Ba-L (env) PV assay. The potencies of these compounds were compared to those of the fusion inhibitor T20, the nucleoside RTI (NRTI) zidovudine (AZT), the NtRTI PMPA, and the NNRTIs UC781 and TMC120 (Table 1).…”

Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Terrazas-Aranda

Herrewege

Hazuda

et al. 2008

Antimicrob Agents Chemother

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Conceptually, blocking human immunodeficiency virus type 1 (HIV-1) integration is the last possibility for preventing irreversible cellular infection. Using cocultures of monocyte-derived dendritic cells and CD4؉ T cells, which represent primary targets in sexual transmission, we demonstrated that blocking integration with integrase strand transfer inhibitors (InSTIs), particularly L-870812, could consistently block cell-free and cell-associated HIV-1 infection. In a pretreatment setting in which the compound was present before and during infection and was afterwards gradually diluted during the culture period, the naphthyridine carboxamide L-870812 blocked infection with the cell-free and cell-associated HIV-1 Ba-L strain at concentrations of, respectively, 1,000 and 10,000 nM. The potency of L-870812 was similar to that of the nucleotide reverse transcriptase inhibitor R-9-(2-phosphonylmethoxypropyl) adenine (PMPA) but one or two orders of magnitude lower than those of the nonnucleoside reverse transcriptase inhibitors UC781 and TMC120. In contrast, the diketo acid RDS derivative InSTIs showed clear-cut but weaker antiviral activity than L-870812. Moreover, L-870812 completely blocked subtype C and CRFO2_AG primary isolates, which are prevalent in the African heterosexual epidemic. Furthermore, the addition of micromolar concentrations of L-870812 even 24 h after infection could still block both cell-free and cell-associated Ba-L, opening the prospect of postexposure prophylaxis. Finally, an evaluation of the combined activity of L-870812 with either T20, zidovudine, PMPA, UC781, or TMC120 against replication-deficient HIV-1 Ba-L (env) pseudovirus suggested synergistic activity for all combinations. Importantly, compounds selected for the study by using the coculture model were devoid of acute or delayed cytotoxic effects at HIV-blocking concentrations. Therefore, these findings provide evidence supporting consideration of HIV-1 integration as a target for microbicide development.

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Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Terrazas-Aranda

Herrewege

Hazuda

et al. 2008

Antimicrob Agents Chemother

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“…L-708,906, L-870,810, 5CITEP, bis-DKA and L-chicoric acid were synthesized as described previously Lin et al, 1999;Anthony et al, 2002;Pais et al, 2002;Hazuda et al, 2004a). Compounds RDS-1997 and RDS-1625 were synthesized by the Di Santo group (Di Santo et al, 2005Santo et al, , 2006. Conocurvone was obtained as a gift from Dr. Jonathan Coates of AMRAD Operations Pty Ltd (Victoria, Australia).…”

Section: Methodsmentioning

confidence: 99%

“…All drug solutions were prepared from powder in 100% dimethyl sulfoxide. Drug concentrations producing 50% inhibition (IC 50 values, Table 1) are from previous reports Di Santo et al, 2006;Johnson et al, 2006b;Stagliano et al, 2006) or were determined as described below. Note that all the compounds shown display anti-HIV activity, except for bis-DKA and 5CITEP (summarized with references in Table 1).…”

Section: Methodsmentioning

confidence: 99%

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Johnson¹,

Marchand²,

Patil³

et al. 2006

Mol Pharmacol

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HIV-1 integrase binds site-specifically to the ends of the viral cDNA. We used two HIV-1 integrase-DNA cross-linking assays to probe the binding sites of integrase inhibitors from different chemical families and with different strand transfer selectivities. The disulfide assay probes cross-linking between the integrase residue 148 and the 5Ј-terminal cytosine of the viral cDNA, and the Schiff base assay probes cross-linking between an integrase lysine residue and an abasic site placed at selected positions in the viral cDNA. Cross-linking interference by eight integrase inhibitors shows that the most potent cross-linking inhibitors are 3Ј-processing inhibitors, indicating that crosslinking assays probe the donor viral cDNA (donor binding site). In contrast, strand transfer-selective inhibitors provide weak cross-linking interference, consistent with their binding to a specific acceptor (cellular DNA) site. Docking and crystal structure studies illustrate specific integrase-inhibitor contacts that prevent cross-linking formation. Four inhibitors that prevented Schiff base cross-linking to the conserved 3Ј-terminal adenine position were examined for inhibition at various positions within the terminal 21 bases of the viral cDNA. Two of them selectively inhibited upper strand cross-linking, whereas the other two had a more global effect on integrase-DNA binding. These findings have implications for elucidating inhibitor binding sites and mechanisms of action. The cross-linking assays also provide clues to the molecular interactions between integrase and the viral cDNA.

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“…1) was tested against HIV-1 integrase using an electrochemiluminescent, high-throughput strand transfer assay (6). In this 96-well-plate-based assay, a biotinylated 3Ј-end-preprocessed donor DNA substrate is incubated for 30 min at 37°C with 250 nM of recombinant integrase.…”

Section: Madurahydroxylactone (Mhl)mentioning

confidence: 99%

Madurahydroxylactone Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and RNase H

Marchand

Beutler

Wamiru

et al. 2008

Antimicrob Agents Chemother

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A series of 29 madurahydroxylactone derivatives was evaluated for dual inhibition of human immunodeficiency virus type 1 (HIV-1) integrase and RNase H. While most of the compounds exhibited similar potencies for both enzymes, two of the derivatives showed 10-to 100-fold-higher selectivity for each enzyme, suggesting that distinct pharmacophore models could be generated. This study exemplifies the common and divergent structural requirements for the inhibition of two structurally related HIV-1 enzymes and demonstrates the importance of systematically screening for both integrase and RNase H when developing novel inhibitors.

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Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis, Biological Activities, and Mechanism of Action

Cited by 83 publications

References 34 publications

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Human Immunodeficiency Virus Type 1 (HIV-1) Integration: a Potential Target for Microbicides To Prevent Cell-Free or Cell-Associated HIV-1 Infection

Probing HIV-1 Integrase Inhibitor Binding Sites with Position-Specific Integrase-DNA Cross-Linking Assays

Madurahydroxylactone Derivatives as Dual Inhibitors of Human Immunodeficiency Virus Type 1 Integrase and RNase H

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