Examination of halogen substituent effects on HIV-1 integrase inhibitors derived from 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones and 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones

Abstract

Using 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one and 4,5-dihydroxy-1H-isoindole-1,3(2H)-dione based HIV-1 integrase inhibitors as display platforms, we undertook a thorough examination of the effects of modifying the halogen substituents on a key benzyl ring that is hypothesized to bind in a hydrophobic pocket of the integrase•DNA complex. Data from this study suggest that in general dihalo -substituted analogues have higher potency than monohalo -substituted compounds, but that further addition of halogens is not beneficial.Integrase (IN) is a key enzyme in the life cycle of human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS). Approximately 30 drugs that have been approved by the FDA for treatment of HIV-1 infection, 1 Raltegravir [Merck & Co.,] 2 is the most recently approved drug (October 2007) and the only integrase inhibitor. Another IN inhibitor, Elvitegravir, [Gilead Sciences, 3 is currently undergoing phase III clinical trials in HIV-1-infected patients. These two inhibitors show high potency against IN -catalyzed "strand transfer" (ST) reactions, while being less effective against the IN 3′ -processing (3′-P) step. 4 This combination of characteristics is characteristic of a broad range of IN inhibitors, many of which contain the elements typified by General Structure I (Figure 1). A key component of these inhibitors is an array of heteroatoms that are hypothesized to chelate two divalent metal ions associated with catalytically essential IN residues Asp64, Asp116 and Glu152 ("DDE" motif). 5 Aromatic functionality, frequently in the form of a benzyl group linked to the chelating portion of the inhibitor, can make a significant contribution to overall binding affinity. The empirical observation that halogen substituents on this aryl ring can enhance potency has led to the hypothesis that this aryl ring may bind in one or more hydrophobic pockets of the IN•DNA complex. 6,7Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A diversity of halogen-substituted benzyl groups has been introduced into IN inhibitors ( Figure 1). [8][9][10][11][12][13][14][15][16] We recently reported a series of 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-ones (general structure A , Table 1) that exhibit potent ST inhibition in extracellular assays and antiviral efficacies in HIV-1 infected cells. 14 The closely related 4,5-dihydroxy-1H-isoindole-1,3(2H)-diones (general structure B , Table 1) represent phthalimide -based analogues that can be prepared by the chemistry described in our earlier report. 14 For series A we had observ...

Development of tricyclic hydroxy-1H-pyrrolopyridine-trione containing HIV-1 integrase inhibitors

“…One of the design rationales for introducing a nitrogen into the parent 4,5-dihydroxy-1 H -isoindole-1,3(2 H )-diones ( 3 ) was to remove catechol functionality and thereby reduce cytotocity. As shown in Table 5, the cytotoxicity of 4b-1 (CC 50 = 291 μM) was 30-fold lower than the previously reported value of the related catechol-containing analogue 3-1 (CC 50 = 9.5 μM), 5 In addition, consistent with the in vitro data obtained for the Raltegravir-resistant IN mutants (Table 4), Raltegravir showed a greater than 400-fold loss of antiviral efficacy with the G140S/Q148H vector as compared to the wild-type IN vector (Table 5). In contrast to Raltegravir, inhibitor 4b-1 displayed only a 2-fold loss of potency when challenged with the G140S/Q148H mutant vector, thereby making it 200-times less sensitive to the effects of this mutation.…”

MK-0536 Inhibits HIV-1 Integrases Resistant to Raltegravir

“…Comparing the RAL-PFV IN structure to the MK-0536-PFV IN structure, the loss of the -interaction between the oxadiazole moiety and the protein may be compensated for by the di-halogen substitution which lies deeper and interacts more tightly with the hydrophobic pocket formed between the C-G base pair, E152 and P145 (Fig. 1B) (22).…”

Molecular Dynamics Approaches Estimate the Binding Energy of HIV-1 Integrase Inhibitors and Correlate with In Vitro Activity

“…Shown in Fig. 1, XZ89 and CHI-1043 are structurally distinct from any of the four compounds used to verify the MD approach (21,56). INSTI 1 is similar to RAL (16).…”