Design and Optimization of Tricyclic Phtalimide Analogues as Novel Inhibitors of HIV-1 Integrase

Abstract

Human immunodeficiency virus type-1 integrase is an essential enzyme for effective viral replication and hence a valid target for the design of inhibitors. We report here on the design and synthesis of a novel series of phthalimide analogues as integrase inhibitors. The short synthetic pathway enabled us to synthesize a series of analogues with a defined structure diversity. The presence of a single carbonyl-hydroxy-aromatic nitrogen motif was shown to be essential for the enzymatic activity and this was confirmed by molecular docking studies. The enzymatically most active compound from this series is 7-(3,4-dichlorobenzyl)-5,9-dihydroxypyrrolo[3,4-g]quinoxaline-6,8-dione (15l) with an IC(50) value of 112 nM on the HIV-1 integrase enzyme, while ((7-(4-chlorobenzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione (15k)) showed an EC(50) of 270 nM against HIV-1 in a cell-based assay.

Modeling, Analysis, and Validation of a Novel HIV Integrase Structure Provide Insights into the Binding Modes of Potent Integrase Inhibitors

“…[25][26][27][28][29] After studying other modeling efforts for integrase, [26][27][28][29][30][31] we decided to take a new approach in which it was necessary to include all the key biologically relevant components during the modeling stage. We focused our efforts on the development of an energetically refined activesite model based on the integrase core domain bound to viral DNA.…”

HIV-1 integrase inhibitors: 2007-2008 update

“…Because of the conformational constraint on the carboxamide carbonyl, these tricyclic inhibitors are planar and exhibit IN inhibitory profiles similar to that of diketo acid and naphthyridine carboxamide inhibitors. 58 Replacement of the pyridine ring with pyrazine led to a new class of pyrrolloquinolone inhibitors. 59 Further, C-5 substitution in the pyrrolloquinolone core had led to compounds with potent activity in cell-based assays (Fig.…”

HIV‐1 integrase inhibitors: 2005–2006 update

“…[64][65][66][67] The naphthyridine carboxamides, exemplified by compound L-870, 810 (2), are strand transfer selective IN inhibitors. The tricyclic phthalimides (104 and 105) were designed based on the naphthyridine carboxamide scaffold.…”

“…The tricyclic phthalimides (104 and 105) were designed based on the naphthyridine carboxamide scaffold. 64 The replacement of the carboxamide moiety in the naphthyridine carboxamide compounds with an imide resulted in a novel series of tricyclic phthalimide IN inhibitors (Fig. 16) and hydroxyl oxygens chelate the Mg 2þ ion in the active site.…”