A Novel Small Molecular Weight Compound with a Carbazole Structure That Demonstrates Potent Human Immunodeficiency Virus Type-1 Integrase Inhibitory Activity

Abstract

The integration of reverse transcribed proviral DNA into a host genome is an essential event in the human immunodeficiency virus type 1 (HIV-1) replication life cycle. Therefore, the viral enzyme integrase (IN), which plays a crucial role in the integration event, has been an attractive target of anti-retroviral drugs. Several IN inhibitory compounds have been reported previously, yet none has been successful in clinical use. To find a new, more successful IN inhibitor, we screened a diverse library of 12 000 small molecular weight compounds randomly by in vitro strand-transfer assay. We identified a series of substituted carbazoles that exhibit strand-transfer inhibitory activity at low micromolar concentrations. Of these, the most potent compound exhibited an IC50 of 5.00+/-3.31 microM (CA-0). To analyse the structural determinants of strand-transfer inhibitory activity of the carbazole derivatives, we selected 23 such derivatives from our compound library and performed further analyses. Of these 23 compounds, six showed strong strand-transfer inhibition. The inhibition kinetics analyses and ethidium bromide displacement assays indicated that the carbazole derivatives are competitive inhibitors and not intercalators. An HeLa4.5/LTR-nEGFP cell line was employed to evaluate in vitro virus replication inhibition of the carbazole derivatives, and IC50 levels ranged from 0.48-1.52 microM. Thus, it is possible that carbazole derivatives, which possess structures different from previously-reported IN inhibitors, may become novel lead compounds in the development of IN inhibitors.

Carbazole Alkaloids from Clausena anisum-olens: Isolation, Characterization, and Anti-HIV Evaluation

“…The new carbazole alkaloid 1 exhibited an anti-HIV EC 50 value of 2.4 µg/mL and SI of 7.1, comparable or better than the values for similar carbazoles. Based on the current and prior literature results [4][5][6][7][8][9][10], carbazole alkaloids might be candidates for further study as potential anti-HIV agents. Structural analyses and synthetic modification of carbazole alkaloids and their derivatives are in progress to possibly increase the compounds' anti-HIV-1 activity.…”

“…Yan et al studied the antiviral activity of small molecular weight compounds with a carbazole structure using a single replication infectivity assay in HeLa 4.5/EGFP cells. 8-Chloro-2-[2-(dimethylamino)ethyl]-9-hydroxy-5-methylpyrrolo [3,4-c]carbazole-1,3(2H,6H)-dione demonstrated potent strand-transfer inhibitory activity and could be used as a lead compound to develop novel inhibitors [9]. Later, a pentacyclic indolocarbazole, xiamycin, from Streptomyces sp.…”

HIV‐1 integrase inhibitors: 2005–2006 update

“…17). 72 Based on their unique structural features, carbazoles (116-122) are considered a novel class of IN inhibitors. Most of the previously disclosed potent IN inhibitors contain two key structural units, namely a hydrophobic part and a metal ion chelating moiety (negatively charged or H-bond acceptor groups).…”

9-(2,5-Dimethoxybenzyl)-9H-carbazole: sheets built from C—H...π and π–π interactions

“…Carbazole compounds are used as host materials for both small-molecule organic light-emitting diodes (OLEDs) and polymer OLEDs, due to their high triplet energy and good hole-transporting capability (Brunner et al, 2004;. Carbazole derivatives exhibit antitumour (Leon et al, 1988;Martin et al, 2002;Routier et al, 2005), antimycobacterial (Sunthitikawinsakul et al, 2003), antifungal (Segall et al, 2003) and potent anti-HIV (Yan et al, 2005;Hirata et al, 1999) activities. We report here the structure of the title compound, (I), a carbazole derivative.…”