3-Phenylcoumarins as Inhibitors of HIV-1 Replication

Dionisio Olmedo,José L López-Pérez,Rocío Sancho,Mahabir P Gupta,Eduardo Muñoz,Arturo San Feliciano,José Alcamí,Luis M Bedoya,Esther Del Olmo

doi:10.3390/molecules17089245

Abstract

We have synthesized fourteen 3-phenylcoumarin derivatives and evaluated their anti-HIV activity. Antiviral activity was assessed on MT-2 cells infected with viral clones carrying the luciferase gene as reporter. Inhibition of HIV transcription and Tat function were tested on cells stably transfected with the HIV-LTR and Tat protein. Six compounds displayed NF-κB inhibition, four resulted Tat antagonists and three of them showed both activities. Three compounds inhibited HIV replication with IC50 values < 25 µM. The antiviral effect of the 4-hydroxycoumarin derivative 19 correlates with its specific inhibition of Tat functions, while compound 8, 3-(2-chlorophenyl)coumarin, seems to act through a mechanism unrelated to the molecular targets considered in this research.

Highlights

Human immunodeficiency virus (HIV) infection is the cause of acquired immunodeficiency syndrome (AIDS) [1], one of the leading causes of morbidity and mortality in the World [2]
They were structurally related to the inophyllum series of coumarins, without cyclisation of the prenyl groups across the 5- and/or 7-hydroxyl groups [34]. These compounds were tested in vitro against sensitive and multi-drug-resistant strains of Mycobacterium tuberculosis (MTB) with positive results, which will be published shortly. These relevant facts induced us to continue our research focused on the synthesis of new neoflavones and 3-phenylcoumarin derivatives
In this paper we report on the synthesis and the results of anti-HIV evaluation of fourteen structurally diverse 3-phenylcoumarin derivatives

Summary

Introduction

Human immunodeficiency virus (HIV) infection is the cause of acquired immunodeficiency syndrome (AIDS) [1], one of the leading causes of morbidity and mortality in the World [2]. Active Antiretroviral Therapy (HAART) has resulted highly effective in suppressing HIV load and in decreasing mortality of AIDS patients, current treatments do not eradicate the virus from the infected host. After HIV entry into the host cell, viral RNA is transcribed to proviral DNA, transported to cell nucleus and stably integrated into the host genome. At this point, depending on several cellular and viral factors, provirus can be actively transcribed to viral RNAs or remain in a latent state, integrated in the genome of CD4+ cells, constituting viral reservoirs [3], not reached by HAART [4]. Novel targets for anti-HIV drugs are necessary, and viral transcription seems to be relevant in this context

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