Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides.

Cristina Tintori,Claudio Zamperini,Filippo Canducci,Annalaura Brai,Elena Dreassi,Giulia Iovenitti,Roberto Ferrarese,Maurizio Botta,Elisa Rita Ceresola,Valeria Cagno,David Lembo,Giulio Poli

doi:10.1371/journal.pone.0198478

Abstract

Although highly active antiretroviral therapies (HAART) remarkably increased life expectancy of HIV positive people, the rate of novel HIV-1 infections worldwide still represent a major concern. In this context, pre-exposure prophylaxis (PrEP) approaches such as vaginal microbicide gels topically releasing antiretroviral drugs, showed to have a striking impact in limiting HIV-1 spread. Nevertheless, the co-presence of other genital infections, particularly those due to HSV-1 or 2, constitute a serious drawback that strongly limits the efficacy of PrEP approaches. For this reason, combinations of different compounds with mixed antiviral and antiretroviral activity are thoroughly investigated Here we report the synthesis and the biological evaluation of a novel series of rhodanine derivatives, which showed to inhibit both HIV-1 and HSV-1/2 replication at nanomolar concentration, and were found to be active also on acyclovir resistant HSV-2 strains. The compounds showed a considerable reduction of activity in presence of serum due to a high binding to serum albumin, as determined through in vitro ADME evaluations. However, the most promising compound of the series maintained a considerable activity in gel formulation, with an EC50 comparable to that obtained for the reference drug tenofovir. Moreover, the series of compounds showed pharmacokinetic properties suitable for topical formulation, thus suggesting that the novel rhodanine derivatives could represent effective agents to be used as dual anti HIV/HSV microbicides in PrEP approaches.

Highlights

Several studies confirmed the efficacy of topical pre-exposure prophylaxis (PrEP) approaches to limit the burden of novel human immunodeficiency virus type 1 (HIV-1) infections and to enhance global efforts to eradicate this virus
Multipurpose combinations of different compounds with antiviral and antiretroviral activity are intensively investigated, sometimes associated with unintended pregnancy prevention compounds [23,24,25,26,27,28]. Compounds acting on both viruses such as the rhodanine derivatives described in this paper, represent effective agents to be used in candidate PrEP approaches without the need of dual-agents preparations
We demonstrated in our previous paper that these molecules block very early step in virus replication, preventing viral entry into cells

Summary

Introduction

All currently available PrEP approaches, including vaginal gels containing antiretroviral or intravaginal rings with long-acting antiretroviral drugs or implantable and injectable formulations, selectively inhibit HIV-1 replication but have no or very limited activity against HSV-1 or 2 [16] their efficacy may be limited or not sufficient to prevent new infections especially in high prevalence settings for both viral infections. In our previous papers [17,18,19], we demonstrated that these molecules block very early step in HIV-1 replication, preventing viral entry into cells This may be relevant to increase bioavailability of antiretroviral agents in topical preparations. A preliminary ADME evaluation was performed by determining water solubility, passive membrane permeability and metabolic stability of selected derivatives

Results and discussion

Conclusions

Materials and methods