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P5.03 Discovery of triazole based inhibitor of hiv and hcv with favourable metabolic profile
  1. Amita Verma,
  2. Udaya Pratap Singh
  1. Sam Higginbottom Institute of Agriculture Technology and Sciences, India

Abstract

Introduction The HIV and HCV coinfection poses greatest threat to the clinical fraternity for its management because of similar mode of transmission. According to an estimate, nearly two million people infected with HIV are co-infected with hepatitis C virus (HCV) globally. The present study aimed at the development of novel hybrid derivatives of 1,2,4-triazole-thiol hybrids as a inhibitor of HIV and HCV infection.

Method The target compounds were developed via nucleophilic reaction with basic amines/thiols. These molecules have been subsequently tested for anti-HIV activity using TZM-bl cell lines along with Luciferase expression profile of the TZM-bl cells after infecting with NL4.3 virus and MTT assay for the cytotoxicity determination. The anti-HCV activity was also determined by capability to obstruct the HCV replicase (HCV NS5B) activity in vitro and HCV replication in a cell culture system carrying replicating HCV subgenomic RNA replicon. The metabolic profiling of the active compound was also carried out to define the formation of metabolites by the oral route.

Results Among the tested derivatives, compound 6d found to exhibit 98% of inhibition of HIV with Ki of 245.12 nM against HIV-RT with more than 50% inhibition of HIV replication. Moreover, compound 6e showed significant inhibition of RNA dependent RNA polymerase (RdRp) activity of HCV replicase in vitro with IC507.8 µg/ml. It also showed significant inhibition of HCV replication in culture system which leads to reduction in HCV RNA titre and translation level of viral proteins in concentration-dependent manner. In metabolic analysis, it has been found that, the skeleton of the hybrid compound remained intact during metabolic assay for the longer duration to exert its effect.

Conclusion Together with excellent bioactivities against HIV and HCV infection and favourable metabolic profile, the derivatives of triazole-thiol showed promising option to develop newer therapeutics against the HIV and HCV co-infection.

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