Synthesis of IR‐415 Derivatives and Evaluation of their Antiviral Activity Against Hepatitis B Virus

Abstract

AbstractA candidate molecule 1‐(3‐(1H‐imidazol‐1‐yl) propyl)‐3‐(2,4‐difluorophenyl) thiourea (coded as ‘IR‐415’) exhibiting excellent antiviral efficacy in cell culture model was identified after a high‐throughput screening of the Maybridge library.[7] Twenty derivatives of IR‐415 hereafter referred to as DSA‐00 were synthesized and evaluated for their antiviral activity against hepatitis B virus (HBV) in cell culture. The HBV‐expressing HepG2.2.15 cells or HBV‐permissive HepG2‐hNTCP‐C4 cells were treated with DSA‐00 or its new derivatives. A significant and improved inhibition in viral DNA replication and secretion of hepatitis B surface antigen were observed in the presence two derivatives, viz., 1‐(2,4‐Difluoro‐phenyl)‐3‐(4‐imidazol‐1‐yl‐butyl)‐thiourea and 1‐(3,5‐Difluoro‐phenyl)‐3‐(4‐imidazol‐1‐yl‐butyl)‐thiourea. Consistent with these antiviral properties, our molecular docking studies predicted a high affinity interaction of these derivatives with HBx protein. Importantly, DSA‐00 and its derivatives exhibited minimal toxicity at higher concentrations. Thus, these derivatives have the potential to be developed as new therapeutics for mono or combination therapy for the management of HBV infection.