Computer Assisted Design and Synthesis of Novel Chiral Piperazine Derivatives from 3-Hydroxynopinone

Background: Hepatitis C virus (HCV) Flaviviridae family comprises of positive sense singlestranded RNA ((+)ssRNA), which infects 3% of the world population that leads to the liver cirrhosis. There is no permanent cure available without side effects till date. Many drug discovery groups around the globe are heading to discover promising anti-HCV drug candidates for this deadly virus. Therefore, it is an urgent need to identify new anti viral agents that target HCV and ultimately give the permanent cure. The genome of HCV contains structural proteins (capsid protein C, membrane protein M, envelope protein E) and non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Protease/ helicase NS3 is one non-structural protein, a multifunctional enzyme with serine-protease and NTPase/ helicase activities implicated in the processing of viral polyprotein and to make copies of the HCV genome. Methods: A simple and efficient method has been developed for the synthesis of designed chiral piperazine ligands through the condensation of 1,2-diamino-cyclohexane or 1,2-diphenylethylenediamine with 3-hydroxynopinone derived from β-pinene in 4 steps with overall very good yields. Results: Four new piperazine based molecules have been designed, synthesized with limited DLP violations, good QPlogP, QPlogS values and excellent human % oral absorption values using Schrodinger suite. All the molecules showed better binding scores (G-Score & DG-Score) for drug like molecules. Conclusion: Molecular docking insights, interaction profiles and synthetic feasibilities of these molecules suggest that these could become good biologically active compounds against HIV and HCV. In future, we synthesized high enantiomeric excess biologically potent molecules with these diamine piperazine chiral auxiliaries.