Synthetic routes towards antiviral agents from the houttuynoid family: structure–activity relationships and antiviral efficacy against herpes simplex virus type 1

Abstract

Natural products remain a cornerstone of drug discovery, offering unparalleled chemical diversity and evolved biological specificity. Among these, houttuynoids, a unique class of flavonoid-based metabolites isolated from Houttuynia cordata, have emerged as compelling leads due to their potent antiviral activity against herpes simplex virus-1 (HSV-1). Despite their therapeutic promise, the structural complexity of these glycosides necessitates the development of robust, scalable synthetic methodologies to facilitate in-depth chemobiological investigation and lead optimization. This review delineates the total synthesis of houttuynoids, highlighting a diverse chemical toolkit that includes Corey–Fuchs alkynylation, Claisen–Schmidt condensation, Oxa–Michael addition, and metal-catalyzed transformations such as Sonogashira and Heck coupling. We further examine the utility of endo-dig cyclization, Baker–Venkataraman rearrangement, and selective oxidation protocols including Pinnick and Rubottom oxidation. By synthesizing current data on synthetic routes, structure–activity relationships (SARs), and antiviral efficacy, this work provides a blueprint for the design of next-generation houttuynoid analogues with enhanced pharmacological profiles.