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, the houttuynoids are unique class of flavonoid based metabolites isolated from Hottuynia 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 chemobilogical investigation and lead optimization. This review delineates the total synthesis of houttuynoids, highlighting a diverse chemical toolkit that includes Corey-Fuchs alkynylation, Claisen-Schmidt and Oxa-Michael additions, and metal-catalyzed transformations such as Sonogashira and Heck couplings. We further examine the utility of Endo-dig cyclizations, Baker-Venkataraman, rearrangements, and selective oxidative protocols including Pinnick and Rubottom oxidations. By synthesizing current data on synthetic routes, structure-activity relationships (SAR), and antiviral efficacy, this work provides a blueprint for the design of next-generation houttuynoid analogues with enhanced pharmacological profiles.