Introduction
Influenza, abbreviated as influenza (influenza or flu), is an acute respiratory infectious disease caused by infection with the influenza virus and has become the viral infectious disease with the highest mortality rate. The influenza virus belongs to the Orthomyxoviridae family and is a single-stranded, negative-sense, segmented RNA virus. Individuals aged 65 years or older, children under 2 years of age, and those with chronic respiratory or cardiovascular diseases are at higher risk of developing influenza complications, making them high-risk populations for influenza. Currently, the main pharmacological treatments available in China for influenza include M2 ion channel inhibitors (such as amantadine and rimantadine), neuraminidase (NA) inhibitors (such as zanamivir and oseltamivir), and hemagglutinin HA inhibitors (e.g., Arbidol; Figure 1). Vaccination is the primary method for influenza prevention.
Figure 1 Common influenza medications
According to the 2020 Influenza Diagnosis and Treatment Guidelines, amantadine and oseltamivir are no longer recommended due to resistance in influenza virus strains; arbidol, a hemagglutinin HA inhibitor, requires close monitoring of efficacy and adverse reactions given limited clinical data.
Currently, the primary medications available for treating influenza A and other influenza strains are oseltamivir and baloxavir marboxil (Xofluza) [1]. Unlike M2 ion channel inhibitors, neuraminidase (NA) inhibitors, or hemagglutinin HA inhibitors, baloxavir marboxil (Xofluza) is a selective cap-dependent endonuclease inhibitor. This drug has a long half-life, requiring only a single dose throughout the treatment course.
Baloxavir marboxil: Its Past and Present
Baloxavir marboxil (Xofluza) is a prodrug that is metabolized in vivo by arylacetamide deacetylase into its active form, baloxavir acid [1] (Figure 2a). It was initially developed by SHIONOGI & CO., LTD., based on modifications to the HIV integrase inhibitor dorlevir. Subsequently, Roche Pharmaceuticals of Switzerland partnered with the company to jointly oversee the development and commercialization of baloxavir, with Roche also responsible for global sales outside Japan and Taiwan. In February 2018, it received initial approval in Japan for the treatment of influenza A and B infections in patients aged 12 years and older. In December of the same year, the FDA approved its marketing authorization. By April 2021, baloxavir was approved for use in China and included in the national drug reimbursement list in December of the same year (Figure 2b). Notably, in addition to tablets, a dry suspension formulation is also available.
Figure 2: Mechanism of action and time of market approval
Industrial Synthesis of Baloxavir marboxil
【First-generation synthesis route】
【Second-generation synthetic route】
【Third-generation synthetic route】
Closing Remarks
The established synthetic route for Baloxavir marboxil represents a significant advancement in the field of anti-influenza drug development. From initial laboratory exploration to current industrial-scale production, its synthesis process has been continuously optimized in terms of atomic economy, step efficiency, and environmental friendliness. Looking ahead, the introduction of emerging technologies such as continuous flow chemistry and biocatalysis is expected to further enhance its synthetic efficiency. Moreover, this successful model inspires researchers to design and synthesize additional antiviral drugs with novel mechanisms of action, thereby expanding the arsenal available for addressing global influenza threats.
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