Review on fluorinated nucleoside/non-nucleoside FDA-approved antiviral drugs

Abstract

FDA-approved antiviral agents represent an important class that has attracted attention in recent years to combat current and future threats of viral pandemics. Fluorine ameliorates the electronic, lipophilic and steric problems of drugs. Additionally, fluorine can prolong drug activity and improve metabolic stability, thereby, modifying their pharmacodynamic and pharmacokinetic character. Herein, we summarized the fluorinated FDA-approved antiviral agents, dealing with biological aspects, mechanisms of action, and synthetic pathways.

Scheme 1. Synthesis of tecovirimat (7) from maleic anhydride.

Scheme 2. Synthesis of tecovirimat (7) from heptatriene.

Scheme 3. Synthesis of pleconaril (18) from dimethyl isoxazole 11 and oxirane 12.

Scheme 4. Synthesis of maraviroc 33 from tropinone 22.

Scheme 5. Synthesis of raltegravir 44 from oxadiazole acid chloride 34.

Scheme 6. Synthesis of elvitegravir (56) from difluoro-iodobenzoic acid 45.

Scheme 7. Synthesis of dolutegravir 69 from ethyl chloroacetoacetate 57.

Scheme 8. Synthesis of tipranavir (78) using molybdenum-catalyzed allylic alkylation.

Scheme 9. Synthesis of emtricitabine (88) from trans oxathiolane derivative 81.

Scheme 10. Synthesis of racivir from 2,4-dichloro-5-fluoropyrimidine (89).

Scheme 11. Synthesis of efavirenz 108 from p-chloroaniline (98).

Scheme 12. Synthesis of sofosbuvir (113) from fluorinated deoxynucleoside 110.

Scheme 13. Synthesis of ledipasvir (124) from 2-bromo-9,9-difluoro-7-iodo-9H-fluorene (114).

Scheme 14. Synthesis of trifluridine (127) from uridine.

Scheme 15. Synthesis of favipiravir (134) from pyrazine-2-carboxylate derivative 129.