Betulin-Derived Compounds as Inhibitors of Alphavirus Replication

This paper describes inhibition of Semliki Forest virus (SFV) replication by synthetic derivatives of naturally occurring triterpenoid betulin (<b>1</b>). Chemical modifications were made to OH groups at C-3 and C-28 and to the C-20−C-29 double bond. A set of heterocyclic betulin derivatives was also assayed. A free or acetylated OH group at C-3 was identified as an important structural contributor for anti-SFV activity, 3,28-di-<i>O</i>-acetylbetulin (<b>4</b>) being the most potent derivative (IC<sub>50</sub> value 9.1 μM). Betulinic acid (<b>13</b>), 28-<i>O</i>-tetrahydropyranylbetulin (<b>17</b>), and a triazolidine derivative (<b>41</b>) were also shown to inhibit Sindbis virus, with IC<sub>50</sub> values of 0.5, 1.9, and 6.1 μM, respectively. The latter three compounds also had significant synergistic effects against SFV when combined with 3′-amino-3′-deoxyadenosine. In contrast to previous work on other viruses, the antiviral activity of <b>13</b> was mapped to take place in virus replication phase. The efficacy was also shown to be independent of external guanosine supplementation.