Lupane-type
pentacyclic triterpenes such as
betulin and
betulinic acid play an important role in the search for new
therapies that would be effective in controlling
viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for
phosphate derivatives of 3-carboxyacylbetulin 3-5 as well as an in silico study of new compounds as potential
ligands of the C-terminal domain of the HIV-1 capsid-spacer
peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3',3'-dimethylsuccinyl)betulin (compound 3), the
phosphate analog of
bevirimat (
betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to
bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the
phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)-spacer
peptide 1 (SP1) fragment of
Gag protein, designated as CTD-SP1. Compared with interactions between
bevirimat (BVM) and the
protein, an increased number of strong interactions between
ligand 3 and the
protein, generated by the
phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2
proteins, in as far as the intrinsically imprecise docking scores suggest.