New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

Abstract

Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.

Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study

“…The above-mentioned literature data and results of the anti-HIV activity test obtained for phosphate and phosphonate derivatives of betulinic acid [ 12 ] have become the starting point for the synthesis of betulin phosphate derivatives. The obtained compounds have a carboxyacyl group in position C3, whose presence is important for action against HIV-1, and a diethyl phosphate group in position C28 ( Scheme 1 ).…”

“…Corresponding phosphorus derivative 4 demonstrated good activity and selectivity that were higher than obtained for 4′,4′-dimethylglutaric derivative 5 . On the other hand, compound 4 was more active than the previously described 3′,3′-dimethylglutaric derivatives of betulinic acid, which in the C30 position contained a diethylphosphate or diethylphosphonate group (IC 50 = 0.6 μM and 0.9 μM, respectively) [ 12 ].…”

“…Synthesis of BVM [3- O -(3’,3’-dimethylsuccinyl)betulinic acid], used in the study as a reference, was performed as was previously described [ 12 ]. The final product was obtained at a yield of 70%.…”

“…Indeed, several patents describing phosphorus derivatives of triterpenes with antiviral activity can be found in the literature [ 9 , 10 , 11 ]. Anti-HIV-1 activity has also been reported for BVM analogues that contain a phosphate or phosphonate substituent in the isopropenyl moiety [ 12 ]. For example, 30-diethoxyphosphoryl-3- O -(3′,3′-dimethylsuccinyl)betulinic acid described in the work [ 12 ] demonstrates in vitro anti-HIV-1 activity with an IC 50 value similar to that of BVM, and with a lower cytotoxicity.…”

“…Anti-HIV-1 activity has also been reported for BVM analogues that contain a phosphate or phosphonate substituent in the isopropenyl moiety [ 12 ]. For example, 30-diethoxyphosphoryl-3- O -(3′,3′-dimethylsuccinyl)betulinic acid described in the work [ 12 ] demonstrates in vitro anti-HIV-1 activity with an IC 50 value similar to that of BVM, and with a lower cytotoxicity. The results of molecular docking into the Gag C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) fragment, which is the molecular target of maturation inhibitors, suggest that the potential molecular mechanism of these compounds may be the same, but is further enhanced by the introduction of a phosphonate moiety [ 12 ].…”