The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 μM and from 0.5 to 6.1 μM were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 μM (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 μM in CEM-SS and 19 and 2 μM in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity.

Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 μM and from 0.5 to 6.1 μM were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 μM (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 μM in CEM-SS and 19 and 2 μM in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity.

Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 μM and from 0.5 to 6.1 μM were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 μM (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 μM in CEM-SS and 19 and 2 μM in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity.

Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 μM and from 0.5 to 6.1 μM were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 μM (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 μM in CEM-SS and 19 and 2 μM in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity.

Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 μM and from 0.5 to 6.1 μM were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 μM (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 μM in CEM-SS and 19 and 2 μM in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity.

Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 μM and from 0.5 to 6.1 μM were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 μM (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 μM in CEM-SS and 19 and 2 μM in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity.

Concerning the phosphoramidate series, low anti-HIV activities ranging from 70 nM to 1.9 μM and from 0.5 to 6.1 μM were measured when TK+ CEM-SS and MT-4 cells were incubated with these derivatives, respectively. Although these prodrugs degraded very rapidly, these values are much higher than that of AZT, indicating that (i) AZT is not the major metabolite that has been released upon hydrolysis in the extra- and intra-cellular medium, (ii) AZT-MP has not been released at an efficient inhibitory level into the intracellular medium, and/or (iii) the other metabolites are poor anti-HIV active agents. It is noteworthy that the highest antiviral activity was achieved by the prodrug that released the largest amount of AZT, that is, 21. That its antiviral activity is related to AZT and not to AZT-MP is further supported by the absence of inhibition measured on TK- cells. However, among the eight phosphoramidate conjugates 15-22, six were found to have a weak inhibitory activity on HIV replication in TK- CEM cells with IC50 values of about 40-100 μM (for example, 15-18, 20 and 22). This could indicate that a low amount of free AZT-MP has been released into the cells. However, two of these conjugates (15 and 16) were found to be moderately toxic in CEM-SS and MT-4 cells (CC50 of 40 and 18 μM in CEM-SS and 19 and 2 μM in MT-4 cells, respectively). On TK- CEM cells, the IC50 and the CC50 of compound 15 are very close, indicating a non-specific antiviral activity.