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The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) ( 1 ) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of derivatives were synthesized. The synthesized compounds were characterized by 1H NMR, IR, UV, and mass spectrometry. In addition, several of the synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single round infection assay using TZM-bl cells at 100 ng/mL. TFV ( 1 ) was used as a positive control and inhibited HIV infection by 35%. Among all the evaluated compounds, the disubstituted heptanolyl ester alanine phosphonamidate with naphthol oleate ( 69 ), pentanolyl ester alanine phosphonamidate with phenol oleate ( 62 ), and butanolyl ester alanine phosphonamidate with naphthol oleate ( 87 ) ester conjugates of TFV were more potent than parent drug TFV with 79.0%, 76.5%, 71.5% inhibition, respectively, at 100 ng/mL. Furthermore, two fatty acyl amide conjugates of tenofovir alafenamide (TAF) were synthesized and evaluated for comparative studies with TAF and TFV conjugates. Tetradecanoyl TAF conjugate 95 inhibited HIV infection by 99.6% at 100 ng/mL and showed comparable activity to TAF (97-99% inhibition) at 10-100 ng/mL but was more potent than TAF when compared at molar concentration.

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5'- O -fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC 50 value of 0.07 µM against HCoV-229E with TC 50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5'- O -fatty acyl conjugates of NRTIs, 5'- O -tetradecanoyl ester conjugate of FTC showed modest activity with EC 50 and TC 50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.

Lipophilic 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG) was evaluated for its improved lymph node delivery by comparison with the parental nucleoside (ddG) in vitro and in vivo. The in vitro studies with rat plasma, lymph node homogenate and stomach content indicated that 6-Cl-ddG converted to ddG more effectively in the lymph node homogenate and that 6-Cl-ddG was more stable than ddG in the stomach content. In an in vivo study, plasma and lymph nodes were collected from rats after a subcutaneous or oral administration of 6-Cl-ddG or ddG. With the subcutaneous administrations of the drugs, the area under the concentration time-curve (AUC) value in the plasma for converted ddG following a 6-Cl-ddG administration was less than half the value for ddG following a ddG administration but the converted ddG AUC values in the lymph nodes due to 6-Cl-ddG administration were 1.4- to 2.0-fold higher than the ddG AUC values due to ddG administration. Moreover, with the oral administrations, the converted ddG AUC value in plasma after a 6-Cl-ddG administration was 3-fold higher than ddG after a ddG administration, and high levels of converted ddG were detected in the lymph nodes, but no ddG was detected in the lymph node following ddG administration. These results suggest that lipophilic 6-Cl-ddG is a useful prodrug for delivering ddG into the lymph nodes by oral administration.

Spathodea campanulata stem bark decoction (SCD) has shown hypoglycemic activity in mice. It was separated by column chromatography into different fractions, which were evaluated for their hypoglycemic, anticomplement and anti-HIV activities. The most polar fraction exerted by far the most prominent effect in different biological models.