Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir
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 be...
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MDPI AG
2022-07-01
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| author | Aaminat Qureshi Louise A. Ouattara Naglaa Salem El-Sayed Amita Verma Gustavo F. Doncel Muhammad Iqbal Choudhary Hina Siddiqui Keykavous Parang |
| author_facet | Aaminat Qureshi Louise A. Ouattara Naglaa Salem El-Sayed Amita Verma Gustavo F. Doncel Muhammad Iqbal Choudhary Hina Siddiqui Keykavous Parang |
| author_sort | Aaminat Qureshi |
| collection | DOAJ |
| description | 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) (<b>1</b>) 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 (<b>1</b>) 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 (<b>69</b>), pentanolyl ester alanine phosphonamidate with phenol oleate (<b>62</b>), and butanolyl ester alanine phosphonamidate with naphthol oleate (<b>87</b>) 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 <b>95</b> 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. |
| first_indexed | 2024-03-09T10:14:08Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T10:14:08Z |
| publishDate | 2022-07-01 |
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| spelling | doaj.art-1edcf300ec62427ebb5514d9430ed7f82023-12-01T22:29:46ZengMDPI AGMolecules1420-30492022-07-012714444710.3390/molecules27144447Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of TenofovirAaminat Qureshi0Louise A. Ouattara1Naglaa Salem El-Sayed2Amita Verma3Gustavo F. Doncel4Muhammad Iqbal Choudhary5Hina Siddiqui6Keykavous Parang7H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanCONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USACenter for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USACenter for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USACONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USAH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, PakistanCenter for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USAThe 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) (<b>1</b>) 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 (<b>1</b>) 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 (<b>69</b>), pentanolyl ester alanine phosphonamidate with phenol oleate (<b>62</b>), and butanolyl ester alanine phosphonamidate with naphthol oleate (<b>87</b>) 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 <b>95</b> 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.https://www.mdpi.com/1420-3049/27/14/4447anti-HIV activityester conjugates of TFVphosphonamidatetenofovir (TFV)tenofovir alafenamide (TAF) |
| spellingShingle | Aaminat Qureshi Louise A. Ouattara Naglaa Salem El-Sayed Amita Verma Gustavo F. Doncel Muhammad Iqbal Choudhary Hina Siddiqui Keykavous Parang Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir Molecules anti-HIV activity ester conjugates of TFV phosphonamidate tenofovir (TFV) tenofovir alafenamide (TAF) |
| title | Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir |
| title_full | Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir |
| title_fullStr | Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir |
| title_full_unstemmed | Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir |
| title_short | Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir |
| title_sort | synthesis and evaluation of anti hiv activity of mono and di substituted phosphonamidate conjugates of tenofovir |
| topic | anti-HIV activity ester conjugates of TFV phosphonamidate tenofovir (TFV) tenofovir alafenamide (TAF) |
| url | https://www.mdpi.com/1420-3049/27/14/4447 |
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