{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T04:26:56Z","timestamp":1787286416042,"version":"build-2736575974"},"reference-count":34,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T00:00:00Z","timestamp":1657584000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chapman University School of Pharmacy"},{"name":"Eastern Virginia Medical School"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u201399% inhibition) at 10\u2013100 ng\/mL but was more potent than TAF when compared at molar concentration.<\/jats:p>","DOI":"10.3390\/molecules27144447","type":"journal-article","created":{"date-parts":[[2022,7,12]],"date-time":"2022-07-12T03:50:36Z","timestamp":1657597836000},"page":"4447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["RETRACTED: Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir"],"prefix":"10.3390","volume":"27","author":[{"given":"Aaminat","family":"Qureshi","sequence":"first","affiliation":[{"name":"H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Ouattara","sequence":"additional","affiliation":[{"name":"CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naglaa","family":"El-Sayed","sequence":"additional","affiliation":[{"name":"Center 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, USA"},{"name":"Cellulose and Paper Department, National Research Center, Dokki, Cairo 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6653-7335","authenticated-orcid":false,"given":"Amita","family":"Verma","sequence":"additional","affiliation":[{"name":"Center 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, USA"},{"name":"Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo","family":"Doncel","sequence":"additional","affiliation":[{"name":"CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA 23507, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Choudhary","sequence":"additional","affiliation":[{"name":"H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"},{"name":"Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"},{"name":"Department of Biochemistry, King Abdul Aziz University, Jeddah 21452, Saudi Arabia"},{"name":"Department of Chemistry, Faculty of Science and Technology, Universitas Airlangga, Komplek Campus C, Surabaya 60115, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0432-2237","authenticated-orcid":false,"given":"Hina","family":"Siddiqui","sequence":"additional","affiliation":[{"name":"H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8600-0893","authenticated-orcid":false,"given":"Keykavous","family":"Parang","sequence":"additional","affiliation":[{"name":"Center 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, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"615","DOI":"10.2174\/1381612024607207","article-title":"Non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors: Past, present, and future perspectives","volume":"8","author":"Campiani","year":"2002","journal-title":"Curr. Pharm. 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