title: Design, synthesis, and biological evaluation of novel 2H-pyran-2-one derivatives as potential HIV-1 reverse transcriptase inhibitors.
abstract: In search for more effective drugs against HIV infection acting as non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of new molecules with hybrid structures based on the natural product (+)-calanolide A and the synthetic molecule α-APA, known as potent and selective inhibitors of this enzyme, were selected by docking calculations. A convergent synthetic strategy gave 21 compounds with a 2H-pyran-2-one structural unit and bearing isosteric modifications, which were tested against HIV-infected CEM cell cultures. Only compound 6 (4-((2-(1H-indol-3-yl)ethyl)amino)-6-methyl-2H-pyran-2-one) displayed inhibitory activity (EC50 : 25-50 µM). However, it was associated with a relatively high cytostatic effect on human T lymphocyte (CEM) cell cultures, not easily predictable, neither by the chemical structure nor by the computational approach. Although this drug design has failed in selecting a novel scaffold for NNRTIs, the results have driven the interest towards new potential antitumor molecules showing activity against L1210 murine leukemia and HeLa cervix carcinoma cells, among which compound 21 (6-methyl-4-((2-(naphthalen-1-yl)ethyl)sulfonyl)-2H-pyran-2-one) was the most effective (IC50 : 0.95 and 2.9 µM, respectively).
authors.affiliation: Dipartimento di Fisica, Università degli studi di Trento, Povo, Trento, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Defant
authors.forename: Ines
authors.initials: I
authors.lastname: Mancini
authors.forename: Rossella
authors.initials: R
authors.lastname: Tomazzolli
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011714:Pyrans / Q000138:chemical synthesis* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D011714:Pyrans; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: Cytotoxic activity; HIV-1; NNRTIs; Rational drug design