title: Parallel solution-phase and microwave-assisted synthesis of new S-DABO derivatives endowed with subnanomolar anti-HIV-1 activity.
abstract: A simple and efficient methodology for the parallel solution-phase synthesis has been set up to obtain a series of thiouracils, in turn selectively S-benzylated under microwave irradiation to give new S-DABOs. Biological screening led to the identification of compounds with nanomolar activity toward both the highly purified recombinant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) enzyme (wild-type and mutants) and wild-type (wt) and mutant HIV-1 strains. In particular, 20 was found to be the most potent S-DABO reported so far (ID50 = 26 nM toward the isolated wt enzyme) with subnanomolar activity toward both the wt and the pluriresistant virus (IRLL98) HIV-1 strain (EC50 < 0.14 nM and EC50 = 0.22 nM, respectively). Molecular modeling calculations were also performed to investigate the binding mode of such compounds onto the non-nucleoside reverse transcriptase inhibitor binding site and to rationalize the relationships between their chemical structure and activity values toward wt RT.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Imma
authors.initials: I
authors.lastname: Clotet-Codina
authors.forename: Mercedes
authors.initials: M
authors.lastname: Armand-Ugón
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Reynel
authors.initials: R
authors.lastname: Cancio
authors.forename: Claudia
authors.initials: C
authors.lastname: Mugnaini
authors.forename: Cesare
authors.initials: C
authors.lastname: Bernardini
authors.forename: Andrea
authors.initials: A
authors.lastname: Togninelli
authors.forename: Caterina
authors.initials: C
authors.lastname: Carmi
authors.forename: Maddalena
authors.initials: M
authors.lastname: Alongi
authors.forename: Elena
authors.initials: E
authors.lastname: Petricci
authors.forename: Silvio
authors.initials: S
authors.lastname: Massa
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D024921:Drug Resistance, Multiple, Viral; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008872:Microwaves; D008958:Models, Molecular; D009154:Mutation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: C507633:6-(2,6-dichlorobenzyl)-2-(2-(4-methoxyphenyl)ethylthio)-5-methylpyrimdin-4(3H)-one; D019380:Anti-HIV Agents; D011743:Pyrimidines; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D012996:Solutions; D054303:HIV Reverse Transcriptase