title: Discovery of chiral cyclopropyl dihydro-alkylthio-benzyl-oxopyrimidine (S-DABO) derivatives as potent HIV-1 reverse transcriptase inhibitors with high activity against clinically relevant mutants.
abstract: The role played by stereochemistry in the C2-substituent (left part) on the S-DABO scaffold for anti-HIV-1 activity has been investigated for the first time. A series of S-DABO analogues, where the double bond in the C2-substituent is replaced by an enantiopure isosteric cyclopropyl moiety, has been synthesized, leading to the identification of a potent lead compound endowed with picomolar activity against RT (wt) and nanomolar activity against selected drug-resistant mutants. Molecular modeling calculation, enzymatic studies, and surface plasmon resonance experiments allowed us to rationalize the biological behavior of the synthesized compounds, which act as mixed-type inhibitors of HIV-1 RT K103N, with a preferential association to the enzyme-substrate complex. Taken together, our data show that the right combination of stereochemistry on the left and right parts (C6-substituent) of the S-DABO scaffold plays a key role in the inhibition of both wild-type and drug-resistant enzymes, especially the K103N mutant.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, University of Siena,Via Alcide de Gasperi 2, I-53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Maddalena
authors.initials: M
authors.lastname: Alongi
authors.forename: Lucilla
authors.initials: L
authors.lastname: Angeli
authors.forename: Alberta
authors.initials: A
authors.lastname: Samuele
authors.forename: Samantha
authors.initials: S
authors.lastname: Zanoli
authors.forename: Luca
authors.initials: L
authors.lastname: Bellucci
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
authors.forename: Gianni
authors.initials: G
authors.lastname: Casaluce
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Mercedes
authors.initials: M
authors.lastname: Armand-Ugon
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gonzalez
authors.forename: José A
authors.initials: JA
authors.lastname: Esté
authors.forename: Mireille
authors.initials: M
authors.lastname: Baltzinger
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bec
authors.forename: Philippe
authors.initials: P
authors.lastname: Dumas
authors.forename: Eric
authors.initials: E
authors.lastname: Ennifar
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D045744:Cell Line, Tumor; D003198:Computer Simulation; D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D009154:Mutation; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology*; D020349:Surface Plasmon Resonance
chemical_list: D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase