Dihydro-alkylthio-benzyl-oxopyrimidines as inhibitors of reverse transcriptase: synthesis and rationalization of the biological data on both wild-type enzyme and relevant clinical mutants.
A series of novel S-DABO analogues, characterized by different substitution patterns at positions 2, 5, and 6 of the heterocyclic ring, were synthesized in a straightforward fashion by means of parallel synthesis and evaluated as inhibitors of human immunodeficiency virus type-1 (HIV-1). Most of the compounds proved to be highly active on the wild-type enzyme both in enzymatic and cellular assays, with one of them emerging as the most active reverse transcriptase inhibitor reported so far (EC50wt=25 pM). The general loss of potency displayed by the compounds toward clinically relevant mutant strains was deeply studied through a molecular modeling approach, leading to the evidence that the dynamic of the entrance in the non-nucleoside binding pocket could represent the basis of the inhibitory activity of the molecules.
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via Alcide De Gasperi 2, I-53100 Siena, Italy.
Claudia
C
Mugnaini
Maddalena
M
Alongi
Andrea
A
Togninelli
Harsukh
H
Gevariya
Antonella
A
Brizzi
Fabrizio
F
Manetti
Cesare
C
Bernardini
Lucilla
L
Angeli
Andrea
A
Tafi
Luca
L
Bellucci
Federico
F
Corelli
Silvio
S
Massa
Giovanni
G
Maga
Alberta
A
Samuele
Marcella
M
Facchini
Imma
I
Clotet-Codina
Mercedes
M
Armand-Ugón
José A
JA
Esté
Maurizio
M
Botta
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D019380:Anti-HIV Agents; D011743:Pyrimidines; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase