Parallel synthesis, molecular modelling and further structure-activity relationship studies of new acylthiocarbamates as potent non-nucleoside HIV-1 reverse transcriptase inhibitors.
The structure-activity relationships (SARs) of acylthiocarbamates (ATCs), a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors, have been expanded. Sixty-six new analogues were prepared by parallel solution-phase synthesis. In general, the potency of new ATCs was better than that of the first series and O-[2-phthalimidoethyl] 4-chlorophenyl(3-nitrobenzoyl) thiocarbamate turned out to be the most potent ATC so far synthesized (EC(50)=1.5nM). Several ATCs were active at micromolar concentrations against HIV-1 strains carrying the RT Y181C mutation and one of them was also moderately active against the K103R variant. Docking simulations were carried out to rationalize the most relevant SARs.
Spallarossa
Andrea
A
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy.
Cesarini
Sara
S
Ranise
Angelo
A
Schenone
Silvia
S
Bruno
Olga
O
Borassi
Alberto
A
La Colla
Paolo
P
Pezzullo
Margherita
M
Sanna
Giuseppina
G
Collu
Gabriella
G
Secci
Barbara
B
Loddo
Roberta
R
D003198:Computer Simulation; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D008958:Models, Molecular; D020125:Mutation, Missense; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology
D018894:Reverse Transcriptase Inhibitors; D013859:Thiocarbamates; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase