Novel quinolinonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, and biological activities.
Novel quinolinonyl diketo acids were designed to obtain integrase (IN) inhibitors selectively active against the strand transfer (ST) step of the HIV integration process. Those new compounds are characterized by a single aryl diketo acid (DKA) chain in comparison to 4, a bifunctional diketo acid reported by our group as an anti-IN agent highly potent against both the 3'-processing and ST steps. Compound 6d was the most potent derivative in IN enzyme assays, while 6i showed the highest potency against HIV-1 in acutely infected cells. The selective inhibition of ST suggested the newly designed monofunctional DKAs bind the IN-DNA acceptor site without affecting the DNA donor site.
Di Santo
Roberto
R
Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur, Fondazione Cenci BolognettiUniversità di Roma, La Sapienza, Roma, Italy. roberto.disanto@uniroma1.it
Costi
Roberta
R
Roux
Alessandra
A
Miele
Gaetano
G
Crucitti
Giuliana Cuzzucoli
GC
Iacovo
Alberto
A
Rosi
Federica
F
Lavecchia
Antonio
A
Marinelli
Luciana
L
Di Giovanni
Carmen
C
Novellino
Ettore
E
Palmisano
Lucia
L
Andreotti
Mauro
M
Amici
Roberta
R
Galluzzo
Clementina Maria
CM
Nencioni
Lucia
L
Palamara
Anna Teresa
AT
Pommier
Yves
Y
Marchand
Christophe
C
D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007651:Keto Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D011804:Quinolines; C037219:quinoline