Structure modifications of 6-aminoquinolones with potent anti-HIV activity.
We have recently discovered that 6-aminoquinolone derivatives could be valid leads for the development of new anti-HIV agents because of their new and diversified mode of action. In fact, studies carried out on the lead WM5 showed that this derivative is able to inhibit the Tat-mediated long terminal repeat driven transcription, an essential step in the HIV-1 replication cycle. Thus, starting from lead WM5, we performed the design and synthesis of an enlarged series of 6-aminoquinolones, which permitted some very potent anti-HIV 6-amino derivatives to be obtained and the structure-activity relationship to be delineated. Some derivatives, 26c, 26e, 26i, and 26j, proved to be highly effective in inhibiting HIV replication at 50% inhibitory concentration in the range of 0.0087-0.7 microg/mL in MT-4, PBMCs and CEM cell lines coupled with positive selectivity indexes that reach values higher than 1000 on CEM cell lines for compounds 26e and 26i. Time-of-addition experiments clearly confirm that the new, potent 6-aminoquinolones interact at a postintegration step in the replication cycle of HIV.
Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy.
Oriana
O
Tabarrini
Miguel
M
Stevens
Violetta
V
Cecchetti
Stefano
S
Sabatini
Micaela
M
Dell'Uomo
Giuseppe
G
Manfroni
Manlio
M
Palumbo
Christophe
C
Pannecouque
Erik
E
De Clercq
Arnaldo
A
Fravolini
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D000634:Aminoquinolines; D019380:Anti-HIV Agents