Non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis and biological evaluation of novel quinoxalinylethylpyridylthioureas as potent antiviral agents.
New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L1001, K103N, V106A, Y1811 and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.
Campiani
G
G
Dipartimento di Scienze Farmaceutiche, Facolta' di Farmacia, Universita' degli Studi di Salerno, Fisciano (Salerno), Italy. campiani@unisa.it
Fabbrini
M
M
Morelli
E
E
Nacci
V
V
Greco
G
G
Novellino
E
E
Maga
G
G
Spadari
S
S
Bergamini
A
A
Faggioli
E
E
Uccella
I
I
Bolacchi
F
F
Marini
S
S
Coletta
M
M
Fracasso
C
C
Caccia
S
S
D019943:Amino Acid Substitution; D000818:Animals; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009154:Mutation; D009705:Nucleosides / Q000737:chemistry; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
C413464:N-(2-(6-fluoro-4-oxopyrrolo(1,2-a)quinoxalin-5-yl)ethyl)-N'-(2-(5-bromopyridyl))thiourea; D009705:Nucleosides; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D013890:Thiourea