Optimization of potent and selective quinazolinediones: inhibitors of respiratory syncytial virus that block RNA-dependent RNA-polymerase complex activity.
A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC50 = 2.1 μM), moderate efficacy in reducing viral progeny (4.2 log at 10 μM), and marginal cytotoxic liability (selectivity index, SI ∼ 24). Scaffold optimization delivered analogs with improved potency and selectivity profiles. Most notable were compounds 15 and 19 (EC50 = 300-500 nM, CC50 > 50 μM, SI > 100), which significantly reduced viral titer (>400,000-fold), and several analogs were shown to block the activity of the RNA-dependent RNA-polymerase complex of RSV.
University of Kansas Specialized Chemistry Center, University of Kansas , Lawrence, Kansas 66047, United States.
Daljit S
DS
Matharu
Daniel P
DP
Flaherty
Denise S
DS
Simpson
Chad E
CE
Schroeder
Donghoon
D
Chung
Dan
D
Yan
James W
JW
Noah
Colleen B
CB
Jonsson
E Lucile
EL
White
Jeffrey
J
Aubé
Richard K
RK
Plemper
William E
WE
Severson
Jennifer E
JE
Golden
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018357:Respiratory Syncytial Virus Infections / Q000188:drug therapy* / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D001549:Benzamides; C000595866:N-(3-methoxypropyl)-4-((1-(4-nitrobenzyl)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl)benzamide; D052999:Quinazolinones; D012324:RNA-Dependent RNA Polymerase