Coumarins and pyranocoumarins, potential novel pharmacophores for inhibition of measles virus replication.
A series of coumarin and pyranocoumarin analogues were evaluated in vitro for antiviral efficacy against measles virus (MV), strain Chicago. Of the 22 compounds tested for inhibition, six were found to have selectivity indices greater than 10. These were compounds 5-hydroxy-7-propionyloxy-4-propylcoumarin (2a), 5,7-bis(tosyloxy)-4-propylcoumarin (7); 5-hydroxy-4-propyl-7-tosyloxy-coumarin (8); 6,6-dimethyl-9-propionyloxy-4-propyl-2H,6H-benzo[1,2-b:3,4-b']dipyran-2-one (9); 6,6-dimethyl-9-pivaloyloxy-4-propyl-2H,6H-benzo[1,2-b:3,4-b']dipyran-2-one (10); and 7,8-cis-10,11,12-trans-4-propyl-6,6,10,11-tetramethyl-7,8,9-trihydroxy-2H,6H,12H-benzo[1 ,2-b:3,4-b':5,6-b'']tripyran-2-one (18). Three of the active drugs were propyl coumarin analogues (2a, 7 and 8), two were dipyranone or chromeno-coumarins (9 and 10), and one was a benzotripyranone with a coumarin nucleus (18). Some appeared to be rather specific and potent inhibitors of MV with EC50 values ranging from 0.2 to 50 microg/ml and the majority of the EC50 values being less than 5 pg/ml. The compounds inhibited an additional nine strains of MV, and in virucidal tests the drugs did not physically disrupt the virion to inhibit virus replication. The inhibitory activity for one of the compounds tested (7) was somewhat dependent on virus concentration and it was still active when added to cells up to 24 h after virus exposure. When used in combination with ribavirin, compound 7 appeared not to profoundly affect the antiviral efficacy of ribavirin or its cell-associated toxicity. However, a slightly antagonistic MV-inhibitory effect was observed at the highest concentration of ribavirin used in combination with most concentrations of compound 7 tested. This and related compounds may be valuable leads in the development of a potent and selective class of MV inhibitors that could be used in future in the clinic.
Barnard
Dale L
DL
Institute for Antiviral Research, Utah State University, Logan, USA. honery@cc.usu.edu
Xu
Z e Q i
Ze
Stowell
Valerie D
VD
Yuan
Hongwei
H
Smee
Donald F
DF
Samy
Raghu
R
Sidwell
Robert W
RW
Nielsen
M Kim
MK
Sun
Lihui
L
Cao
Hua
H
Li
Ailing
A
Quint
Clay
C
Deignan
Jeffrey
J
Crabb
Jennifer
J
Flavin
Michael T
MT
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004396:Coloring Agents / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003588:Cytopathogenic Effect, Viral; D004357:Drug Synergism; D006801:Humans; D020128:Inhibitory Concentration 50; D008459:Measles virus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D009499:Neutral Red / Q000378:metabolism; D039681:Pyranocoumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D012254:Ribavirin / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014771:Virion / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004396:Coloring Agents; D003374:Coumarins; D039681:Pyranocoumarins; D009499:Neutral Red; D012254:Ribavirin