Synthesis of analogues of Congo red and evaluation of their anti-prion activity.
No cure as of yet exists for any of the transmissible spongiform encephalopathies. In this paper, we describe the synthesis of analogues of Congo red and evaluation against a cellular model of infection, the SMB (scrapie mouse brain) persistently infected cell line, for their ability to inhibit the infectivity of the abnormal form of prion protein (PrP-res). The compounds have also been tested for their ability to inhibit the polymerization of PrPC by PrP-res. A number of analogues showed inhibition of PrP-res infectivity at nanomolar concentrations. Several analogues show promise; the most active compound, 2a, inhibits the formation of PrP-res in SMB cells with an EC50 of 25-50 nM.
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK.
Shane
S
Sellarajah
Tamuna
T
Lekishvili
Claire
C
Bowring
Andrew R
AR
Thompsett
Helene
H
Rudyk
Christopher R
CR
Birkett
David R
DR
Brown
Ian H
IH
Gilbert
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000494:pharmacology; D001704:Biopolymers; D001713:Biphenyl Compounds; D001921:Brain / Q000473:pathology; D002460:Cell Line; D003224:Congo Red / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D062385:Hydroxybenzoates / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D018621:PrPC Proteins / Q000737:chemistry; D018620:PrPSc Proteins / Q000737:chemistry; D011328:Prions / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012608:Scrapie / Q000473:pathology; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
D001549:Benzamides; D001704:Biopolymers; D001713:Biphenyl Compounds; D062385:Hydroxybenzoates; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; C493521:bis(methyl 4-(((4'-(aminocarbonyl)-1,1'-biphenyl-4-yl)carbonyl)amino)-3-hydroxybenzoate); D003224:Congo Red