Design and synthesis of fluorescent pilicides and curlicides: bioactive tools to study bacterial virulence mechanisms.
Bottom Line: To facilitate studies of the interaction between these compounds and the pili and curli assembly systems, fluorescent pilicides and curlicides have been synthesized.This was achieved by using a strategy based on structure-activity knowledge, in which key pilicide and curlicide substituents on the ring-fused dihydrothiazolo 2-pyridone central fragment were replaced by fluorophores.We created fluorescent pilicides and curlicides by introducing coumarin and 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) fluorophores at two positions on the peptidomimetic pilicide and curlicide central fragment.
Affiliation: Department of Chemistry, Umeå University, 90187 Umeå, Sweden.Show MeSH
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Mentions: The photophysical evaluation of 11 a–d showed relatively low quantum yields of fluorescence (ΦF, Table 1). The C8 phenyl-substituted 11 a displayed highest quantum yield (ΦF=5 %), followed by the C8 3-trifluomethylphenyl-substituted 11 b (ΦF=1 %), the C8 2-thiophenyl-substituted 11 c (ΦF=0.7 %), and finally the C8 cyclopropyl-substituted 11 d (ΦF=0.4 %). These results may be due to a quenching effect of the fluorophore by the neighboring dihydrothiazolo ring-fused 2-pyridone pilicide/curlicide central fragment. In an attempt to circumvent this, the linker between the fluorophore and the 2-pyridone central fragment was increased by a one carbon extension. This was realized by using deprotonated 4-methyl coumarins as nucleophiles on bromomethyl-substituted 2-pyridone central fragments. By using this strategy the introduction of both a 7-methoxy-substituted coumarin and a 7-diethylamine-substituted coumarin could be accomplished (Scheme 2). The intermediate bromomethyl-substituted 2-pyridone central fragments (13 a and 13 b) were synthesized following a previously published procedure.23 Addition of lithiated coumarins (14 a and 14 b) to 13 a and 13 b generated the one carbon extended coumarin-substituted ring-fused 2-pyridones 15 a–d in 74–83 % yield. Subsequent hydrolysis rendered 16 a–d in high yields (81–91 %; Scheme 2).
Affiliation: Department of Chemistry, Umeå University, 90187 Umeå, Sweden.