Antinociceptive Benzothiazine and Benzothiazole Natural Products from Marine Croceibacter atlanticus

With the goal of identifying new therapeutic leads to treat pain, we screened a library of microbial chemical extracts using the Embryonic Zebrafish Irritant-evoked Hyperlocomotion (EZIH) assay, an in vivo phenotypic assay for analgesic/antinociceptive activity. We found that extracts from the bacterium Croceibacter atlanticus substantially altered behavioral responses. Using behavior-guided fractionation to identify the active partitions, we determined that the known 1,4-benzothiazin-3-one BPSS2111-2113:C and the new benzothiazole croceithiazole A suppress behavioral responses to painful and/or nociceptive stimuli without apparent acute toxicity. Further investigation with radioligand binding assays revealed that BPSS2111-2113:C shows selective binding to both the serotonin receptor 5-HT2B and the benzodiazepine site of GABAA receptors, while croceithiazole A appears to bind the peripheral benzodiazepine receptor. These results suggest that BPSS2111-2113:C and croceithiazole A are interesting leads as analgesics, sedatives, anesthetics, or molecular probes.