Bicyclic bridged isothioureas: synthesis and evaluation of activity in a model of lipopolysaccharide-induced septic shock

A convenient synthetic pathway to bridged isothioureas via cyclization of tert-butyl-substituted cyclohex-3-en-1-ylthiourea by the action of bromine has been developed. The effective use of tert-butyl protective group was demonstrated, and the crystal structure of synthesized (3aRS,7SR,7aRS)-7-bromo-3a,4, 5,6,7,7a-hexahydro-1,3-benzothiazol-2-amine hydrobromide was determined by X-ray analysis. (1RS,5SR)-2-Thia-4-aza-bicyclo[3.3.1]non-3-en-3-amine as a strong inducible nitric oxide synthase inhibitor in vitro surprisingly caused additional hypotension in LPS-induced acute endotoxic shock model while its C⁸-hydroxy-derivative displayed prominent and durable vasoconstrictive effect.