Cloricromene conjugates with short-chain alkylamino acids: Synthesis and biological evaluation

Lipophilic amide conjugates of cloricromene (AD6) with alkylamino acids were designed in order to improve their central nervous system efficacy and to obtain more stable molecules in the bloodstream. In vivo effects on mean arterial blood pressure (MAP) and tumor necrosis factor (TNF)-alpha plasma levels in Sprague-Dawley rats subjected to endotoxic shock, induced by administration of Escherichia coli lipopolysaccharides (LPS) along with AD6 or its amide conjugates, were evaluated to assess whether the modification of the drug's carboxylic moiety through an amide bond would affect its pharmacological activity. LPS (4 mg kg(-1) iv) elicited a time-dependent decrease in MAP. Administration of AD6 conjugates 1 h prior to LIPS delayed the development of late-phase hypotension. LPS-induced increases in TNF-alpha plasma levels were also inhibited by the tested conjugates, with efficacies close to that of free AD6. In vitro stability studies of the conjugates indicated that they did not degrade rapidly into AD6 in the culture medium, suggesting that the observed effects can be ascribed to the conjugates themselves, and not to the cloricromene released after their hydrolytic degradation. (C) 2002 Wiley-Liss, Inc.