Synthesis and characterization of 9-[P-(N, N-dipropyl sulfamide)] benzoylamino-1,2,3,4-4H-acridine--a potential prodrug for the CNS delivery of tacrine.

9-[P-(N,N-dipropylsulfamide)]benzoylamino-1,2,3,4-4H-acridine (PTHA) was synthesized as a prodrug to improve the curative effect of tacrine hydrochloride (THA), to prolong the activation time in brain, and to decrease the hepatic toxicity. The prodrug was prepared by attaching carboxyl group of probenecid to 9-amino group of THA. The structure of PTHA was confirmed by IR, HNMR, MS and UV. The physiochemical properties and stabilities of the prodrug under various conditions were investigated. Possibility of the prodrug passing through the blood-brain barrier (BBB) was evaluated in vitro by biopartition micellar chromatography (BMC). The concentrations of THA and PTHA in various tissues were determined by reversed-phase high-performance liquid chromatography after intravenous (i.v.) administration. The results showed PTHA was stable in various pHs and temperatures. It was indicated by partition coefficient in ethyl acetate/water that lipophilicity of the prodrug increased and it was predicted by BMC that the prodrug could improve the infiltration ability across BBB of THA. In-vivo experiment showed the concentrations of THA in brain and liver kept stable for about 4 h, which was beneficial for the treatment of Alzheimer's disease (AD). Compared with THA at the same time, AUC in liver decreases significantly, the overall targeting efficiency (TE) was enhanced from 10.97 to 16.11% and AUC(brain)/AUC(liver) increased from 1.52 to 2.53, which suggests the possibility to reduce the hepatic toxicity of THA by the way of the prodrug.