Novel central nervous system targeted semisynthetic penicillins.

Abstract

A novel series of semisynthetic penicillins was designed and synthesized. The compounds have as an integral part of the molecule a pyridinium <--> dihydropyridine redox system as a substituent at the 6-position. Esters of the dihydropyridine (pro-prodrug) forms of the drugs were expected, because of their pronounced lipophilic character, to easily penetrate biological membranes, including the blood-brain barrier, and to give rise to esters of polar pyridinium ions (prodrug) (via enzymic oxidation of the dihydropyridine moiety). The resulting ions were expected to be rapidly excreted from the periphery, but to be "locked" in the central nervous system; subsequent enzymic cleavage of the ester function was expected to release the free acid-pyridinium salts (drug) in the central nervous system in a sustained manner. The design approach, synthesis, study of some important physicochemical properties, stability determinations and preliminary in vivo distribution and potency evaluations of the novel drugs are described.