Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors.

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against ß-amyloid aggregation. All novel molecules 3a-3i interacted with both cholinesterases-acetylcholinesterase and butyrylcholinesterase-delivered nanomolar IC50 values. The structure-activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50  = 31.2 nm), and it was more active than reference drug, tacrine (IC50  = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50  = 8.0 nm), also higher than tacrine (IC50  = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited ß-amyloid aggregation (at the concentration 10 µm-24.96% of inhibition, 25 µm-72%, 50 µm-78.44%, and 100 µm-84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease.

Determination of stability constants and acute toxicity of potential hepatotropic gadolinium complexes.

Due to their high specificity for the hepatobiliary system, iminodiacetic acid derivatives are known to form a class of hepatobiliary agents. In this paper we present new hepatotropic gadolinium complexes to be used as potential MRI contrast agents. Derivatives of N-(2-phenylamine-2-oxoethyl) iminodiacetic acid are introduced as ligands into such complexes. In this way, we hope to achieve a valuable diagnostic tool for investigating of pathological changes in the liver. Stability constants of complexes were determined by potentiometric titration in 0.1 mol L(-1) NaNO3 solution at 20.0 +/- 0.1 degrees C. Stability and selectivity constants were also determined for endogenous metal ions such as Cu2+, Ca2+, and Zn2+ with the use of SUPERQUAD computer program. Acute toxicity of new gadolinium complexes was assessed in mice and histopathology examinations were carried out.