| Institution: | 1. Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria;2. Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria;3. Research Platform “Translational Cancer Therapy Research”, University of Vienna and Medical University of Vienna, Vienna, Austria;4. Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria;5. Institute of Pharmacology and Toxicology, Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria;1. Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary;2. Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria;3. University of Vienna, Research Platform Translational Cancer Therapy Research, Waehringer Str. 42, A-1090 Vienna, Austria;4. School of Chemical Sciences, University of Auckland, PB: 92019, 1142 Auckland, New Zealand |
| Abstract: | The delivery of drugs to the brain is complicated by the multiple factors including low blood–brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT1A and 5-HT2A with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log KQ = 5.3–6.0 which corresponds to ?8.12 to ?7.15 kcalmol?1 of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log KQ coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow’s site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket. |
