Several neurodegenerative disorders including Alzheimer's disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease's progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development.

b University Hospital in Hradec Kralove Biomedical Research Center Hradec Kralove Czech Republic

c National Institute of Mental Health Klecany Czech Republic

e Centro de Investigaciones Biologicas CSIC Madrid Spain

f Instituto de Quimica Medica CSIC Madrid Spain

g Charles University and General University Hospital Prague 1st Faculty of Medicine Department of Psychiatry Prague Czech Republic

University of Hradec Kralove Faculty of Science Department of Chemistry Hradec Kralove Czech Republic

University of St Andrews Medical and Biological Sciences Building School of Biology St Andrews UK

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