Synthesis and biological activity of derivatives of tetrahydroacridine as acetylcholinesterase inhibitors Paweł Szyman ´ ski ⇑ , Magdalena Markowicz, El _ zbieta Mikiciuk-Olasik Department Pharmaceutical Chemistry and Drug Analyses, Medical University, ul. Muszyn ´skiego 1, 90-151 Lodz, Poland article info Article history: Received 2 February 2011 Available online 12 May 2011 Keywords: Alzheimer’s disease Acetylcholinesterase inhibitors HYNIC abstract Current state of medical sciences does not allow to treatment neurodegenerative diseases such as Alzhei- mer’s disease (AD). At present treatment of AD is severely restricted. The main class of medicines which are applied in AD is acetylcholinesterase inhibitors (AChEIs) like tacrine, donepezil, galantamine and riv- astigmine that do not contribute to significant and long-term improvement in cognitive and behavioural functions. In this work, we report synthesis and biological evaluation of new hybrids of tacrine-6-hydrazinonic- otinamide. The synthesis was based on the condensation reaction between tacrine derivatives and the hydrazine nicotinate moiety (HYNIC). All obtained compounds present affinity for both cholinesterases and are characterized by high selectivity in relation to butyrylcholinesterase (BChE). Ó 2011 Elsevier Inc. All rights reserved. 1. Introduction AD is the most common ailment contributing to decline of cog- nitive function. It accounts for 50–60% of all reasons of dementia. The chances of developing AD increase in conjunction with advanced age, rising from 1% in people below 65 years old to more than 24% in those aged 85 years [1]. Beside advanced age there are other risk factors for acquiring AD. One of them is a diminished reserve capacity of the brain which may be a result of low educa- tional background or decreased mental or physical activity during the lifetime. Another cause confirmed by several epidemiological researches is head injury [1]. The most degenerated by AD are the cortex and hippocampus, regions in brain which are associated with the highest and more complex functions [2]. Progressive development of forgetfulness, deterioration of cognitive functions such as language, memory and behavioural disturbances are characteristic features of patients suffering from AD [3,4]. Pathogenic background of AD is highly complicated. Scientists have proposed several theories explaining the mechanism of AD development. Among them there are: loss of cholinergic function (known as cholinergic hypothesis), the amyloid cascade (amyloid hypothesis), oxidative stress, decrease of steroid hormone concen- tration and inflammation process [2,3]. Cholinergic hypothesis has received plentiful verification and has been widely approved. The most characteristic abnormality associated with AD is a decrease in central cholinergic neurotransmission. This pathology is a result of decreased activity of choline acetyltransferase (ChAT), the enzyme that synthesizes acetylcholine (Ach). There is a corre- lation between reduction of ChAT activity in AD and severity of cognitive disturbances [5,6]. AChE inhibitors are at present the one of two groups of drugs used for the clinical treatment of AD. The symptomatic efficacy of AChEIs is attained through their increase of acetylcholine- mediated transmission between neurons. However, these agents do not reverse the progression of the disease and contribute only to modest improvement in cognitive function in the mild to mod- erate stages AD. Advances in knowledge of the pathogenesis of AD have led to numerous studies conducting investigations of new potential cho- linergic drugs for the treatment of AD [2]. Recent endeavours have been focused on increasing cholinergic neurotransmission, utiliz- ing cholinergic receptor agonists or AChEIs [2,6]. In this article we describe the synthesis and biological evalua- tion of a series of tetrahydroacridine derivatives with hydrazine nicotinate (HYNIC) moiety as bifunctional acetylcholinesterase inhibitors. The fragment of tetrahydroacridine has possibility to inhibit the enzymes and HYNIC moiety could be used by standard as a co-ligand to radiolabeling. These new compounds can be new potential drugs for treatment of AD or a good ligand to radioiso- topes as a marker in neurological process. 2. Material and methods 2.1. Chemistry Reactions were monitored by TLC using 25 DC-Alufolien Kiesel- gel 60F 254 (Merck), and detection was done by UV Lamp (254 nm). Melting points were measured on an electrothermal apparatus in 0045-2068/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.bioorg.2011.05.001 ⇑ Corresponding author. Fax: +48 42 677 92 50. E-mail address: pawel.szymanski@umed.lodz.pl (P. Szyman ´ ski). Bioorganic Chemistry 39 (2011) 138–142 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg