ORIGINAL RESEARCH Polyoxometalates as potent inhibitors for acetyl and butyrylcholinesterases and as potential drugs for the treatment of Alzheimer’s disease Jamshed Iqbal • Maria Barsukova-Stuckart • Masooma Ibrahim • Syed Usman Ali • Aftab Ahmed Khan • Ulrich Kortz Received: 9 March 2012 / Accepted: 23 May 2012 / Published online: 9 June 2012 Ó Springer Science+Business Media, LLC 2012 Abstract Polyoxometalates (POMs) show significant importance in medicine due to their enzyme inhibition, antiviral and anticancer properties. In this study, some polyoxotungstates were identified as potent inhibitors of acetyl and butyrylcholinesterases. Compounds [H 2 W 12 O 42 ] 10- and [TeW 6 O 24 ] 6- have the most potent acetyl- cholinesterase activity, exhibiting IC 50 values of 0.29 ± 0.01 and 0.31 ± 0.01 lM, respectively. Whereas, com- pound [(O 3 PCH 2 PO 3 ) 4 W 12 O 36 ] 16- was a potent and selec- tive inhibitor of butyrylcholinesterase with IC 50 value of 0.18 ± 0.05 lM. In general, POMs were found to be effective cholinesterase inhibitors in terms of efficiency as well as selectivity and represent non-classical cholinester- ase inhibitors. Keywords Acetylcholinesterase Á Anti-Alzheimer Á Butyrylcholinesterase Á Enzyme Inhibition Á Polyoxometalates Introduction Alzheimer’s disease (AD) is the most common cause of dementia in elderly people (Samadi et al., 2011). It is characterized by profound memory impairments, emotional disturbance, and personality changes (Rouleau et al., 2011). The cholinergic hypothesis postulates that memory impairments in patients with AD result from a decrease in hippocampus and cortical levels of the neurotransmit- ter acetylcholine (Komloova et al., 2011). Cholinesterase inhibitors are used in the treatment of Alzheimer’s disease by increasing the level of acetylcholine in the brain (Rouleau et al., 2011). However, clinical use of cholines- terase inhibitors is often limited because of their adverse effects and loss of efficacy on long-term use (Tasso et al., 2011). The selective inhibitors of acetyl and butyrycho- linesterase are reported to increase the level of acetylcho- line in the brain and also reduce the formation of abnormal amyloid. However, the other approach is the development of dual inhibitors for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as BChE activity seems to correlate with AChE activity in AD and a cognitive improvement could be reached (Alptuzun et al., 2010). Cholinesterase inhibitors such as galanthamine, donepezil, rivastigmine, and huperzine increase the brain acetylcho- line levels by preventing the degradation of released neu- rotransmitter, thereby enhancing neurotransmission at cholinergic synapses (Marco et al., 2004; Korabecny et al., 2010). Therefore, it is highly desirable to discover potent and highly selective inhibitors of AChE and BChE. Poly- oxometalates (POMs) are anionic complexes of transition- metal oxide clusters, possessing extremely rich diversity in composition, structure and electronic properties (Acerete et al., 1990; Kortz et al., 1994; Contant et al., 2007; Dong et al., 2011b). Some of the POMs also exhibit high ther- modynamic and kinetic stability in aqueous solutions at biologic pH (Sarafianos et al., 1996; Dong et al., 2011b). Some features of POMs namely polarity, surface charge distribution, and shape can be tuned at the molecular level to enhance the selectivity and reactivity of POMs towards target proteins. In addition to well-developed applications in catalysis, separations, analysis, and as electron-dense J. Iqbal (&) Á S. U. Ali Á A. A. Khan Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan e-mail: drjamshed@ciit.net.pk M. Barsukova-Stuckart Á M. Ibrahim Á U. Kortz School of Engineering and Science, Jacobs University, P.O. Box 750 561, 28725 Bremen, Germany 123 Med Chem Res (2013) 22:1224–1228 DOI 10.1007/s00044-012-0125-8 MEDICINAL CHEMISTR Y RESEARCH