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  • Alzheimer s disease AD is a chronic progressive neurodegener


    Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder of the rolipram which is considered a leading cause of dementia and affects 20–30 million people worldwide. Presently, a suitable treatment and prevention strategy against AD is hardly available. Various studies have been carried out so far without satisfactory results. However, etiology of AD is now partially understood at molecular level which describes the role of hyper phosphorylated tau protein, β-amyloid aggregation, and deficiency of cholinergic neurotransmitter in the pathogenesis of AD (Leoutsakos et al., 2012). The cholinergic hypothesis postulates that the main cause of memory deterioration in patients with AD is the deficiency in cholinergic functions of the brain (Rouleau et al., 2011). This provides a fresh incentive to the scientific research in this field. In recent years, many treatment strategies are planned to interfere with the mechanisms which involve the progression of AD, but the most common one that has gained an outstanding importance is the reduction or blockade of global cognitive decline. Therefore, currently prescribed drugs for AD aim to increase neurotransmitter (i.e ACh) level in the brain by stopping AChE and BChE activity. However, the clinical use of FDA approved ChE inhibitors (Donepezil, Rivastigmine etc.) are sometimes limited due to their more adverse effects and prudent benefits to AD patients. Therefore, the novel and more effective ChE inhibitors are necessary to be developed. Chalcones are synthetic molecules which exhibit a number of biological properties including antiviral, anti-HIV (Trivedi et al., 2007), antimalarial (Wu et al., 2003), anti-leishmanial (Wu et al., 2002), antioxidant (Mukherjee et al., 2001), anti-tuberculosis (Sivakumar et al., 2007), analgesic (Viana et al., 2003), antifungal (Nowakowska, 2007), etc. Furthermore, these are considered as therapeutic agents with anti-amoebic (Budakoti et al., 2006), molluscicidal, anti-inflammatory (Barsoum et al., 2006) and monoamine oxidase (MAO) inhibitory (Zaib et al., 2015) potential. Keeping in view the above mentioned biological importance of chalcone derivatives, we investigated SAR of quinolinyl chalcones derivatives against ChEs. Moreover, molecular docking studies were also performed with homology model by utilizing both ChEs and discovered probable binding mode of the most potent inhibitor of ChEs.
    Materials and methods
    Results and discussion
    Conclusions In this study, two series of quinolinyl chalcones derivatives, 2,6-dimethylquinoline derivatives (4a-l) and 2-methyl-6-methoxyquinoline (5a-s) were screened for ChEs inhibition. All synthesized derivatives emerged as highly effectual inhibitors of BChE. Most of the compounds displayed significant inhibition for AChE. The structural activity relationship of most potent compounds is drawn by using enzyme kinetic studies. The presence of methyl group (−CH3) in basic structure and dioxane in side chian (4j) demonstrated highest inhibition potential against BChE as compared to methoxy group (−OCH3) in basic structure and dioxane ring in side structure (5q). Molecular docking studies were also performed by using homology model of both ChEs in order to explore probable binding modes of the most potent inhibitors. Moreover, drug likeliness properties of most potent inhibitors were determined and these were found to have a favourable ADME profile. This finding supported good oral bioavailability. Therefore, compounds are safer to use and can be novel drugs that would act as cholinesterase inhibitors.
    Acknowledgements Jamshed Iqbal is thankful to the Organization for the Prohibition of Chemical Weapons (OPCW), The Hague, The Netherlands and the Higher Education Commission of Pakistan for the financial support through Project No. 20-3733/NRPU/R&D/14/520.
    Introduction Benzofuran derivatives are an important class of organic compounds that occur in natural products because of their pharmacological activities, including antitumoral properties. They can be used as anti-inflammatory, antimicrobial, antagonists of the angiotensin II receptor, analgesic, ligands of adenosine A1 receptor and so forth [1].