Research paper Discovery of imidazopyridines containing isoindoline-1,3-dione framework as a new class of BACE1 inhibitors: Design, synthesis and SAR analysis Sara Azimi a , Afsaneh Zonouzi a , Omidreza Firuzi b , Aida Iraji b , Mina Saeedi c, d , Mohammad Mahdavi e, ** , Najmeh Edraki b, * a School of Chemistry, College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran b Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran c Medicinal Plants Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran d Persian Medicine and Pharmacy Research Center, Tehran University of Medical Sciences, Tehran, Iran e Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran article info Article history: Received 6 March 2017 Received in revised form 31 May 2017 Accepted 22 June 2017 Available online 24 June 2017 Dedicated to Professor Abbas Shafiee (1937 e2016) for his lifetime achievement in pharmaceutical sciences research and education Keywords: Alzheimer's disease b-Secretase inhibitor GroebkeeBlackburneBienayme reaction Imidazopyridines Phthalimide Molecular docking abstract Alzheimer's disease is characterized by chronic neurodegeneration leading to dementia. The main cause of neurodegeneration is considered to be the accumulation of amyloid-b. Inhibiting BACE1 is a well- studied approach to lower the burden of amyloid-b aggregates. We designed a series of imidazopyridines-based compounds bearing phthalimide moieties as inhibitors of BACE1. The com- pounds 8a-o were synthesized by the GroebkeeBlackburneBienaym e three-component reaction of heteroaromatic amidines, aldehydes and isocyanides. Evaluating the BACE1 inhibitory effects of the synthesized compounds revealed that introducing an aminocyclohexyl moiety in the imidazopyridine core resulted in a significant improvement in its BACE1 inhibitory potential. In this regard, compound 8e was the most potent against BACE1 with an IC 50 value of 2.84 (±0.95) mM. Molecular docking revealed that the nitrogen atom of imidazopyridines and the oxygen atom of the phenoxypropyl linker were involved in hydrogen bound interactions with Asp228 and Asp32 of BACE1 active site, respectively. The phthalimide moiety oriented toward the flap pocket and interacted with phe108, lle110, Trp115, Ile118 through van der Waal's and hydrophobic interactions. These findings demonstrate that imidazopyridines-based compounds bearing phthalimide moiety have the potential to decrease amyloid- b levels and ameliorate the symptoms of Alzheimer's disease. © 2017 Published by Elsevier Masson SAS. 1. Introduction Alzheimer's disease is a neurodegenerative disorder and the most common cause of dementia in the elderly [1]. The patho- genesis of the disease is often described by the “Amyloid Cascade Hypothesis” (ACH) [2], which suggests that the deposition of am- yloid beta (Ab) is the first pathological event that causes neuronal death and eventually leads to dementia. Two proteases known as b- and g-secretase endoproteolyze the amyloid precursor protein (APP) to produce the Ab peptide. b-Secretase is active in most tis- sues of the body [3,4]; however, b-site amyloid precursor protein cleaving enzyme-1 (BACE1) is the major b-secretase in the CNS compared to BACE2 (close homolog of BACE1), which has a more widespread expression pattern? [5]. BACE1 activity is increased in the brains of patients with sporadic Alzheimer's disease [6]. Consequently, BACE1 inhibitors have emerged as ideal candidates for the treatment of Alzheimer's disease by preventing Ab accu- mulation and aggregation [7e9]. The first generation of BACE1 in- hibitors were designed based on peptide analogs of APP [10]. Although they have shown high in vitro inhibitory activity, unfa- vorable in vivo pharmacological properties were observed due to low blood-brain barrier (BBB) permeability or oral bioavailability. * Corresponding author. Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. ** Corresponding author. Endocrinology and Metabolism Clinical Sciences Insti- tute, Tehran University of Medical Sciences, Tehran, Iran. E-mail addresses: mahdavi.chem@gmail.com (M. Mahdavi), edrakin@sums.ac.ir, najmeh_edraki@yahoo.com (N. Edraki). Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2017.06.040 0223-5234/© 2017 Published by Elsevier Masson SAS. European Journal of Medicinal Chemistry 138 (2017) 729e737