Mol Divers DOI 10.1007/s11030-017-9774-3 ORIGINAL ARTICLE Synthesis of novel 7-aryl and 7-spiropyrazolo[4 ′ ,3 ′ :5,6]pyrido [2,3-d ]pyrimidine derivatives and their study as AChE inhibitors Paola Acosta 1 · Braulio Insuasty 1 · Rodrigo Abonia 1 · Margarita Gutierrez 2 · Jairo Quiroga 1 Received: 18 January 2017 / Accepted: 24 July 2017 © Springer International Publishing AG 2017 Abstract An efficient route for the synthesis of novel 7- aryl and 7-spiropyrazolo[4 ′ ,3 ′ :5,6]pyrido[2,3-d ]pyrimidine derivatives is described. These compounds were obtained by a cyclocondensation reaction between pyrazolopyridine- diamines 4 and aldehydes 5 or cyclic ketones 6 in the presence of acetic acid as catalyst. This procedure provides the desired compounds in good yields under a simple two- step methodology. The obtained compounds were evaluated as AChE inhibitors and showed weak AChe inhibition with IC 50 = 115−470 μM. Keywords Pyrazolopyridines · Pyrimidines · Spiropy- rimidines · Aromatic aldehydes · Cyclic ketones · Cyclocondensation reaction Introduction Nitrogen-containing heterocycles occupy an important posi- tion in natural product and medicinal chemistry. Fused het- erocyclic systems, containing pyrimidine scaffold as a core unit in their structures are important targets and have exhib- ited various biological and pharmaceutical activities [1–9]. In particular, compounds containing a pyrido[2,3-d ]pyrimidine Electronic supplementary material The online version of this article (doi:10.1007/s11030-017-9774-3) contains supplementary material, which is available to authorized users. B Jairo Quiroga jairo.quiroga@correounivalle.edu.co 1 Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A.A. 25360 Cali, Colombia 2 Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), Institute of Chemistry of Natural Resources, Universidad de Talca, Casilla 747, Talca, Chile ring have demonstrated a wide range of biological proper- ties, such as antibacterial [10], antitumor [11], cardiotonic [12], antihistaminic [13], anti-inflammatory [14, 15] and CNS depressant [16]. Moreover, functionalized pyrido[2,3- d ]pyrimidines exhibit variety of promising pharmacological activities, such as potent inhibitor of dihydrofolate reduc- tase [17], in a treatment of diarrhea [18], specific inhibitor of cyclic-dependent kinase 4 [19] and induce apoptosis of K562 cells [20]. On the other hand, spiro compounds are rather exciting due to the presence of a spiro carbon that gives structural rigidity to the molecules by conformational restrictions, which considerably influence biological activity. So, it is challenging and at the same time interesting to construct spirocyclic compounds by employing new methods [21, 22]. Alzheimer’s disease (AD) is the most complex and common form of dementia in elderly people. It is a neu- rodegenerative disease that causes progressive damage to the central nervous system and is manifested with a cog- nitive deterioration, changes in brain function, including disordered behavior and impairment in language and compre- hension [23]. Currently, it is estimated that AD is the fourth leading cause of death afflicting more than seven million people worldwide [24]. According to the cholinergic hypoth- esis, the pathogenesis of AD is a result of the progressive decline of cholinergic transmission mediated via the neuro- transmitter acetylcholine. Cholinesterase [25] is a family of enzymes that catalyzes the hydrolysis of the neurotransmitter acetylcholine (ACh) into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its rest- ing state after activation. These findings support the need to control the activity of the cholinesterases enzymes at differ- ent stages of AD progression. Many heterocycles have been reported as potential inhibitors of cholinesterase enzymes, including pyrazoloquinolines [26], pyridopyrazines [27], 123