Naturally Inspired Privileged Structures in Drug Discovery: Multifunctional Compounds for Alzheimer's Disease Treatment

Polypharmacology-based strategies are gaining ever-increasing attention as useful approaches to develop disease-modifying drug candidates for effective Alzheimer’s disease (AD) treatment. In this scenario, multitarget-directed ligands could increase efficiency by simultaneous modulation of several targets involved in AD pathogenesis. In drug discovery, natural products (NPs) represent an excellent source of evolutionary-chosen “privileged structures”. In this thesis, the polyphenol curcumin, found in Curcuma longa L, encompassing the essential structural elements for the concurrent inhibition of two validated AD targets, BACE-1 and GSK-3β, was rationally identified as lead compound. Aimed at developing well-balanced dual BACE-1/GSK-3β modulators with good BBB permeability, different series of curcumin-based derivatives were designed and synthetized by introducing suitable chemical modifications on the side aryl ring(s) and in the 4-position of the main scaffold. Furthermore, considering the pivotal role of the intramolecular H-bond network of curcumin’s central fragment in establishing appropriate interactions with target binding sites, several complexation and bioisosteric cyclization strategies were performed. Thanks to its strong Michael acceptor reactivity toward critical cysteine residues, curcumin exerts neuroprotection by additional activation of the Keap1-Nrf2-ARE signaling pathway. Thus, aimed at affecting the electrophilicity of its α,β-unsaturated carbonyl fragment, allowing a fine-tuning of its reactivity, diverse electrophilic functions were inserted in different positions of the curcumin scaffold. Furthermore, considering the neuroprotective and antioxidant potentials of simple coumarins, several curcumin-coumarin hybrids were also prepared. Recently, the inhibition of additional AD-correlated protein kinases (PKs), such as CK1 and LRRK2, could offer promises to achieve a successful treatment and indole was envisaged as useful scaffold for both PKs’ inhibition. Thus, a small library of indole-based derivatives was designed and synthetized as valuable BBB permeable pharmacological tools. Finally, chitosan (CS), a natural, nontoxic, biocompatible and biodegradable polysaccharide, was selected to develop CS-based bioconjugates for nanoparticles’ preparation as innovative drug delivery and targeting systems

Dopamine D3 receptor ligands: a patent review (2014-2020)

Introduction: Compelling evidence identified D3 dopamine receptor (D3R) as a suitable target for therapeutic intervention on CNS-associated disorders, cancer, and other conditions. Several efforts have been made toward developing potent and selective ligands for modulating signaling pathways operated by these GPCRs. The rational design of D3R ligands endowed with a pharmacologically relevant profile has traditionally not encountered much support from computational methods due to a very limited knowledge of the receptor structure and of its conformational dynamics. Recent progress in structural biology will change this state of affairs in the next decade. Areas covered: This review provides an overview of the recent (2014-2020) patent literature on novel classes of D3R ligands developed within the framework of CNS-related diseases, cancer, and additional conditions. When possible, an in-depth description of both in vitro and in vivo generated data is presented. New therapeutic applications of known molecules with activity at D3R are discussed. Expert opinion: Building on current knowledge, future D3R-focused drug discovery campaigns will be propelled by a combination of unprecedented availability of structural information with advanced computational and analytical methods. The design of D3R ligands with the sought activity, efficacy, and selectivity profile will become increasingly more streamlined

Recent progress on curcumin-based therapeutics: a patent review (2012-2016). Part II: curcumin derivatives in cancer and neurodegeneration

Introduction: Curcumin, the main bioactive compound found in the rhizome of Curcuma longa L., is considered a \ue2\u80\u98privileged structure\ue2\u80\u99, due to its ability to modulate different signaling pathways involved in the pathogenesis of several diseases. Unfortunately, its poor pharmacodynamic and pharmacokinetic properties, mainly related to chemical instability, low solubility and rapid metabolism, greatly reduce its therapeutic potential. In the last years a number of derivatives were developed and patented, aimed both at improving its multifaceted biological profile and overcoming its undesired effects. Areas covered: This review summarizes the patent literature of the last five years dealing with synthetic curcumin-related compounds in cancer and neurodegeneration, properly designed in order to avoid the so-called \ue2\u80\u98dark side of curcumin\ue2\u80\u99, and to take advantage of the beneficial properties of this molecule, worth to be further exploited to obtain effective therapeutics. Expert opinion: Due to the synergistic binding to several networked targets, curcumin turned out to be suitable for polypharmacological approaches, and its \ue2\u80\u98privileged structure\ue2\u80\u99 could also provide the key scaffold to develop novel multipotent drugs useful for treating multifactiorial pathologic conditions such as cancer and neurodegeneration

Recent progress on curcumin-based therapeutics: a patent review (2012-2016). Part I: Curcumin

Introduction: curcumin is the main bioactive component contained in Curcuma Longa, largely employed in traditional medicine. Recently, beneficial properties, useful for prevention and treatment of several disorders, have been discovered for this compound. Peculiar structural feature is an α,β-unsaturated carbonyl system essential for establishing contacts with critical cysteine residues of several targets. This distinctive mechanism of action imparts to the molecule the ability to affect a large number of targets, accounting for its pleiotropic behaviour and definition of “privileged structure”. Areas covered: The objective of the review is an examination of the recent developments in the field of the anti-cancer applications of curcumin, together with formulation issues, considering the patent literature in the years 2012-2016. Expert opinion: The wide therapeutic efficacy of curcumin is related to synergistic interactions with several biological targets, along with the modulation of several signaling pathways. This peculiar behaviour could be useful in the treatment of multifactorial diseases such as cancer. Combination of curcumin with a first line antineoplastic drug proved to be a valuable strategy to obtain an amplified response with minimized side effects. Innovative curcumin formulations based on the nanotechnology approach allowed improving both bioavailability and therapeutic efficacy

Modulation of Amyloid β-Induced Microglia Activation and Neuronal Cell Death by Curcumin and Analogues

: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is not restricted to the neuronal compartment but includes important interactions with immune cells, including microglia. Protein aggregates, common pathological hallmarks of AD, bind to pattern recognition receptors on microglia and trigger an inflammatory response, which contributes to disease progression and severity. In this context, curcumin is emerging as a potential drug candidate able to affect multiple key pathways implicated in AD, including neuroinflammation. Therefore, we studied the effect of curcumin and its structurally related analogues cur6 and cur16 on amyloid-β (Aβ)-induced microglia activation and neuronal cell death, as well as their effect on the modulation of Aβ aggregation. Primary cortical microglia and neurons were exposed to two different populations of Aβ42 oligomers (Aβ42Os) where the oligomeric state had been assigned by capillary electrophoresis and ultrafiltration. When stimulated with high molecular weight Aβ42Os, microglia released proinflammatory cytokines that led to early neuronal cell death. The studied compounds exerted an anti-inflammatory effect on high molecular weight Aβ42O-stimulated microglia and possibly inhibited microglia-mediated neuronal cell toxicity. Furthermore, the tested compounds demonstrated antioligomeric activity during the process of in vitro Aβ42 aggregation. These findings could be investigated further and used for the optimization of multipotent candidate molecules for AD treatment

A Versatile and Sustainable Multicomponent Platform for the Synthesis of Protein Degraders: Proof-of-Concept Application to BRD4-Degrading PROTACs

The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape, and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are highly demanded. Herein we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs. As a proof of principle, our platform has been applied to the preparation of potential BRD4-degrading PROTACs, resulting in the discovery of a set of degraders endowed with high degradation efficiency. Compared to the existing methods, our approach offers a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful candidates

The multitarget FAAH inhibitor/D3 partial agonist ARN15381 decreases nicotine self-administration in male rats

: Tobacco use disorder is a worldwide health problem for which available medications show limited efficacy. Nicotine is the psychoactive component of tobacco responsible for its addictive liability. Similar to other addictive drugs, nicotine enhances mesolimbic dopamine transmission. Inhibition of the fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), reduces nicotine-enhanced dopamine transmission and acquisition of nicotine self-administration in rats. Down-regulation of dopamine transmission by antagonists or partial agonists of the dopamine D3 receptor (DRD3) also reduced nicotine self-administration and conditioned place preference. Based on these premises, we evaluated the effect of ARN15381, a multitarget compound showing FAAH inhibition and DRD3 partial agonist activity in the low nanomolar range, on nicotine self-administration in rats. Pretreatment with ARN15381 dose dependently decreased self-administration of a nicotine dose at the top of the nicotine dose/response (D/R) curve, while it did not affect self-administration of a nicotine dose laying on the descending limb of the D/R curve. Conversely, pretreatment with the selective FAAH inhibitor URB597 and the DRD3 partial agonist CJB090 failed to modify nicotine self-administration independent of the nicotine dose self-administered. Our data indicates that the concomitant FAAH inhibition and DRD3 partial agonism produced by ARN15381 is key to the observed reduction of nicotine self-administration, demonstrating that a multitarget approach may hold clinical importance for the treatment of tobacco use disorder

Naturally inspired molecules as multifunctional agents for Alzheimer's disease treatment

Alzheimer's disease (AD) has been defined as a multi-factorial disorder resulting from a complex array of networked cellular and molecular mechanisms. In particular, elevated levels of A\u3b2 protein and its aggregation products in the presence of metal ions proved to be highly neurotoxic and therapeutic strategies aimed at preventing A\u3b2 generation and oxidative stress may represent an effective approach for AD treatment. A recent paradigm for the treatment of complex diseases such as AD suggests the employment of multifunctional compounds, single chemical entities capable of simultaneously modulating different targets involved in the pathology. In this paper, the "pharmacophores combination" strategy was applied, connecting the main scaffold of the BACE-1 ligand 1 to that of the chalcone 2, as metal chelating pharmacophore, to obtain a small library of compounds. Conjugate 5 emerged as the most interesting derivative, proving to inhibit BACE-1 with low-micromolar potency, and showing neuroprotective effects. In particular, 5 proved to be able to protect from metal-associated oxidative stress by hampering intracellular Cu2+-induced ROS formation without any direct neurotoxic effect

Novel fragment-derived colchicine-site binders as microtubule-destabilizing agents

Microtubules (MTs) are dynamic filaments of the cytoskeleton, which are formed by the polymerization of their building block tubulin. Perturbation of MT dynamics by MT-targeting agents (MTAs) leads to cell cycle arrest or cell death, a strategy that is pursued in chemotherapy. We recently performed a combined computational and crystallographic fragment screening approach and identified several tubulin-binding fragments. Here, we sought to capitalize on this study with the aim to demonstrate that low affinity tubulin-binding fragments can indeed be used as valuable starting points for the development of active, lead-like antitubulin small molecules. To this end, we report on a new, rationally designed series of 2-aminobenzimidazole derivatives that destabilize MTs by binding tubulin at the colchicine-binding site (CBS). We applied a fragment growing strategy by combining X-ray crystallography and computer-aided drug design. Preliminary structure-activity-relationship studies afforded compound 18 that inhibits HeLa cell viability with a submicromolar activity (IC50 of 0.9 mu M). X-ray crystallography confirmed the compound pose in the CBS, while immunostaining experiments suggested a molecular mechanism of action alike classical CBS ligands with antimitotic and antitumor activity associated with MTs destabilization. This promising outcome underpins that our previously performed combined computational and crystallographic fragment screening approach provides promising starting points for developing new MTAs binding to the CBS of tubulin and, eventually, to further tubulin pockets