Multifunctional Ligands Research Articles

High-performance antibacterial film via synergistic effect between uniformly dispersed TiO2 nanoparticles and multifunctional quaternary ammonium cationic ligand

Due to the extraordinary photocatalytic effect, TiO2 nanoparticles (TiO2 NPs) have been widely applied in antibacterial fields. However, the agglomeration problem and dependence on light of TiO2 NPs seriously limit their antibacterial activity and practical applications. This study proposed an ingenious, facile and effective strategy for the preparation of polyacrylate/TiO2 nanocomposite antibacterial films by emulsion polymerization. In this work, a quaternary ammonium cationic ligand Vinylbenzyldimethyldodecylammonium chloride (VDAC) was successfully synthesized, which acted as a trinity of cationic ligand, organic antibacterial agent and polymerizable emulsifier to improve the dispersion of TiO2 NPs by electrostatic interaction and play the synergistic antibacterial effect with TiO2 NPs. The results demonstrated that TiO2 NPs were truly uniformly dispersed in the matrix and the particles sizes were reduced to around 5 nm. Moreover, the systematic investigations of antibacterial performance indicated that the prepared nanocomposite films displayed excellent antibacterial and antibiofouling abilities through the synergistic antibacterial effect of TiO2 NPs and VDAC. The films could maintain close to 100 % antibacterial rate and completely inhibit bacterial adhesion and biofilm formation in 7 days, exhibiting long-term and stable antibacterial performance. The nanocomposite films in this work exhibit a great potential to be applied to antibacterial coatings and other fields requiring high antibacterial properties.

Strain Differences in the Delta Opioid Receptor Agonist Properties of the Multifunctional Opioid Glycopeptide MMP2200

Mu-opioid receptor (MOR) agonists, such as morphine, are clinically effective analgesics but present a host of serious side effects including constipation, respiratory depression, tolerance, and dependence. Therefore, there is a clinical need for safer and more effective analgesics for the treatment of chronic pain. Previous literature has provided evidence that coactivation of mu and delta opioid receptors (MOR, DOR, respectively) produce antinociceptive effects with reduced side effects. MMP2200, or lactomorphin, is a glycosylated peptide based on the structure of enkephalin and has been demonstrated to have equal affinity for DOR and MOR in vitro. A previously published study characterized the MOR effects in vivo. However, little is known about the DOR-mediated effects. Therefore, the goal of this study was to assess DOR-mediated behaviors in male and female C57BL/6N and ICR mice. We hypothesized that MMP2200 would produce DOR-mediated convulsions and antidepressant-like effects in the mouse forced swim test in both mouse strains. Male and female C57BL6/N and ICR mice (Envigo) were individually and continuously observed for 30-60 min in clear observation cages, and all behavioral changes were noted. Latency to convulse and duration of convulsion and catalepsy were recorded, and a modified Racine score was used to assess severity of convulsions. Antidepressant-like effects were measured in the forced swim test (6 min, 25°C, 3-4 L tap water) in C57BL6/N mice. MMP2200 produced dose-dependent, DOR-mediated convulsions in both male and female C57BL6/N mice but did not produce convulsions in ICR mice up to the largest doses tested (100 mg/kg). Further, MMP2200 did not enhance the convulsive effects of pentylenetetrazol (PTZ) in ICR mice, unlike other DOR agonists such as SNC80. MMP2200 did not alter immobility in the mouse forced swim test, suggesting that it does not have antidepressant-like effects in C57BL6/N mice. Additionally, no antidepressant-like effect was revealed by blocking the MOR with the irreversible antagonist bFNA (32 mg/kg, 48 h). In summary, MMP2200 produced strain-dependent convulsive effects but no antidepressant-like effects. This unique profile suggests that DOR-mediated behavioral effects of multifunctional opioid ligands may be different than those produced by selective DOR agonists, and future studies will examine the role that the MOR agonist properties may play in mediating these effects. Finally, these results highlight the importance of strain differences when assessing DOR agonist activity in vivo.

Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity

Limited evidence has suggested that terpenes found in Cannabis sativa are analgesic, and could produce an “entourage effect” whereby they modulate cannabinoids to result in improved outcomes. However this hypothesis is controversial, with limited evidence. We thus investigated Cannabis sativa terpenes alone and with the cannabinoid agonist WIN55,212 using in vitro and in vivo approaches. We found that the terpenes α-humulene, geraniol, linalool, and β-pinene produced cannabinoid tetrad behaviors in mice, suggesting cannabimimetic activity. Some behaviors could be blocked by cannabinoid or adenosine receptor antagonists, suggesting a mixed mechanism of action. These behavioral effects were selectively additive with WIN55,212, suggesting terpenes can boost cannabinoid activity. In vitro experiments showed that all terpenes activated the CB1R, while some activated other targets. Our findings suggest that these Cannabis terpenes are multifunctional cannabimimetic ligands that provide conceptual support for the entourage effect hypothesis and could be used to enhance the therapeutic properties of cannabinoids.

Discovery of multifunctional anti-Alzheimer’s agents with a unique mechanism of action including inhibition of the enzyme butyrylcholinesterase and γ-aminobutyric acid transporters

Looking for an effective anti-Alzheimer's agent is very challenging; however, a multifunctional ligand strategy may be a promising solution for the treatment of this complex disease. We herein present the design, synthesis and biological evaluation of novel hydroxyethylamine derivatives displaying unique, multiple properties that have not been previously reported. The original mechanism of action combines inhibitory activity against disease-modifying targets: β-secretase enzyme (BACE1) and amyloid β (Aβ) aggregation, along with an effect on targets associated with symptom relief - inhibition of butyrylcholinesterase (BuChE) and γ-aminobutyric acid transporters (GATs). Among the obtained molecules, compound 36 exhibited the most balanced and broad activity profile (eeAChE IC50=2.86μM; eqBuChE IC50=60nM; hBuChE IC50=20nM; hBACE1 IC50=5.9μM; inhibition of Aβ aggregation=57.9% at 10μM; mGAT1 IC50=10.96μM; and mGAT2 IC50=19.05μM). Moreover, we also identified 31 as the most potent mGAT4 and hGAT3 inhibitor (IC50=5.01μM and IC50=2.95μM, respectively), with high selectivity over other subtypes. Compounds 36 and 31 represent new anti-Alzheimer agents that can ameliorate cognitive decline and modify the progress of disease.

N-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)-1H-indazole-3-carboxamide (D2AAK3) as a potential antipsychotic: In vitro, in silico and in vivo evaluation of a multi-target ligand

Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D2 receptor antagonists. We found compound D2AAK3 with affinity to dopamine D2 receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M1 and H1 receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice.

Ligand-Assisted Direct Photolithography of Perovskite Nanocrystals Encapsulated with Multifunctional Polymer Ligands for Stable, Full-Colored, High-Resolution Displays.

Micropatterns with a high stability, definition, and resolution are an absolute requirement in advanced display technology. Herein, patternable perovskite nanocrystals (PNCs) with excellent stability were prepared by exchanging pristine ligands with multifunctional polymer ligands, poly(2-cinnamoyloxyethyl methacrylate). The polymer backbone contains a cinnamoyl group that has been widely employed as a photo-cross-linker under 365 nm UV irradiation. Also, the terminal group is readily adjustable among NH3Cl, NH3Br, and NH3I, allowing us to obtain multicolored PNCs via instant anion exchange. Furthermore, the resulting ligand exchanged PNCs exhibited enhanced stability toward polar solvents without any undesirable influence on the structural or optical properties of the PNCs. Using anion exchanged PNCs, RGB microarrays with a subpixel size of 10 μm × 40 μm were successfully demonstrated. Our results highlight the versatility and feasibility of a simplified patterning strategy for nanomaterials, which can be generally applied in the fabrication of various optoelectronic devices.

MCRT, a multifunctional ligand of opioid and neuropeptide FF receptors, attenuates neuropathic pain in spared nerve injury model

Chimeric peptide MCRT (YPFPFRTic-NH2 ) was a multifunctional ligand of opioid and neuropeptide FF (NPFF) receptors and reported to be potentially antalgic in acute tail-flick test. Here, we developed spared nerve injury (SNI) model to explore its efficacy in chronic neuropathic pain. Analgesic tolerance, opioid-induced hyperalgesia and gastrointestinal transit were measured for safety evaluation. Intracerebroventricular (i.c.v.) and intraplantar (i.pl.) injections were conducted as central and peripheral routes, respectively. Results demonstrated that MCRT alleviated neuropathic pain effectively and efficiently, with the ED50 values of 4.93nmol/kg at the central level and 3.11nmol/kg at the peripheral level. The antagonist blocking study verified the involvement of mu-, delta-opioid and NPFF receptors in MCRT produced anti-allodynia. Moreover, the separation of analgesia from unwanted effects was preliminarily achieved and that MCRT caused neither analgesic tolerance nor hyperalgesia after chronic i.c.v. administration, nor constipation after i.pl. administration. Notably, the local efficacy of MCRT in SNI mice was about one thousandfold higher than morphine and ten thousandfold higher than pregabalin, indicating a great promise in the future treatment of neuropathic pain.

AIE and ESIPT Schiff base ligands and corresponding Eu(III) complexes: Multiple-color and fluorescence properties

The organic ligands with good coordination ability to Eu(III) ion attracted great attention, but the preparation of multifunctional organic ligands with excellent performance and the potential application was still a challenge in the field of rare earth coordination. In this work, a series of Schiff-base ligands and their corresponding Eu(III) complexes were successfully prepared. The ligands L1−4 exhibited typical AIE properties with various fluorescence emissions and high fluorescence quantum yields in an aggregated state. The luminescence intensity and luminescence lifetime of Eu(III) complexes were investigated by comparing different substituents of ligands. Density functional theory (DFT) calculations suggested that the electronegativity of the ligands L1−4 changed with the change of the substituents on the salicylaldehyde, which led to the phenomenon that the ligands exhibited diverse fluorescence emission from green to orange (maximum emission wavelengths were 525 nm, 546 nm 569 nm and 582 nm, respectively). All target Eu(III) complexes exhibited red luminescence of Eu(III) ions, accompanied by outstanding thermal stability and long luminescence lifetime. The effect of various substituent groups on luminescence intensity and luminescence lifetime of complexes was ordered: EuL3(Phen)(NO3)3 > EuL2(Phen)(NO3)3 > EuL1(Phen)(NO3)3 > EuL4(Phen)(NO3)3. Based on the above results, all ligands and corresponding target Eu(III) complexes had good application prospects in the field of optical materials.

2’-Hydroxy-4’,5’-dimethyl-4-dimethylaminochalcone, a novel fluorescent flavonoid with capacity to detect aluminium in cells and modulate Alzheimer’s disease targets

Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder with several factors contributing to its aetiology such as abnormal protein aggregation (e.g., β-amyloid peptide), oxidative stress, alterations in neurotransmitter levels (e.g., acetylcholine, monoamines) and ion metal accumulation in the brain (e.g., aluminium), among others. Due to the complex nature of this disease, there is a critical need to develop multitarget-directed compounds to address the alternative pathways involved.In this context, the aim of this work was to synthesise a simple chalcone derivative with capacity to affect different key targets of AD neurodegeneration. Consequently, we report here a microwave-assisted synthesis of a new chalcone derivative, namely 2’-hydroxy-4’,5’-dimethyl-4-dimethylaminochalcone (1).Compound 1 selectively chelated aluminium, inhibited the aggregation of Aβ 1-42 peptide, behaved as a radical scavenger and inhibited acetylcholinesterase in vitro. An extensive spectral study (UV/visible, fluorescence and MS) of chalcone 1/Al3+ complex as well as a molecular modelling study of its 3D conformation confirmed the structure of the complex. Additionally, chalcone 1 was capable of interacting with aluminium in cell lines HEK293 T and SH-SY5Y.In conclusion, chalcone 1 is a novel probe for the detection of Al3+ in cells and, moreover, it can be regarded as a promising multifunctional ligand for AD treatment.

Nanoscale interfacial engineering enables highly stable and efficient perovskite photovoltaics.

We present a facile molecular-level interface engineering strategy to augment the long-term operational and thermal stability of perovskite solar cells (PSCs) by tailoring the interface between the perovskite and hole transporting layer (HTL) with a multifunctional ligand 2,5-thiophenedicarboxylic acid. The solar cells exhibited high operational stability (maximum powering point tracking at one sun illumination) with a stabilized TS80 (the time over which the device efficiency reduces to 80% after initial burn-in) of ≈5950 h at 40 °C and a stabilized power conversion efficiency (PCE) over 23%. The origin of high device stability and performance is correlated to the nano/sub-nanoscale molecular level interactions between ligand and perovskite layer, which is further corroborated by comprehensive multiscale characterization. These results provide insights into the modulation of the grain boundaries, local density of states, surface bandgap, and interfacial recombination. Chemical analysis of aged devices showed that molecular passivation suppresses interfacial ion diffusion and inhibits the photoinduced I2 release that irreversibly degrades the perovskite. The interfacial engineering strategies enabled by multifunctional ligands can expedite the path towards stable PSCs.

HIV-1 Reverse Transcriptase/Integrase Dual Inhibitors: A Review of Recent Advances and Structure-activity Relationship Studies.

The significant threat to humanity is HIV infection, and it is uncertain whether a definitive treatment or a safe HIV vaccine is. HIV-1 is continually evolving and resistant to commonly used HIV-resistant medications, presenting significant obstacles to HIV infection management. The drug resistance adds to the need for new anti-HIV drugs; it chooses ingenious approaches to fight the emerging virus. Highly Active Antiretroviral Therapy (HAART), a multi-target approach for specific therapies, has proved effective in AIDS treatment. Therefore, it is a dynamic system with high prescription tension, increased risk of medication reactions, and adverse effects, leading to poor compliance with patients. In the HIV-1 lifecycle, two critical enzymes with high structural and functional analogies are reverse transcriptase (RT) and integrase (IN), which can be interpreted as druggable targets for modern dual-purpose inhibitors. Designed multifunctional ligand (DML) is a new technique that recruited many targets to be achieved by one chemical individual. A single chemical entity that acts for multiple purposes can be much more successful than a complex multidrug program. The production of these multifunctional ligands as antiretroviral drugs is valued with the advantage that the viral-replication process may end in two or more phases. This analysis will discuss the RT-IN dual-inhibitory scaffolds’ developments documented so far.

Multifunctional Ligands with Glycogen Synthase Kinase 3 Inhibitory Activity as a New Direction in Drug Research for Alzheimers Disease

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Advancements in multifunctional manganese complexes for catalytic hydrogen transfer reactions.

Catalytic hydrogen transfer reactions have enormous academic and industrial applications for the production of diverse molecular scaffolds. Over the past few decades, precious late transition-metal catalysts were employed for these reactions. The early transition metals have recently gained much attention due to their lower cost, less toxicity, and overall sustainability. In this regard, manganese, which is the third most abundant transition metal in the Earth's crust, has emerged as a viable alternative. However, the key to the success of such manganese-based complexes lies in the multifunctional ligand design and choice of appropriate ancillary ligands, which helps them mimic and, even in some cases, supersede noble metals' activities. The metal-ligand bifunctionality, achieved via deprotonation of the acidic C-H or N-H bonds, is one of the powerful strategies employed for this purpose. Alongside, the ligand hemilability in which a weakly chelating group tunes in between the coordinated and uncoordinated stages could effectively stabilize the reactive intermediates, thereby facilitating substrate activation and catalysis. Redox non-innocent ligands acting as an electron sink, thereby helping the metal center in steps gaining or losing electrons, and non-classical metal-ligand cooperativity has also played a significant role in the ligand design for manganese catalysis. The strategies were not only employed for the chemoselective hydrogenation of different reducible functionalities but also for the C-X (X = C/N) coupling reactions via HT and downstream cascade processes. This article features multifunctional ligand-based manganese complexes, highlighting the importance of ligand design and choice of ancillary ligands for achieving the desired catalytic activity and selectivity for HT reactions. We have also discussed the detailed reaction pathways for metal complexes involving bifunctionality, hemilability, redox activity, and indirect metal-ligand cooperativity. The synthetic utilization of those complexes in different organic transformations has also been detailed.

Gold(I) complexes with multifunctional phosphane ligands: Synthesis and catalysis

Two novel gold(I) complexes with a phosphoguanidine ligand and with a novel cationic phosphane ligand have been prepared and structurally characterized. The phosphoguanidine ligand supports oxidative addition of biphenylene to the gold(I) centre, though the yield of the reaction is low. The phopshoguanidine gold(I) complexes is also able to efficiently catalyze the hydroamination of phenylacetylene with mesitylamine, whereas the gold(I) complex with the cationic phosphane ligand, due to its more electron-poor character, promotes the hydroarylation of ethyl propiolate with mesitylene.

Green Ir(III) complexes with multifunctional ancillary ligands for highly efficient solution-processed phosphorescence organic light-emitting diodes with high current efficiency

Abstract Two new highly efficient green emitting heteroleptic Ir(III) complexes, namely, bis[5-(2-ethylhexyl)-8-(trifluoromethyl)benzo[c][1,5]naphthyridin-6(5H)-one]iridium-4-((3,5-di(9H-carbazol-9-yl)benzyl)oxy)picolinate (Ir-HT) and bis[5-(2-ethylhexyl)-8-(trifluoromethyl) benzo[c][1,5]naphthayridin-6(5H)-one]iridium-4-((4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzyl) oxy)picolinate (Ir-ET) were designed and synthesized for solution-processed phosphorescence organic light-emitting diodes (PHOLEDs). These new Ir(III) complexes are based on amide-bridged trifluoromethyl (-CF3) substituted phenylpyridine unit as main ligand and 1,3-bis(N-carbazolyl)benzene (mCP) unit and 1,3,4-oxadiazole (OXD) unit functionalized picolinate (pic) as an ancillary ligand. These multifunctional groups were attached into the 4-position of pic ancillary ligands via ether linkage. Interestingly, the solution-processed PHOLED device using Ir-HT as a dopant exhibited a maximum external quantum efficiency (EQEmax) of 20.92% and a maximum current efficiency (CEmax) of 64.04 cd A−1. Whereas PHOLED device using Ir-ET displayed a EQEmax of 20.68% and a CEmax of 65.02 cd A−1. This is one of best CE with high EQE for green Ir(III) complexes via solution-processed PHOLEDs using multifunctional ancillary ligands so far.

Metal–Organic Framework as Anode Materials for Lithium-Ion Batteries with High Capacity and Rate Performance

Because of the diversity of bonding properties between transition metal ions and multifunctional organic ligands, metal–organic frameworks (MOFs) with slow ion transport kinetics are considered as ...

Cinnamoyl-N-Acylhydrazone-Donepezil Hybrids: Synthesis and Evaluation of Novel Multifunctional Ligands Against Neurodegenerative Diseases.

A new series of ten multifunctional Cinnamoyl-N-acylhydrazone-donepezil hybrids was synthesized and evaluated as multifunctional ligands against neurodegenerative diseases. The molecular hybridization approach was based on the combination of 1-benzyl-4-piperidine fragment from the anti-Alzheimer AChE inhibitor donepezil (1) and the cinnamoyl subunit from curcumin (2), a natural product with remarkable antioxidant, neuroprotective and anti-inflammatory properties, using a N-acylhydrazone fragment as a spacer subunit. Compounds 4a and 4d showed moderate inhibitory activity towards AChE with IC50 values of 13.04 and 9.1µM, respectively. In addition, compound 4a and 4d showed a similar predicted binding mode to that observed for donepezil in the molecular docking studies. On the other hand, compounds 4a and 4c exhibited significant radical scavenging activity, showing the best effects on the DPPH test and also exhibited a significant protective neuronal cell viability exposed to t-BuOOH and against 6-OHDA insult to prevent the oxidative stress in Parkinson's disease. Similarly, compound 4c was capable to prevent the ROS formation, with indirect antioxidant activity increasing intracellular GSH levels and the ability to counteract the neurotoxicity induced by both OAβ1-42 and 3-NP. In addition, ADMET in silico prediction indicated that both compounds 4a and 4c did not show relevant toxic effects. Due to their above-mentioned biological properties, compounds 4a and 4c could be explored as lead compounds in search of more effective and low toxic small molecules with multiple neuroprotective effects for neurodegenerative diseases.

Azo-Label Heterometal-Organic Rhomboids Exhibiting Photoswitchable NIR Luminescence in Crystalline State.

Photochromism is an important strategy for realizing reversible light-controllable fluorescence switching. In spite of several reports on fluorescence switching via a photochromic process, the success of photochromic multimetallic complexes reversibly showing fluorescence switching in the solid or crystalline state has been limited for their application importance. Here, we report a photoswitchable near-infrared (NIR) fluorescence based on photochromism in the azo-label 3d/4f heterometal-organic rhomboids, azo-Zn2Ln2 (Ln = Eu (1), Yb (2), and Er (3)), in the crystalline state. An individual metallorhomboid contains up to four azobenzene fragments, which is prepared via the three-component assembly of a trans-azobenzene-grafted multifunctional ligand, and 3d and 4f metal ions. The photoisomerization quantum yields of azo-Zn2Ln2 complexes can be retained or even higher when compared to the free ligand due to the modification of electronic structure. The impressive crystalline-state NIR luminescence is observed for the complexes of azo-Zn2Yb2 (2) and azo-Zn2Er2 (3) at room temperature. Intriguingly, the switchable NIR luminescence can be effectively regulated by photochromism in the crystalline state. These features endow the self-assembly of the 3d/4f metallorhomboid with synergetic multifunctional behavior between photochromism and NIR luminescence.

The application of sulfonated tetraphenyl calix[4] resorcinarene as a novel, multi-functional and eco-friendly ligand in zirconium tanning system

The complex of resorcinarene and zirconium was used in the tanning process of goat skin with the optimal dosage of 5% resorcinarene and 4% zirconium. The shrinkage temperature of combination tanned leather kept at 88.9 °C although the additive amount of zirconium decreased by 8%. Meanwhile, the tear strength and tensile strength of tanned leather increased by 77% and 141%, respectively. The function of resorcinarene and its interaction with zirconium were studied by SEM-EDX and FT-IR technologies. The results indicated that resorcinarene can act as a ligand of zirconium, promoting the permeation of zirconium as well as decreasing the usage amount of zirconium. Furthermore, the tanning mechanism was explored by FT-IR and XRD methods. It showed that the three helix structures of collagen fiber were remained and the tanning agent had not enter the micro fibrils of the collagen. Moreover, the introduction of resorcinarene increased the biodegradability of wastewater remained after tanning process. This paper gives a new strategy for chrome-free tanning and provides a strong support for the wide application of zirconium tanning agent.

Multifunctional Ligands Targeting Phosphodiesterase as the Future Strategy for the Symptomatic and Disease-Modifying Treatment of Alzheimer's Disease.

Alzheimer's Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive impairments such as memory loss, decline in language skills, and disorientation that affects over 46 million people worldwide. Patients with AD also suffer from behavioral and psychological symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia. A large body of evidence indicates that impaired signaling pathways of cyclic-3',5'- Adenosine Monophosphate (cAMP) and cyclic-3',5'-guanosine Monophosphate (cGMP) may contribute to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors, commonly known as cAMP and/or cGMP modulators, were found to be involved in the phosphorylation of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood, and emotion processing. The purpose of this review was to update the most recent reports on the development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic and disease-modifying therapy of AD. This review collected the chemical structures of representative multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies, and current opinions regarding the potential utility of these compounds for the comprehensive therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds were calculated and discussed.