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Excessive melanin deposition in the skin leads to various skin pigmentation diseases, such as chloasma and age spots. The deposition is induced by several factors, including tyrosinase activities and ultraviolet-induced oxidative stress. Herein, we propose a multi-component, multi-pathway drug combination, with glabridin, 3-O-ethyl-L-ascorbic acid, and tranexamic acid employed as, respectively, a tyrosinase inhibitor, an antioxidant, and a melanin transmission inhibitor. Considering the poor skin permeability associated with topical application, dissolving microneedles (MNs) prepared with hyaluronic acid/poly(vinyl alcohol)/poly(vinylpyrrolidone) were developed to load the drug combination. The drug-loaded microneedles (DMNs) presented outstanding skin insertion, dissolution, and drug delivery properties. In vitro experiments confirmed that DMNs loaded with active ingredients had significant antioxidant and inhibitory effects on tyrosinase activity. Furthermore, the production of melanin both in melanoma cells (B16-F10) and in zebrafish was directly reduced after using DMNs. Clinical studies demonstrated the DMNs' safety and showed that they have the ability to effectively reduce chloasma and age spots. This study indicated that a complex DMN based on a multifunctional combination is a valuable depigmentation product worthy of clinical application. [ABSTRACT FROM AUTHOR]

The treatment of periodontitis can be very challenging due to its complex etiologies. A new pharmacologic strategy entitled “host-modulation therapy,” has been introduced to improve periodontal treatment outcomes. Supposedly, a multifunctional drug with the potential for bacterial infection prevention, host-response modulation and bone healing promotion would be a promising option for periodontitis therapy, but related studies remain substantially lacking. In this study, we successfully conjugated tetracycline with odanacatib (a selective inhibitor of cathepsin K) to construct a multifunctional drug (TC-ODN). We discovered that TC-ODN could promote macrophages polarizing toward anti-inflammatory phenotype and promote osteogenesis of PDLSCs under inflammatory microenvironment. In vivo, TC-ODN could be absorbed and distributed specifically to the bone after systemic administration, and accumulation of TC-ODN increased bone mineral density in ovariectomized rats. Importantly, periodontal administration of TC-ODN could successfully promote bone healing in periodontitis rats with alveolar bone loss. The findings in our study uncovered the excellent biocompatibility and multifunction of TC-ODN, including bone-targeted accumulation, immunoregulation, anti-inflammatory activity and promotion of bone healing, which might contribute to the clinical treatment of periodontitis.

[Display omitted] To follow up on our previous report on bivalent compounds exhibiting potent co-operative binding at dopamine D2 receptors, we modified the structure of the linker in our earlier bivalent molecules (S)-6-((9-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)nonyl)-(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ia) and (S)-6-((10-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)decyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ib) (Fig. 1) connecting the two pharmaophoric moieties to observe any tolerance in maintaining similar affinities and potencies. Specifically, we introduced aromatic and piperazine moieties in the linker to explore their effect. Overall, similar activities at D2 receptors as observed in our earlier study was maintained in the new molecules e.g. (6 S ,6′ S)-6,6′-((1,4-phenylenebis(ethane-2,1-diyl))bis(propylazanediyl))bis(5,6,7,8-tetrahydronaphthalen-1-ol) (D-382) (Ki, D2 = 3.88 nM). The aromatic moiety in D-382 was next functionalized by introducing hydroxyl groups to mimic polyhydroxy natural products which are known to interact with amyloidogenic proteins. Such a transformation resulted in development of compounds like 2,5-bis(2-(((S)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)benzene-1,4-diol (D-666) (Ki, D2 = 7.62 nM) which retained similar affinity and potency at D2 receptors. Such dihydroxyl compounds turned out to be potent inhibitors against aggregation and toxicity of recombinant alpha synuclein protein. The work reported here is in line with our overall goal to develop multifunctional dopamine agonist for symptomatic and disease modifying treatment of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Aggregation of misfolded α-synuclein (α-syn) protein in the periphery and central nervous system (CNS) gives rise to a group of disorders, which are labeled collectively as synucleinopathies. These clinically distinct disorders are known as pure autonomic failure, Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). In the case of PD, it has been demonstrated that toxic aggregates of α-syn protein not only cause apoptosis of dopamine neurons but its accumulation in the neocortex and limbic area principally contributes to dementia. In our multifunctional drug discovery research for PD, we converted one of our catechol-containing lead dopamine agonist molecules D-520 into its prodrug D-685 . The prodrug exhibited higher in vivo anti-Parkinsonian efficacy in a reserpinized PD animal model than the parent D-520 and exhibited facile brain penetration. In our study with an α-syn transgenic animal model (D line) for PD and dementia with Lewy bodies (DLB), we have shown that 1 month of chronic treatment with the compound D-685 was sufficient to reduce the accumulation of α-syn and phospho-α-syn in the cortex, hippocampus, and striatum areas significantly compared to the control tg mice. Furthermore, D-685 did not exhibit any deleterious effect in the CNS as was evident from the neuron and microglia studies. Future studies will further explore in depth the potential of D-685 to modify disease progression while addressing symptomatic deficits.

Our ongoing drug development endeavor to design compounds for symptomatic and neuroprotective treatment of Parkinson’s disease (PD) led us to carry out a structure activity relationship study based on dopamine agonists pramipexole and 5-OHDPAT. Our goal was to incorporate structural elements in these agonists in a way to preserve their agonist activity while producing inhibitory activity against aggregation of α-synuclein protein. In our design we appended various catechol and related phenol derivatives to the parent agonists via different linker lengths. Structural optimization led to development of several potent agonists among which (−)- 8a , (−)- 14 and (−)- 20 exhibited potent neuroprotective properties in a cellular PD model involving neurotoxin 6-OHDA. The lead compounds (−)- 8a and (−)- 14 were able to modulate aggregation of α-synuclein protein efficiently. Finally, in an in vivo PD animal model, compound (−)- 8a exhibited efficacious anti-parkinsonian effect. [ABSTRACT FROM AUTHOR]

Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the “ N -methyl” position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo . Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H 2 O 2 -induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Twelve 4-hydroxy-methylpiperidinyl- N -benzyl-acylarylhydrazone hybrids were synthesized. • The lead compound PQM-181 showed the best-balanced multifunctional properties. • PQM-181 showed a similar binding mode as donepezil to the AChE enzyme in molecular docking studies. • PQM-181 showed adequate predicted ADMET parameters and low cytotoxicity. • PQM-181 seems to be a promising MTDL drug prototype candidate for Alzheimer's disease. The search for new drug candidates against Alzheimer's disease (AD) remains a complex challenge for medicinal chemists due to its multifactorial pathogenesis and incompletely understood physiopathology. In this context, we have explored the molecular hybridization of pharmacophore structural fragments from known bioactive molecules, aiming to obtain a novel molecular architecture in new chemical entities capable of concomitantly interacting with multiple targets in a so-called multi-target directed ligands (MTDLs) approach. This work describes the synthesis of 4-hydroxymethyl)piperidine- N- benzyl-acyl-hydrazone derivatives 5a-l , designed as novel MTDLs, showing improved multifunctional properties compared to the previously reported parent series of N -benzyl-(3-hydroxy)piperidine-acyl-hydrazone derivatives 4. The new improved derivatives were studied in silico, regarding their mode of interaction with AChE enzyme, and in vitro, for evaluation of their effects on the selective inhibition of cholinesterases, cellular antioxidant, and neuroprotective activities as their cytotoxicity in human neuroblastoma (SH-SY5Y) cells. Overall, compound PQM-181 (5 k) showed the best balanced selective and non-competitive inhibition of AChE (IC 50 = 5.9 μM, SI > 5.1), with an additional antioxidant activity (IC 50 = 7.45 µM) against neuronal t -BOOH-induced oxidative stress and neuroprotective ability against neurotoxicity elicited by both t -BOOH and OAβ 1-42 , and a moderate ability to interfere in Aβ 1-42 aggregates, with low cytotoxicity and good predictive druggability properties, suggesting a multifunctional pharmacological profile suitable for further drug development against AD. [ABSTRACT FROM AUTHOR]

Highlights: [•] First reported LC–MS/MS technique for the quantification of NGP1-01. [•] Method was validated for determination of NGP1-01 in mouse serum according to FDA bio analytical method guidelines. [•] Ammonium acetate in the mobile phase enhanced the signal and improved the peak shapes of analyte and internal standard. [ABSTRACT FROM AUTHOR]

The treatment of periodontitis can be very challenging due to its complex etiologies. A new pharmacologic strategy entitled "host-modulation therapy," has been introduced to improve periodontal treatment outcomes. Supposedly, a multifunctional drug with the potential for bacterial infection prevention, host-response modulation and bone healing promotion would be a promising option for periodontitis therapy, but related studies remain substantially lacking. In this study, we successfully conjugated tetracycline with odanacatib (a selective inhibitor of cathepsin K) to construct a multifunctional drug (TC-ODN). We discovered that TC-ODN could promote macrophages polarizing toward anti-inflammatory phenotype and promote osteogenesis of PDLSCs under inflammatory microenvironment. In vivo , TC-ODN could be absorbed and distributed specifically to the bone after systemic administration, and accumulation of TC-ODN increased bone mineral density in ovariectomized rats. Importantly, periodontal administration of TC-ODN could successfully promote bone healing in periodontitis rats with alveolar bone loss. The findings in our study uncovered the excellent biocompatibility and multifunction of TC-ODN, including bone-targeted accumulation, immunoregulation, anti-inflammatory activity and promotion of bone healing, which might contribute to the clinical treatment of periodontitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zhang, Ye, Liu, Li, Wang, Shi, Zheng, An, Ma, Hu, Zhou and Xue.)

Abstract: Antidiabetic agents possessing dual functions, α-glucosidase inhibition and antioxidant, have been accepted to be more useful than currently used antidiabetic drugs because they not only suppress hyperglycemia but also prevent risk of complications. Herein, we design antidiabetic bioconjugates comprising of (+)-proto-quercitol as a glucomimic and cinnamic analogs as antioxidant moieties. Fifteen quercitylcinnamates were synthesized by direct coupling through ester bond in the presence of DCC and DMAP. Particular quercityl esters 6a, 7a and 8a selectively inhibited rat intestinal maltase and sucrose 4–6 times more potently than their parents 6, 7 and 8. Of synthesized bioconjugates, 6a was the most potent inhibitor against maltase and sucrose with IC50 values of 5.31 and 43.65 μM, respectively. Of interest, its inhibitory potency toward maltase was 6 times greater than its parent, caffeic acid (6), while its radical scavenging (SC50 0.11 mM) was comparable to that of commercial antioxidant BHA. Subsequent investigation on mechanism underlying inhibitory effect of 6a indicated that it blocked maltase and sucrose functions by mixed inhibition through competitive and noncompetitive manners. [Copyright &y& Elsevier]

Abstract: A series of berberine-phenyl-benzoheterocyclic (26–29) and tacrine-phenyl-benzoheterocyclic hybrids (44–46) were synthesised and evaluated as multifunctional anti-Alzheimer’s disease agents. Compound 44b, tacrine linked with phenyl-benzothiazole by 3-carbon spacers, was the most potent AChE inhibitor with an IC50 value of 0.017μM. This compound demonstrated similar Aβ aggregation inhibitory activity with cucurmin (51.8% vs 52.1% at 20μM, respectively), indicating that this hybrid is an excellent multifunctional drug candidate for AD. [Copyright &y& Elsevier]

Abstract: The novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to various neurodegenerative diseases, such as Alzheimer''s disease, Parkinson''s disease, and amyotrophic lateral sclerosis. In the present study, we demonstrate that systemic chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1α protein levels in various brain regions (e.g. cortex, striatum, and hippocampus) and spinal cord of adult mice. Real-time RT-PCR revealed that M30 differentially induced HIF-1α-dependent target genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), enolase-1, transferrin receptor (TfR), heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and glucose transporter (GLUT)-1. In addition, mRNA expression levels of the growth factors, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) and three antioxidant enzymes (catalase, superoxide dismutase (SOD)-1, and glutathione peroxidase (GPx)) were up-regulated by M30 treatment in a brain-region-dependent manner. Signal transduction immunoblotting studies revealed that M30 induced a differential enhanced phosphorylation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), protein kinase B (PKB/Akt), and glycogen synthase kinase-3β (GSK-3β). Together, these results suggest that the multifunctional iron chelator M30 can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain that might function as important therapeutic targets for the drug in the context of neurodegenerative disease therapy. [Copyright &y& Elsevier]

Amygdalin possesses anticancer properties and induces apoptosis. Based on experimental studies the presence of amygdalin with cancer cells led to activate the caspase-3 and BAX and inhibits Bcl-2 and Poly (ADP-ribose) polymerase-1 (PARP-1) but without deep information on action mode of these activities. Herein, we leaped forward to examine the molecular dynamics of the bound amygdalin and free ligand proteins, to identify precise action (conformation changes in targeted proteins) of amygdalin through using double docking and molecular dynamics (MD) simulations for 50 ns time scale. The MD simulations revealed that the binding of amygdalin led to disrupting the interaction between the Bcl-2/BAX complex. We furthermore conducted MD simulation for Bcl-2/amygdalin to investigate the stability of the complex which is responsible for inhibition of Bcl-2. It has been obtained a stable Bcl-2/amygdalin complex during the 50 ns. The results give a detail explanation of how amygdalin activates BAX and inhibits Bcl-2. For caspase-3, the matter is different, we found that amygdalin led to disrupting the interaction of caspase-3's two chains for intervals during 50 ns and then bind together repeatedly. The mechanism of caspase-3's activation through switching by disrupt the interacts for periodic intervals manner. For PARP-1, the dynamics simulations results indicated amygdalin interacts with PARP-1's binding site and forms stable interaction during simulation to render it inactive. Hence, amygdalin revealed a supernatural behavior through the MD simulations: it revealed a further clarification of the mystery amygdalin's experimental action which can act as a multifunctional drug in the cancer therapeutics.Communicated by Ramaswamy H. Sarma.

We have developed a series of carbazole-derived compounds based on our hybrid D 2 /D 3 agonist template to design multifunctional compounds for the symptomatic and disease-modifying treatment of Parkinson's disease (PD). The lead molecules (-)-11b (D-636), (-)-15a (D-653), and (-)-15c (D-656) exhibited high affinity for both D 2 and D 3 receptors and in GTPγS functional assay, the compounds showed potent agonist activity at both D 2 and D 3 receptors (EC 50 (GTPγS); D 2 = 48.7 nM, D 3 = 0.96 nM for 11b, D 2 = 0.87 nM, D 3 = 0.23 nM for 15a and D 2 = 2.29 nM, D 3 = 0.22 nM for 15c). In an animal model of PD, the test compounds exhibited potent in vivo activity in reversing hypolocomotion in reserpinized rats with a long duration of action compared to the reference drug ropinirole. In a cellular antioxidant assay, compounds (-)-11b, (-)-15a, and (-)-15c exhibited potent activity in reducing oxidative stress induced by neurotoxin 6-hydroxydopamine (6-OHDA). Also, in a cell-based PD neuroprotection model, these lead compounds significantly increased cell survival from toxicity of 6-OHDA, thereby producing a neuroprotective effect. Additionally, compounds (-)-11b and (-)-15a inhibited aggregation and reduced toxicity of recombinant alpha synuclein protein in a cell based in vitro assay. These observations suggest that the lead carbazole-based dopamine agonists may be promising multifunctional molecules for a viable symptomatic and disease-modifying therapy of PD and should be further investigated.

Parkinson's disease (PD) is a progressive neurodegenerative disorder, and development of disease-modifying treatment is still an unmet medical need. Considering the implication of free iron(II) in PD, we report here the design and characterization of a novel hybrid iron chelator, (-)-12 (D-607) as a multitarget-directed ligand against PD. Binding and functional assays at dopamine D 2 /D 3 receptors indicate potent agonist activity of (-)-12. The molecule displayed an efficient preferential iron(II) chelation properties along with potent in vivo activity in a reserpinized PD animal model. The compound also rescued PC12 cells from toxicity induced by iron delivered intracellularly in a dose-dependent manner. However, Fe 3+ selective dopamine agonist 1 and a well-known antiparkinsonian drug pramipexole produced little to no neuroprotection effect under the same experimental condition. These observations strongly suggest that (-)-12 should be a promising multifunctional lead molecule for a viable symptomatic and disease modifying therapy of PD.