Caerulomycin and collismycin antibiotics share a trans-acting flavoprotein-dependent assembly line for 2,2'-bipyridine formation.

Linear nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs) template the modular biosynthesis of numerous nonribosomal peptides, polyketides and their hybrids through assembly line chemistry. This chemistry can be complex and highly varied, and thus challenges our understanding in NRPS and PKS-programmed, diverse biosynthetic processes using amino acid and carboxylate building blocks. Here, we report that caerulomycin and collismycin peptide-polyketide hybrid antibiotics share an assembly line that involves unusual NRPS activity to engage a trans-acting flavoprotein in C-C bond formation and heterocyclization during 2,2'-bipyridine formation. Simultaneously, this assembly line provides dethiolated and thiolated 2,2'-bipyridine intermediates through differential treatment of the sulfhydryl group arising from L-cysteine incorporation. Subsequent L-leucine extension, which does not contribute any atoms to either caerulomycins or collismycins, plays a key role in sulfur fate determination by selectively advancing one of the two 2,2'-bipyridine intermediates down a path to the final products with or without sulfur decoration. These findings further the appreciation of assembly line chemistry and will facilitate the development of related molecules using synthetic biology approaches.

Functionalisation of gold nanoparticles with ruthenium(II) polypyridyl complexes for their application in cellular imaging.

Two new dinuclear Ru(ii) polypyridyl complexes containing an alkyl disulphide functionalised bipyridine-based ligand and either 1,10-phenanthroline (phen) or 1,4,5,8-tetraazaphenanthrene (TAP) as ancillary ligands have been synthesised and characterised. Their attachment onto the surface of gold nanoparticles (AuNPs, average diameter of ca. 2.5 nm) resulted in the formation of two new water-soluble Ru(ii)-AuNP conjugates that combine the advantageous properties of both moieties. Both free complexes show the attractive photophysical properties of Ru(ii) polypyridyl complexes and a rapid cellular uptake in HeLa cervical cancer cells. However, their corresponding gold conjugates displayed lower quantum yields than those determined for the free complexes presumed to be due to an energy transfer quenching of the Ru(ii) luminescence by interaction with the gold surface. Despite their diminished luminescence, confocal fluorescence microscopy studies revealed that the Ru(ii)-AuNP conjugates are successfully internalised into HeLa cells and better tolerated than their free complex counterparts after 24 h incubation, which makes them potential luminescent nanomaterials for bioimaging applications.

Stabilization of an intermolecular RNA triplex by two novel binders Lys- and Arg-rich Ru(II) polypyridyl metallopeptides.

In this work, using [Ru(bpy)2(pip)]2+ (bpy = 2,2'-bipyridine, pip = 2-phenyl-1H-imidazo[4,5-f]-[1,10]-phenanthroline) as chromophores and neutral amino acid glycine as spacers, two novel Arg- and Lys-rich Ru(II) polypyridyl metallopeptides as an intermolecular triplex RNA stabilizers, namely [Ru(bpy)2(pic-Lys2-Gly-Lys2-Gly-Lys2)]8+ (Ru1; pic = 2-(4-carboxy-phenyl)imidazo-[4,5-f] [1,10] phenanthroline, Gly = glycine, Lys = lysine) and [Ru(bpy)2(pic-Arg2-Gly-Arg2-Gly-Arg2)]8+ (Ru2; Arg = arginine), have been synthesized and characterized. The binding properties of Ru1 and Ru2 with poly(U)·poly(A)∗poly(U) triplex have been studied by UV-Vis spectroscopy, fluorescence spectroscopy, viscosity measurements as well as circular dichroism and thermal denaturation. The obtained results suggest that attaching cationic peptides to a Ru(II) polypyridyl complex can obviously enhance the triplex stabilization. Considering the structure natures of Ru1 and Ru2, conceivably besides electrostatic interaction, the forces stabilizing the triplex should also involve hydrophobic interaction and hydrogen binding. Compared with the Lys-rich metallopeptide (Ru1), however, the third-strand stabilizating effect of the Arg-rich one (Ru2) is slightly more marked, which may be due to differences in the interactions of arginine and lysine residues with the third strand of the triplex. The results obtained here may be useful for understanding the interaction of triplex RNA poly(U)·poly(A)∗poly(U) with small molecule, particularly ruthenium(II) complexes.

Chemical Probing of Thymine in the TGG/CGG Triad to Explore the Deamination of 5-Methylcytosine in the CGG Repeat.

The methylation of cytosine in the full mutation of the expanded CGG repeat and subsequent deamination to thymine could be a measure of repeat instability. We report the synthesis of NCD-Bpy, which binds to the TGG/CGG site in the repeat hairpin. NCD-Bpy forces the thymine in the TGG/CGG site to flip out from the π-stack, recruits osmium tetroxide in the vicinity of the flipped-out T, and oxidizes the T. The piperidine-induced cleavage band successfully determined the position of the T in the expanded CGG repeat.

Are Alkynyl Spacers in Ancillary Ligands in Heteroleptic Bis(diimine)copper(I) Dyes Beneficial for Dye Performance in Dye-Sensitized Solar Cells?

The syntheses of 4,4'-bis(4-dimethylaminophenyl)-6,6'-dimethyl-2,2'-bipyridine (1), 4,4'-bis(4-dimethylaminophenylethynyl)-6,6'-dimethyl-2,2'-bipyridine (2), 4,4'-bis(4-diphenylaminophenyl)-6,6'-dimethyl-2,2'-bipyridine (3), and 4,4'-bis(4-diphenylaminophenylethynyl)-6,6'-dimethyl-2,2'-bipyridine (4) are reported along with the preparations and characterisations of their homoleptic copper(I) complexes [CuL2][PF6] (L = 1-4). The solution absorption spectra of the complexes exhibit ligand-centred absorptions in addition to absorptions in the visible region assigned to a combination of intra-ligand and metal-to-ligand charge-transfer. Heteroleptic [Cu(5)(Lancillary)]+ dyes in which 5 is the anchoring ligand ((6,6'-dimethyl-[2,2'-bipyridine]-4,4'-diyl)bis(4,1-phenylene))bis(phosphonic acid) and Lancillary = 1-4 have been assembled on fluorine-doped tin oxide (FTO)-TiO2 electrodes in dye-sensitized solar cells (DSCs). Performance parameters and external quantum efficiency (EQE) spectra of the DSCs (four fully-masked cells for each dye) reveal that the best performing dyes are [Cu(5)(1)]+ and [Cu(5)(3)]+. The alkynyl spacers are not beneficial, leading to a decrease in the short-circuit current density (JSC), confirmed by lower values of EQEmax. Addition of a co-absorbent (n-decylphosphonic acid) to [Cu(5)(1)]+ lead to no significant enhancement of performance for DSCs sensitized with [Cu(5)(1)]+. Electrochemical impedance spectroscopy (EIS) has been used to investigate the interfaces in DSCs; the analysis shows that more favourable electron injection into TiO2 is observed for sensitizers without the alkynyl spacer and confirms higher JSC values for [Cu(5)(1)]+.

Tautomerism and Self-Association in the Solution of New Pinene-Bipyridine and Pinene-Phenanthroline Derivatives.

Two novel pinene-type ligands have been synthesized and their tautomeric and self-associating behavior studied in solution and in the solid state. The first ligand, an acetylated derivative of 5,6-pinene-bipyridine, displays keto-enol tautomerism in solution. This tautomeric equilibrium was studied by NMR and UV-Vis spectroscopy in various solvents, and the results were compared with the ones obtained through DFT calculations. The second ligand was obtained by an unusual oxidation of the phenanthroline unit of a pinene-phenanthroline derivative. This compound exists as a single tautomer in solution and aggregates both in solution (as observed by NMR) and in the solid state through H-bonding as observed by X-ray structure determination and confirmed by DFT studies.

Self-Assembly by Tridentate or Bidentate Ligand: Synthesis and Vapor Adsorption Properties of Cu(II), Zn(II), Hg(II) and Cd(II) Complexes Derived from a Bis(pyridylhydrazone) Compound.

Four complexes, [Cu4L2(OCH3)2(CH3OH)2]·2H2O (1), [Zn2L2Cl4]·2H2O·2CH3OH (2), [Hg2L2Br4]·4CH3OH (3), and {[CdL2Cl2]·4H2O·4CH3OH}n (4), have been synthesized and characterized from a bis(pyridylhydrazone) ligand (L) with copper(II), zinc(II), mercury(II) or cadmium(II), respectively. Complex 1 exists as a centrosymmetric tetranuclear dimer with L as deprotonated tridentate ligand. Complexes 2 and 3 exist as centrosymmetric metallamacrocycles with L as bidentate ligand. Complex 4 exists as a 1D looped-chain coordination polymer. The thermal stabilities and vapor adsorption properties of the four complexes were investigated as well.

Determination of uric acid in serum using an optical sensor based on binuclear Pd(II) 2-pyrazinecarboxamide-bipyridine doped in a sol gel matrix.

A new highly green luminescent binuclear palladium 2-pyrazinecarboxamide-bipyridine complex [Pd(pyc)(bpy)] was prepared and characterized. The binuclear Pd(pyc)(bpy) complex doped in sol-gel matrix has a strong luminescence intensity at 547 nm with λex = 330 nm in water The method depends on the quenching of the luminescence intensity of the binuclear Pd(pyc)(bpy) complex at 547 nm by different concentrations of uric acid. The remarkable quenching of the luminescence intensity of the binuclear Pd(pyc)(bpy) complex, doped in a sol-gel matrix, by uric acid was successfully used for the determination of uric acid in serum samples of patients with hypouricemia disease. The calibration plot was achieved over the concentration 3.9 × 10-9 to 1.2 × 10-4 mol L-1uric acid with a correlation coefficient of 0.9 and a detection limit of 1.8 × 10-10 mol L-1. The method was used satisfactorily for the assessment of the uric acid in a number of serum samples collected from various patients with Hypouricemia disease.

Modular DNA-based hybrid catalysts as a toolbox for enantioselective hydration of α,ß-unsaturated ketones.

The direct addition of water to a carbon-carbon double bond remains a challenge, but such a reaction is essential for the development of efficient catalysts that enable direct access to chiral alcohols. We now report on the enantioselective hydration of α,ß-unsaturated ketones, catalyzed by modular DNA-based hybrid catalysts, affording ß-hydroxy ketones with up to 87% enantiomeric excess. Oligonucleotides containing an intrastrand bipyridine ligand were readily synthesized by a straightforward process using an automated solid-phase synthesis. A library of DNA-based hybrid catalysts could be systematically generated based on the composition of nucleobases, and the incorporation of a binding ligand and a nonbinding steric moiety. This study demonstrates the potential of modular DNA-based hybrid catalysts as a toolbox to accomplish the challenging enantioselective hydration reaction.

Structure, DNA/proteins binding, docking and cytotoxicity studies of copper(II) complexes with the first quinolone drug nalidixic acid and 2,2'­dipyridylamine.

This work presents the synthesis, structural characterization and biological affinity of the newly synthesized copper(II) complexes with the first antibacterial quinolone drug nalidixic acid (nal) or N-donor ligand 2,2'­dipyridylamine (bipyam). [Cu(II)(nal)(bipyam)Cl], (2) reveals a distorted square pyramidal based geometry in Cu(II) atom confirmed by X-ray crystallography technique. The theoretical stabilities and optimized structures of the complex were obtained from DFT calculations. The ability of the complexes to bind with calf thymus DNA (CT DNA) were investigated by electronic absorption, fluorescence, circular dichroism, and viscosity measurements techniques. The experimental results reveal that the complexes strongly interact with CT DNA via intercalative mode but complex 2 exhibits the highest affinity giving Kb=3.91±0.13×106, M-1. The fluorescence spectroscopy measurements show that both complexes have the superior ability to the replacement of EtBr from DNA-bound EtBr solution and bind to DNA through intercalative mode. Both complex also shows the superior affinity towards proteins with comparatively high binding constant values which have been further revealed by fluorescence spectroscopy measurements. Molecular docking analysis indicates that the interaction of the complexes and proteins are stabilized by hydrogen bonding and hydrophobic interaction. Furthermore, the results of in vitro cytotoxicity reveal that the complex 2 has excellent cytotoxicity than 1 against human breast cancer cell lines (MCF-7).

Methyl-cyclopentadienyl Ruthenium Compounds with 2,2'-Bipyridine Derivatives Display Strong Anticancer Activity and Multidrug Resistance Potential.

New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(η5-MeCp)(PPh3)(4,4'-R-2,2'-bpy)]+ (Ru1, R = H; Ru2, R = CH3; and Ru3, R = CH2OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P21/ c, Ru2 in the triclinic P1̅, and Ru3 in the monoclinic P21/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents.

Photochemical and Photobiological Activity of Ru(II) Homoleptic and Heteroleptic Complexes Containing Methylated Bipyridyl-type Ligands.

Light-activated compounds are powerful tools and potential agents for medical applications, as biological effects can be controlled in space and time. Ruthenium polypyridyl complexes can induce cytotoxic effects through multiple mechanisms, including acting as photosensitizers for singlet oxygen (1O2) production, generating other reactive oxygen species (ROS), releasing biologically active ligands, and creating reactive intermediates that form covalent bonds to biological molecules. A structure-activity relationship (SAR) study was performed on a series of Ru(II) complexes containing isomeric tetramethyl-substituted bipyridyl-type ligands. Three of the ligand systems studied contained strain-inducing methyl groups and created photolabile metal complexes, which can form covalent bonds to biomolecules upon light activation, while the fourth was unstrained and resulted in photostable complexes, which can generate 1O2. The compounds studied included both bis-heteroleptic complexes containing two bipyridine ligands and a third, substituted ligand and tris-homoleptic complexes containing only the substituted ligand. The photophysics, electrochemistry, photochemistry, and photobiology were assessed. Strained heteroleptic complexes were found to be more photoactive and cytotoxic then tris-homoleptic complexes, and bipyridine ligands were superior to bipyrimidine. However, the homoleptic complexes exhibited an enhanced ability to inhibit protein production in live cells. Specific methylation patterns were associated with improved activation with red light, and photolabile complexes were generally more potent cytotoxic agents than the photostable 1O2-generating compounds.

The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold.

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.

Design and synthesis of some new 2,3'-bipyridine-5-carbonitriles as potential anti-inflammatory/antimicrobial agents.

AIM: Inflammation may cause accumulation of fluid in the injured area, which may promote bacterial growth. Other reports disclosed that non-steroidal anti-inflammatory drugs may enhance progression of bacterial infection. RESULTS: This work describes synthesis of new series of 2,3'-bipyridine-5-carbonitriles as structural analogs of etoricoxib, linked at position-6 to variously substituted thio or oxo moieties. Biological screening results revealed that compounds 2b, 4b, 7e and 8 showed significant acute and chronic AI activities and broad spectrum of antimicrobial activity. In addition, similarity ensemble approach was applied to predict potential biological targets of the tested compounds. Then, pharmacophore modeling study was employed to determine the most important structural parameters controlling bioactivity. Moreover, title compounds showed physicochemical properties within those considered adequate for drug candidates. CONCLUSION: This study explored the potential of such series of compounds as structural leads for further modification to develop a new class of dual AI-antimicrobial agents.

Aryl-Substituted Ruthenium(II) Complexes: A Strategy for Enhanced Photocleavage and Efficient DNA Binding.

Ruthenium polypyridine complexes have shown promise as agents for photodynamic therapy (PDT) and tools for molecular biology (chromophore-assisted light inactivation). To accomplish these tasks, it is important to have at least target selectivity and great reactive oxygen species (ROS) photogeneration: two properties that are not easily found in the same molecule. To prepare such new agents, we synthesized two new ruthenium complexes that combine an efficient DNA binding moiety (dppz ligand) together with naphthyl-modified (1) and anthracenyl-modified (2) bipyridine as a strong ROS generator bound to a ruthenium complex. The compounds were fully characterized and their photophysical and photochemical properties investigated. Compound 2 showed one of the highest quantum yields for singlet oxygen production ever reported (ΦΔ= 0.96), along with very high DNA binding (log Kb = 6.78). Such photochemical behavior could be ascribed to the lower triplet state involving the anthracenyl-modified bipyridine, which is associated with easier oxygen quenching. In addition, the compounds exhibited moderate selectivity toward G-quadruplex DNA and binding to the minor groove of DNA, most likely driven by the pendant ligands. Interestingly, they also showed DNA photocleavage activity even upon exposure to a yellow light-emitting diode (LED). Regarding their biological activity, the compounds exhibited an exciting antibacterial action, particularly against Gram-positive bacteria, which was enhanced upon blue LED irradiation. Altogether, these results showed that our strategy succeeded in producing light-triggered DNA binding agents with pharmacological and biotechnological potential.

Dinuclear RuII(bipy)2 Derivatives: Structural, Biological, and in Vivo Zebrafish Toxicity Evaluation.

Ruthenium-based drugs exhibit interesting properties as potential anticancer pharmaceuticals. We herein present the synthesis and characterization of a new family of ruthenium complexes with formulas [{Ru(bipy)2}2(µ-L)][CF3SO3]4 (L = bptz, 1a) and [{Ru(bipy)2}2(µ-L)][CF3SO3]2 (L = arphos, 2a; dppb, 3a; dppf, 4a), which were synthesized from the Ru(II) precursor compound cis-Ru(bipy)2Cl2. The complexes were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, IR spectroscopy, and conductivity measurements. The molecular structures for three Ru(II) compounds were determined by single-crystal X-ray diffraction. The newly developed compounds interact with CT-DNA by intercalation, in particular, 2a, 3a, and 4a, which also seemed to induce some extent of DNA degradation. This effect seemed to be related with the formation of reactive oxygen species. The cytotoxic activity was evaluated against A2780, MCF7, and MDAMB231 human tumor cells. Compounds 2a and 4a were the most cytotoxic with activity compared to cisplatin (∼2 µM, 72 h) in the A2780 cisplatin sensitive cells. All the compounds induced A2780 cell death by apoptosis, however, to a lesser extent for compounds 4a and 2a. For these compounds, the mechanism of cell death in addition to apoptosis seemed to involve autophagy. In vivo toxicity was evaluated using the zebrafish embryo model. LC50 estimates varied from 5.397 (3a) to 39.404 (1a) mg/L. Considering the in vivo toxicity in zebrafish embryos and the in vitro cytotoxicity in cancer cells, compound 1a seems to be the safest having no effect on dechirionation and presenting a good antiproliferative activity against ovarian carcinoma cells.

Strategic Design of 2,2'-Bipyridine Derivatives to Modulate Metal-Amyloid-ß Aggregation.

The complexity of Alzheimer's disease (AD) stems from the inter-relation of multiple pathological factors upon initiation and progression of the disease. To identify the involvement of metal-bound amyloid-ß (metal-Aß) aggregation in AD pathology, among the pathogenic features found in the AD-affected brain, small molecules as chemical tools capable of controlling metal-Aß aggregation were developed. Herein, we report a new class of 2,2'-bipyridine (bpy) derivatives (1-4) rationally designed to be chemical modulators toward metal-Aß aggregation over metal-free Aß analogue. The bpy derivatives were constructed through a rational design strategy employing straightforward structural variations onto the backbone of a metal chelator, bpy: (i) incorporation of an Aß interacting moiety; (ii) introduction of a methyl group at different positions. The newly prepared bpy derivatives were observed to bind to metal ions [i.e., Cu(II) and Zn(II)] and interact with metal-Aß over metal-free Aß to varying degrees. Distinguishable from bpy, the bpy derivatives (1-3) were indicated to noticeably modulate the aggregation pathways of Cu(II)-Aß and Zn(II)-Aß over metal-free Aß. Overall, our studies of the bpy derivatives demonstrate that the alteration of metal binding properties as well as the installation of an Aß interacting capability onto a metal chelating framework, devised via the rational structure-based design, were able to achieve evident modulating reactivity against metal-Aß aggregation. Obviating the need for complicated structures, our design approach, presented in this work, could be appropriately utilized for inventing small molecules as chemical tools for studying desired metal-related targets in biological systems.

Photochemical studies of cis-[Ru(bpy)2(4-bzpy)(CO)](PF6)2 and cis-[Ru(bpy)2(4-bzpy)(Cl)](PF6): Blue light-induced nucleobase binding.

The ruthenium(II) compounds cis-[Ru(bpy)2(4-bzpy)(CO)](PF6)2 (I) and cis-[Ru(bpy)2(4-bzpy)(Cl)](PF6) (II) (4-bzpy=4-benzoylpyridine, bpy=2,2'-bipyridine) were synthesized and characterized by spectroscopic and electrochemical techniques. The crystal structure of II was determined by X-ray diffraction. The photochemical behavior of I in aqueous solution shows that irradiation with ultraviolet light (365nm) releases both CO and 4-bzpy leading to the formation of the cis-[Ru(bpy)2(H2O)2]2+ ion as identified by NMR and electronic spectroscopy. Carbon monoxide release was confirmed with the myoglobin method and by gas chromatographic analysis of the headspace. CO release was not observed when aqueous I was irradiated with blue light (453nm). Changes in the electronic and 1H NMR spectra indicate that I undergoes photoaquation of 4-bzpy to form cis-[Ru(bpy)2(CO)(H2O)]2+. Blue light irradiation of aqueous II released the coordinated 4-bzpy to give the cis-[Ru(bpy)2(H2O)(Cl)]2+ ion. When the latter reaction was carried out in the presence of the nucleobase guanine, Ru-guanine adducts were formed, indicating that the metal containing photoproduct may also participate in biologically relevant reactions. The photochemical behavior of I indicates that it can release either CO or 4-bzpy depending on the wavelength chosen, a feature that may have therapeutic application.

Electrochemical Control of Bioluminescence by Blocking the Adsorption of the Bacterial Luciferase Using a Mercaptobipyridine Self-assembled Monolayer.

An N-butyl-N'-(4-mercaptobutyl)-4,4'-bipyridinium (4BMBP) was modified on a gold electrode to improve the electrochemical control of the bacterial luciferase (BL) luminescence system. The 4BMBP-modified gold electrode (4BMBP/Au) was able to prevent the adsorption of BL on the electrode surface, and enhanced the electrochemical regeneration rate of the reduced flavin mononucleotide (FMNH2), which is one of the substrates of the BL luminescence reaction. By using the 4BMBP/Au, the luminescence intensity increased by about 27% compared to that of a bare gold electrode (bare Au). Moreover, the modified electrode improved the time required for analysis because the modified layer prevented BL adsorption. Even without a refreshing procedure for each measurement, a constant luminescence intensity could be observed, and the analysis time was reduced to half (about 10 min) for one sample. The 4BMBP/Au is not only useful to control of the BL luminescence system, but also for electrochemical measurements in the presence of proteins.

A Novel Iron(II) Preferring Dopamine Agonist Chelator as Potential Symptomatic and Neuroprotective Therapeutic Agent for Parkinson's Disease.

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 D2/D3 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, Fe3+ 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.