A novel fluorogenic substrate for dinuclear Zn(II)-containing metallo-β-lactamases

In an effort to prepare a fluorogenic substrate to be used in activity assays with metallo-β-lactamases, (6R,7R)-8-oxo-7-(2-oxo-2H-chromene-3-carboxamido)-3-((4-(2-oxo-2H-chromene-3-carboxamido)-phenylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (CA) was synthesized and characterized. CA exhibited a fluorescence quantum yield (φ) of 0.0059, two fluorescence lifetimes of 3.63 × 10^?10 and 5.38 × 10^?9 s, and fluorescence intensity that is concentration-dependent. Steady-state kinetic assays revealed that CA is a substrate for metallo-β-lactamases (MβLs) L1 and CcrA, exhibiting K_m and k_cat values of 18 μM and 5 s^?1 and 11 μM and 17 s^?1, respectively.     

Ketone H2-hydrogenation catalysts: Ruthenium complexes with the headphone-like ligand bis(phosphaadamantyl)propane

Treatment of 1,3-diphosphinopropane with acetylacetone in the presence of HCl gives the new chiral bis(phosphaadamantyl)propane ligand (bpap) (1) as a mixture of diastereoisomers. Recrystallization from ethanol gives a mixture enriched in rac diastereoisomer (90% rac/10% meso). The enriched mixture reacts with [RuHCl(PPh₃)₃] in refluxing THF to give [RuHCl(bpap)(PPh₃)] (2) in 73% yield. Compound 2 reacts readily with chiral diamines giving octahedral trans-[RuHCl(bpap)(diamine)] complexes 3 (diamine = (1R,2R)-1,2-diaminocyclohexane) and 4 (diamine = (1R,2R)-1,2-diphenylethylenediamine). Compounds 3 and 4 are very active catalysts for H₂-hydrogenation of neat acetophenone in the presence of KO^tBu as a strong base under mild conditions (room temperature, 3 atm of H₂). The low ee values for 1-phenethanol can be attributed to the similar shapes of two terminal adamantoid cages and the flexible backbone of the bpap ligand. The structures of complexes 2 and 3 have been determined by single-crystal X-ray diffraction.     

Two new cytotoxic eudesmane sesquiterpenoids from Artemisia anomala

Two new eudesmane sesquiterpenoids artanoate (1) and eudesmanomolide (2) were isolated from the aerial parts of Artemisia anomala S. Moore. Their structures were elucidated as methyl (4R, 5S, 6S, 7S, 10R)-1-oxo-4, 6-dihydroxy-eudesma-2, 11 (13)-dien-12-oate (1) and (1R, 5R, 6R, 10R)-3, 13-diacetoxy-1-hydroxy-3, 7(11)-diene-12, 6-olide (2) on the basis of extensive spectroscopic analyses. Compound 1 showed cytotoxicity against HCT-8 cell lines with IC₅₀ value of 9.13 μM, and compound 2 exhibited inhibitory activities against HCT-8 and A549 cell lines with IC₅₀ values of 3.76 and 5.49 μM, respectively.     

Synthesis and pharmacological evaluation of optically pure,novel carbonyl guanidine derivatives as dual 5-HT2B and 5-HT7 receptor antagonists

A series of 9-disubstituted N-(9H-fluorene-2-carbonyl)guanidine derivatives have been discovered as potent and orally active dual 5-HT_2B and 5-HT₇ receptor antagonists. Upon screening several compounds, N-(diaminomethylene)-4′,5′-dihydro-3′H-spiro[fluorene-9,2′-furan]-2-carboxamide (17) exhibited potent affinity for both 5-HT_2B (K_i = 5.1 nM) and 5-HT₇ (K_i = 1.7 nM) receptors with high selectivity over 5-HT_2A, 5-HT_2C, α₁, D₂ and M₁ receptors. Optical resolution of the intermediate carboxylic acid 16 via the formation of diastereomeric salts using chiral alkaloids gave the optically pure compounds (R)-17 and (S)-17. Both enantiomers suppressed 5-HT-induced dural protein extravasation in guinea pigs in a dose-dependent manner and the amount of leaked protein was suppressed to near normal levels when orally administrated at 10 mg/kg. (R)-17 and (S)-17 were therefore selected as candidates for human clinical trials.     

Discovery of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a): Histamine H3 receptor inverse agonist demonstrating potent cognitive enhancing and wake promoting activity

A series of fused cyclopropyl-4,5-dihydropyridazin-3-one (3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one) phenoxypiperidine analogs was designed and synthesized, leading to the identification of (1R,6S)-5-[4-(1-cyclobutyl-piperidin-4-yloxy)-phenyl]-3,4-diaza-bicyclo[4.1.0]hept-4-en-2-one (R,S-4a) as a second-generation pyridazin-3-one H₃R antagonist. Compound R,S-4a was a potent H₃R functional antagonist in vivo in the rat dipsogenia model, demonstrated potent wake activity in the rat EEG/EMG model, and enhanced short-term memory in the rat social recognition memory model at doses as low as 0.03–0.3 mg/kg po.     

1,5-Benzodiazepine inhibitors of HCV NS5B polymerase

Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC₅₀ = 400 nM and 270 nM, respectively) and selective (CC₅₀ > 20 μM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.     

Asymmetric synthesis and effect of absolute stereochemistry of YCZ-2013, a brassinosteroid biosynthesis inhibitor

The four stereoisomers of 2RS,4RS-1-[[2-(2,4-dichlorophenyl)-4-(2-(2-propenyloxy)phenoxymethyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole (YCZ-2013), a novel brassinosteroid biosynthesis inhibitor, were prepared. The diastereomers of 2RS,4R-5 and 2RS,4S-5 were prepared by using the corresponding optically pure R and S toluene-4-sulfonic acid 2,3-dihydroxypropyl ester (R-4,S-4). The enatiomerically and diastereomerically pure acetonide (5) was obtained by a method involving diastereoselective crystallisation of the tosylate salt, followed by re-equilibration with the mother liquor and chromatography. The optical purity of four target compounds (YCZ-2013) was confirmed by chiral high-performance liquid chromatography (HPLC) and NMR. The effects of these stereoisomers on Arabidopsis stem elongation indicated that the cis isomers of 2S,4R-YCZ-2013 and 2R,4S-YCZ-2013 exhibited potent inhibitory activity with IC₅₀ values of approximately 24 ± 3 and 24 ± 2 nM, respectively. The IC₅₀ values of the trans isomers of 2S,4S-YCZ-2013 and 2R,4R-YCZ-2013 are approximately 1510 ± 50 and 3900 ± 332 nM, respectively. Co-application of brassinolide (10 nM), the most potent BR, and GA₃ (1 μM) to Arabidopsis seedlings grown in the dark with 2R,4S-YCZ-2013 and 2S,4R-YCZ-2013 revealed that brassinolide recovered the induced dwarfism of Arabidopsis seedlings, whereas GA₃ showed no effect.     

Synthesis and preliminary evaluation of pharmacological properties of some piperazine derivatives of xanthone

A series of 9 piperazine derivatives of xanthone were synthesized and evaluated for cardiovascular activity. The following pharmacological experiments were conducted: the binding affinity for adrenoceptors, the influence on the normal electrocardiogram, the effect on the arterial blood pressure and prophylactic antiarrhythmic activity in adrenaline induced model of arrhythmia (rats, iv). Three compounds revealed nanomolar affinity for α₁-adrenoceptor which was correlated with the strongest cardiovascular (antiarrhythmic and hypotensive) activity in animals’ models. The most promising compound was 4-(3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (12) which revealed antiarrhythmic activity with ED₅₀ value of 0.69 mg/kg in adrenaline induced arrhythmia (rats, iv). Other synthesized xanthone derivatives, that is, (R,S)-4-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (10) and (R,S)-4-(2-acetoxy-3-(4-(2-methoxyphenyl)piperazine-1-yl)propoxy)-9H-xanthen-9-one hydrochloride (11) also acted as potential antiarrhythmics in adrenaline induced model of arrhythmia in rats after intravenous injection (ED₅₀ = 0.88 mg/kg and 0.89 mg/kg, respectively). These values were lower than values obtained for reference drugs such as propranolol and urapidil, but not carvedilol.Results were quite promising and suggested that in the group of xanthone derivatives new potential antiarrhythmics and hypotensives might be found.     

Two new anti-HBV lignans from Herpetospermum caudigerum

Two new lignans, named (+)-(7′S, 7″S, 8′R, 8″R)-4, 4′, 4″-trihydroxy-3, 5′, 3″-trimethoxy-7-oxo-8-ene [8-3′, 7′-O-9″, 8′-8″, 9′-O-7″] lignoid (1) and (1S)-4-Hydroxy-3-[2-(4-hydroxy-3-methoxy-phenyl)-1-hydroxymethyl-2-oxo-ethyl]-5-methoxy-benzaldehyde (2), along with five known (3–7) ones, have been isolated from the 95% ethanol extract of the seeds of Herpetospermum caudigerum Wall. The structures of the new compounds, including the absolute configurations, were elucidated by spectroscopic and CD analysis. Compounds 1, 2, and 7 displayed inhibitory activities on HBsAg secretion with IC₅₀ values of 20.5, 0.34, and 4.89 μM, while 1, 2, and 7 displayed inhibitory activities on HBeAg secretion with IC₅₀ values of 3.54, 4.83 × 10⁻⁴, and 8.02 μM, and cytotoxicity on HepG 2.2.15 cells with CC₅₀ values of 12.7, 2.96 × 10⁵, and 11.4 μM, respectively.     

New monoterpenes from stalks and infructescence of Sibiraea leavigata

Chemical investigation of the ethanol extract of the stalks and infructescence of Sibiraea leavigata led to the isolation of two new monoterpenes named (4R)-2-(2-hydroxy-4-methyl-3-pentenyl)furan-2(5H)-one (1) and (2R,4R)-2-(2-hydroxyethyl)-4-(2-methyl-1-propenyl)furan-5H-2-one (2) along with eight known phenylpropanoids (3–10). Their structures were established on the basis of the interpretation of spectroscopic data and electronic circular dichroism (ECD) calculations. In addition, all of these isolates were evaluated for their cytotoxic activity. The results showed that compound 3 displayed moderate cytotoxicity with IC₅₀ values ranging from 10.8 to 49.2 μg mL⁻¹ against five cell lines. While 1 showed selective promotion effects on proliferation of gastric cancer MGC803 and RSC96 cell lines.     

Copper(II) and zinc(II) complexes with Schiff-base ligands derived from salicylaldehyde and 3-methoxysalicylaldehyde: Synthesis,crystal structures,magnetic and luminescence properties

The following Schiff bases were employed as ligands in synthesizing copper(II) and zinc(II) complexes: N-[(2-pyridyl)-methyl]-salicylimine (Hsalampy), N-[2-(N,N-dimethyl-amino)-ethyl]-salicylimine (Hsaldmen), and N-[(2-pyridyl)-methyl]-3-methoxy-salicylimine (Hvalampy). The first two ligands were obtained by reacting salicylaldehyde with 2-aminomethyl-pyridyne and N,N-dimethylethylene diamine, respectively, while the third one results from the condensation of 3-methoxysalicylaldehyde with 2-aminomethyl-pyridine. Four new coordination compounds were synthesized and structurally characterized: [Cu(salampy)(H₂O)(ClO₄)] 1, [Cu₂(salampy)₂(H₂trim)₂] 2 (H₂trim^? = the monoanion of the trimescic acid), [Cu₄(valampy)₄](ClO₄)₄ · 2CH₃CN 3, and [Zn₃(saldmen)₃(OH)](ClO₄)₂ · 0.25H₂O 4. The crystal structure of 1 consists of supramolecular dimers resulted from hydrogen bond interactions established between mononuclear [Cu(salampy)(H₂O)(ClO₄)] complexes. Compound 2 is a binuclear complex with the copper ions connected by two monoatomic carboxylato bridges arising from two molecules of monodeprotonated trimesic acid. The crystal structure of 3 consists of tetranuclear cations with a heterocubane {Cu₄O₄} core, and perchlorate ions. Compound 4 is a trinuclear complex with a defective heterocubane structure. The magnetic properties of complexes 1–3 have been investigated. Compound 4 exhibits solid-state photoluminescence at room temperature.     

Derivatives of schisandrin with increased inhibitory potential on prostaglandin E2 and leukotriene B4 formation in vitro

Four derivatives of schisandrin, a major dibenzo[a,c]cyclooctadiene lignan of Schisandra chinensis (Turcz.) Baillon were synthesized and structurally characterized by means of NMR and mass spectroscopy. Furthermore, axial chirality of the biphenyl system was determined by comparison of calculated with measured circular dichroism (CD) spectra. Three of the obtained derivatives showed a ring contraction during chemical modification. While the original lignans were inactive on the performed bioassays, the compounds which showed the cycloheptadiene skeleton revealed remarkable activities. For the inhibition of LTB₄ production the IC₅₀ values of aR-6,7-dihydro-6-(1′-hydroxyethyl)-3,9-dimethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,10,11-tetraol (6) and aR-6-(1′-iodoethyl)-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene (8) were 4.2 ± 0.3 μM and 4.5 ± 0.2 μM, respectively. aR-6,7-Dihydro-6-(1′-hydroxyethyl)-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,3,9,10,11-hexaol (5) revealed dual inhibition on COX-2 (IC₅₀ 32.1 ± 2.5 μM) and on LTB₄ production (37.3 ± 5.5% inhibition at 50 μM).     

Synthesis and biological evaluation of N-mercaptoacylcysteine derivatives as leukotriene A4 hydrolase inhibitors

We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A₄ (LTA₄) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA₄ hydrolase (IC₅₀, 270 nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC₅₀, 520 nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA₄ hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA₄ hydrolase inhibitors.     

Influence of ligands on the fac⇌Δhνmer isomerization in [RuCl3(NO)(P–P)] complexes, [P–P = R2P(CH2)nPR2 (n = 1–3) and R2P(CH2)POR2, PR2–CHCH–PR2, R = Ph and (C6H11)2P-(CH2)2-P(C6H11)2]

[RuCl₃(NO)(P–P)], [P–P = R₂P(CH₂)_nPR₂ (n = 1–3) and R₂P(CH₂)POR₂, PR₂–CHCH–PR₂, R = Ph and (C₆H₁₁)₂P-(CH₂)₂-P(C₆H₁₁)₂] were obtained and characterized by ³¹P {¹H} NMR, IR spectroscopies and cyclic voltammetry. The structures of fac-[RuCl₃(NO)(P–P)], P–P = dppm (1), dppe (2), c-dppen (3) and dppp (4), mer-[RuCl₃(NO)(dcpe)] (6a) and mer-[RuCl₃(NO)(dppmO)] (7) have been determined by X-ray diffraction. Photochemical isomerization of fac- to mer-[RuCl₃(NO)(P–P)] was observed under white light in a CH₂Cl₂ solution and in solid state. The isomerization processes were followed by IR and ³¹P {¹H} spectra. The mer-[RuCl₃(¹⁵NO)(dppb)] isomer was used for the definition of the phosphorus atoms in the structure of the complex in solution. The electrochemical study shows that the oxidation/reduction processes observed in these complexes are dependent on both the isomer (fac or mer) and the solvent. In CH₂Cl₂, the NO⁺ reduction potentials are less negative for the mer-isomers than for the fac ones, while in CH₃CN solvent these potentials are, in general, very close for both isomers.     

Linear homobimetallic 4-thioacetyl-substituted NCN pincer palladium(II) and platinum(II) complexes with N-bidentate connecting units (NCN = [C6H2(CH2NMe2)2-2,6-R-4]−)

The synthesis and characterization of homobimetallic palladium and platinum complexes of type [(Me(O)CS-4-NCN–M ← N^∩N → M–NCN-4-SC(O)Me](OTf)₂ (Me(O)CS-4-NCN = [C₆H₂(CH₂NMe₂)₂-2,6-SC(O)Me-4]^?; N^∩N = 4,4′-bipyridine (bipy); M = Pd, 12; M = Pt, 13) is reported. The required bifunctional thio-acetyl NCN pincer starting compound NC(Br)N-4-SC(O)Me (2) has been synthesized by the consecutive reactions of NC(Br)N–I (I-1-C₆H₂(CH₂NMe₂)₂-3,5-Br-4) (1) with ^tBuLi, S₈ and Me(O)CCl, respectively. Chemoselective metallation at the C_aryl–Br bond was achieved by the reaction of 2 with the palladium(0) source [Pd₂(dba)₃] (3) (dba = dibenzylidene acetone). Treatment of thus formed [Pd(NCN-4-SC(O)Me)(Br)] (4) with [AgOTf] (8) (OTf = triflate, OSO₂CF₃) gave [Pd(NCN-4-SC(O)Me)(H₂O)][OTf] (9) which was further reacted with 0.5 equiv. of 4,4′-bipyridine (11a) to afford rigid-rod structured 12. When [Pt(tol)₂(SEt₂)]₂ (5) (tol = 4-tolyl) was used instead of 3, then 13 was produced via the in situ formation of [PtBr(NCN-4-SC(O)Me)] (7) and [Pt(NCN-4-SC(O)Me)(H₂O)][OTf] (10). Another possibility to synthesize 7 relied upon the subsequent reaction of 1 with 0.5 equiv. of 5 to give [PtBr(NCN-4-I)] (6) which further reacted with ^tBuLi, 1/8 S₈ and Me(O)CCl to afford 7. The cyclic voltammograms of 2, 7, and 13 are discussed.Complex 7 was structurally characterized by single crystal X-ray crystallography. Organometallic 7 crystallizes with three independent molecules in the asymmetric unit and displays a monomeric structure as commonly encountered in d⁸-metal pincer chemistry.     

New pentafluorophenyl complexes with phosphine-amide ligands

A series of nickel(II) and palladium(II) complexes containing one or two pentafluorophenyl ligands and the phosphino-amides o-Ph₂PC₆H₄CONHR [R = ⁱPr (a), Ph (b)] displaying different coordination modes have been synthesised. The chelating ability of these ligands and the influence of both coligands and the metal centre in their potential hemilabile behaviour have been explored. The crystal structure of (b) has been determined and reveals N–H⋯O intermolecular hydrogen bonding. Bis-pentafluorophenyl derivatives [M(C₆F₅)₂(o-Ph₂PC₆H₄CO-NHR)] [M = Ni; R = ⁱPr (1a); R = Ph (1b); M = Pd; R = ⁱPr (2a); R = Ph (2b)] in which (a) and (b) act as rigid P, O-chelating ligands were readily prepared from the labile precursors cis-[M(C₆F₅)₂(PhCN)₂]. X-ray structures of (1a), (1b) and (2a) have been established, allowing an interesting comparative structural discussion. Dinuclear [{Pd(C₆F₅)(tht)(μ-Cl)}₂] reacted with (a) and (b) yielding the monopentafluorophenyl complexes [Pd(C₆F₅)Cl{PPh₂(C₆H₄–CONH–R)}] (R = ⁱPr (3a), Ph (3b)) that showed a P, O-chelating behaviour of the ligands, confirmed by the crystal structure determination of (3a). New cationic palladium(II) complexes in which (a) and (b) behave as P-monodentate ligands have been synthesised by reacting them with [{Pd(C₆F₅)(tht)(μ-Cl)}₂], stoichiometric Ag(O₃SCF₃) and external chelating reagents such as cod [Pd(C₆F₅)(cod){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃)(R = ⁱPr (4a), Ph (4b)) and 2,2′-bipy [Pd(C₆F₅)(bipy){PPh₂(C₆H₄-CONH-R)}](O₃SCF₃) (R = ⁱPr (5a), Ph (5b)). When chloride abstraction in [{Pd(C₆F₅)(tht)(μ-Cl)}₂] is promoted by means of a dithioanionic salt as dimethyl dithiophospate in the presence of (a) or (b), the corresponding neutral complexes [Pd(C₆F₅){S(S)P(OMe)₂}{PPh₂(C₆H₄-CONH-R)}] (R = ⁱPr (6a), Ph (6b)) were obtained.     

Design,synthesis and evaluation of [3H]PF-7191, a highly specific nociceptin opioid peptide (NOP) receptor radiotracer for in vivo receptor occupancy (RO) studies

Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3-((1R,3r,5S)-6′-fluoro-8-azaspiro[bicyclo[3.2.1]octane-3,1′-isochroman]-8-yl)propyl)-N-[³H]-methylacetamide {[³H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (K_i = 0.1 nM), excellent selectivity over other opioid receptors (>1000×) and good brain permeability in rats (C_b,u/C_p,u = 0.29). Subsequent characterization of [³H](+)-11 showed a high level of specific binding and a brain bio-distribution pattern consistent with known NOP receptor expression. Furthermore, the in vivo brain binding of [³H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose–responsive manner. This overall favorable profile indicated that [³H](+)-11 is a robust radiotracer for pre-clinical in vivo receptor occupancy (RO) measurements and a possible substrate for carbon-11 labeling for positron emission tomography (PET) imaging in higher species.     

Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs)

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC₅₀ = 292.17 ± 27.71 μM and 331.94 ± 21.21 μM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC₅₀ = 275.24 ± 13.15 μM). These values are significantly lower than those of ascorbic acid (EC₅₀ = 1129.32 ± 88.79 μM) and α-tocopherol (EC₅₀ = 944.62 ± 148.00 μM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68 ± 0.27; synthetic (S,S)-SDG-1: 2.09 ± 0.16; synthetic (R,R)-SDG-2: 1.96 ± 0.27], peroxyl [natural (S,S)-SDG-1: 2.55 ± 0.11; synthetic (S,S)-SDG-1: 2.20 ± 0.10; synthetic (R,R)-SDG-2: 3.03 ± 0.04] and DPPH [natural (S,S)-SDG-1: EC₅₀ = 83.94 ± 2.80 μM; synthetic (S,S)-SDG-1: EC₅₀ = 157.54 ± 21.30 μM; synthetic (R,R)-SDG-2: EC₅₀ = 123.63 ± 8.67 μM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.     

Coumarin-thiazole and -oxadiazole derivatives: Synthesis,bioactivity and docking studies for aldose/aldehyde reductase inhibitors

In continuation of our previous efforts directed towards the development of potent and selective inhibitors of aldose reductase (ALR2), and to control the diabetes mellitus (DM), a chronic metabolic disease, we synthesized novel coumarin-thiazole 6(a–o) and coumarin-oxadiazole 11(a–h) hybrids and screened for their inhibitory activity against aldose reductase (ALR2), for the selectivity against aldehyde reductase (ALR1). Compounds were also screened against ALR1. Among the newly designed compounds, 6c, 11d, and 11g were selective inhibitors of ALR2. Whereas, (E)-3-(2-(2-(2-bromobenzylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one 6c yielded the lowest IC₅₀ value of 0.16 ± 0.06 μM for ALR2. Moreover, compounds (E)-3-(2-(2-benzylidenehydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6a; IC₅₀ = 2.94 ± 1.23 μM for ARL1 and 0.12 ± 0.05 μM for ARL2) and (E)-3-(2-(2-(1-(4-bromophenyl)ethylidene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6e; IC₅₀ = 1.71 ± 0.01 μM for ARL1 and 0.11 ± 0.001 μM for ARL2) were confirmed as dual inhibitors. Furthermore, compounds 6i, 6k, 6m, and 11b were found to be selective inhibitors for ALR1, among which (E)-3-(2-(2-((2-amino-4-chlorophenyl)(phenyl)methylene)hydrazinyl)thiazol-4-yl)-2H-chromen-2-one (6m) was most potent (IC₅₀ = 0.459 ± 0.001 μM). Docking studies performed using X-ray structures of ALR1 and ALR2 with the given synthesized inhibitors showed that coumarinyl thiazole series lacks the carboxylate function that could interact with the anionic binding site being a common ALR1/ALR2 inhibitors trait. Molecular docking study with dual inhibitor 6e also suggested plausible binding modes for the ALR1 and ALR2 enzymes. Hence, the results of this study revealed that coumarinyl thiazole and oxadiazole derivatives could act as potential ALR1/ALR2 inhibitors.     

8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors

Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson’s disease are, among others, the A_2A adenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A₁ ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure–activity-relationships. Several compounds blocked human and rat A₁ and A_2AARs at similar concentrations representing dual A₁/A_2A antagonists with high selectivity versus the other AR subtypes. Among the best dual A₁/A_2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, K_i human A₁: 65.5 nM, A_2A: 230 nM; K_i rat A₁: 352 nM, A_2A: 316 nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, K_i human A₁: 642 nM, A_2A: 203 nM; K_i rat A₁: 166 nM, A_2A: 121 nM). Compound 57 was found to be well water-soluble (0.7 mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A₁ and A_2AARs and at MAO-B (K_i human A₁: 393 nM, human A_2A: 595 nM, IC₅₀ human MAO-B: 210 nM) thus allowing future in vivo explorations of the intended multi-target approach.