Small-molecular inhibitors of Ca2+-induced mitochondrial permeability transition (MPT) derived from muscle relaxant dantrolene

A structure consisting of substituted hydantoin linked to a 5-(halophenyl)furan-2-yl group via an amide bond was identified as a promising scaffold for development of low-molecular-weight therapeutic agents to treat vascular dysfunction, including ischemia/reperfusion injury. Among the compounds synthesized, 5-(3,5-dichlorophenyl)-N-{2,4-dioxo-3-[(pyridin-3-yl)methyl]imidazolidin-1-yl}-2-furamide (17) possessed the most potent inhibitory activity against Ca²⁺-induced mitochondrial swelling. The structural development, synthesis and structure–activity relationship of these compounds are described.     

Formation of {Cu2(III)(mu-O)2}2+ core due to dioxygen reactivity of a copper(I) complex supported by a new hybrid tridentate ligand: reaction with exogenous substrates

Reaction of a Cu(I) complex of a hybrid tridentate ligand, encompassing [2-(pyridin-2-yl)ethyl]amine and dimethyl-substituted ethylalkylamine with dioxygen, generates in acetone at -80 degrees putative bis(mu-oxo)dicopper(III) intermediate. Structural characterization of a PPh(3)-adduct of a mononuclear Cu(I) complex of this new ligand has been achieved. This ligand coordinates in a facial mode utilizing three N-atoms (-CH(2)CH(2)-Py, -CH(2)CH(2)NMe(2), and -NCH(2)Ph). Reactivity of bis(mu-oxo)dicopper(III) intermediate toward exogenous substrates (2,4-di(tert-butyl)phenol and 2,4,6-tri(tert-butyl)phenol) has also been investigated.     

A comparison of the enantioselective reduction potential of five strains of Saccharomyces cerevisiae towards a selected ketone

The enantioselectivity potential of five strains of Saccharomyces cerevisiae was studied for the reduction of ethyl N-{2-{4-[(2-oxocyclohexyl)methyl]phenoxy}ethyl} carbamate (1), an insect juvenile hormone bioanalog. The products of the reaction, the cis and trans isomers of ethyl N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (2 and 3), were obtained in 45–49% (w/w) chemical yields and with 79 to > 99% enantiomeric purity values. The absolute configurations of the major products were assigned as ethyl (1S,2S)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (2) and ethyl (1S,2R)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl} carbamate (3). The products 2 and 3 belong to the series of the chiral insect juvenile hormone analogs.     

Stereoselective reduction of 2-substituted cyclohexanones by Saccharomyces cerevisiae

A comparative study of two modifications of enzymic reduction of ethyl N-{2-{4-[(2-oxo-cyclohexyl)methyl]phe- noxy}ethyl} carbamate (1), an insect juvenile hormone bioanalog, was performed using Saccharomyces cerevisiae in two bioreactors of different size, 250-ml shake-flask and 1-l fermenter. The two major products of this reduction were obtained in 45–49% (w/w) yields but with > 99% enantiomeric purity. Their absolute configurations were assigned as ethyl (1S,2S)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl}carbamate (2a) and ethyl (1R,2S)-N-{2-{4-[(2-hydroxycyclohexyl)methyl]phenoxy}ethyl}carbamate (3a).     

Synthesis and properties of guanidine-pyridine hybridligands and structural characterisation of their mono- and bis(chelated) cobalt complexes

The synthesis of four guanidine-pyridine hybridligands and their spectroscopic features in MeCN are described. In order to demonstrate their coordinating properties, the corresponding cobalt(II)chloride complexes have been prepared and completely characterised by means of X-ray structure analysis, UV/Vis spectroscopy and mass spectrometry. The neutral complexes {1,1,3,3-tetramethyl-2-(quinolin-8-yl)guanidine}cobalt(II)-dichloride [Co(TMGqu)Cl₂] and {N-(1,3-dimethylimidazolidin-2-yliden)pyridin-8-amine}cobalt(II)-dichloride [Co(DMEGpy)Cl₂] exhibit a tetrahedral coordination of the cobalt atom, whereas in bis[chlorobis{N-(1,3-dimethylimidazolidin-2-yliden)quinolin-8-amine}cobalt(II)]tetrachlorocobaltate [Co(DMEGqu)₂Cl]₂[CoCl₄] and chlorobis{1,1,3,3-tetramethyl-2-((pyridin-2-yl)methyl)guanidine}cobalt(II)chloride [Co(TMGpy)₂Cl]Cl, the cobalt atom is coordinated in a trigonal pyramidal environment. These trigonal pyramidal complex cations represent the first bis(chelated) guanidine cobalt complexes in which the pyridine donor resides on the apical position and the guanidine donor forms with the chlorine atom the base of the pyramid. Besides the structural characterisation, the quenching effect of the cobalt(II) ion (d⁷) on the ligand fluorescence has been studied.     

Novel azolyl-(phenylmethyl)]aryl/heteroarylamines: potent CYP26 inhibitors and enhancers of all-trans retinoic acid activity in neuroblastoma cells

The synthesis and potent inhibitory activity of novel 4-[(imidazol-1-yl and triazol-1-yl)(phenyl)methyl]aryl-and heteroaryl amines versus a MCF-7 CYP26A1 cell assay is described. Biaryl imidazole ([4-(imidazol-1-yl-phenyl-methyl)-phenyl]-naphthalen-2-yl-amine (8), IC(50)=0.5 microM; [4-(imidazol-1-yl-phenyl-methyl)-phenyl]-indan-5-yl-amine (9), IC(50)=1.0 microM) and heteroaryl imidazole derivatives ((1H-benzoimidazol-2-yl)-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (15), IC(50)=2.5 microM; benzooxazol-2-yl-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (16), IC(50)=0.9 microM; benzothiazol-2-yl-{4-[(5H-imidazol-1-yl)-phenyl-methyl]-phenyl}-amine (17), IC(50)=1.5 microM) were the most potent CYP26 inhibitors. Using a CYP26A1 homology model differences in activity were investigated. Incubation of SH-SY5Y human neuroblastoma cells with the imidazole aryl derivative 8, and the imidazole heteroaryl derivatives 16 and 17 potentiated the atRA-induced expression of CYP26B1. These data suggest that further structure-function studies leading to clinical development are warranted.     

Application of a lanthanide fluorescent chelate label for detection of single-nucleotide mutations with peptide nucleic acid probes

We developed the approach to detect single-nucleotide mutation with peptide nucleic acid (PNA) probes and time-resolved fluorometry using a fluorescence lanthanide chelate label, {2,2',2',2'-{4'-{[(4,6-dichloro-1,3,5-triazin-2-yl)amino]biphenyl-4-yl}-2,2': 6',2'-terpyridine-6,6'-diyl}bis(methylenenitrilo)}tetrakis(acetato)}europium(III) (DTBTA-Eu3+). Compared with DNA probes, PNA probes showed lower mismatch signals and gave higher signal/noise (S/N) ratios. Using the system, we examined the single-nucleotide mutations of codon 12 in the c-Ha-ras gene of PCR amplicons of genome DNAs isolated from human umbilical vein endothelial cells (HUVECs) and T24 cells.     

In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study

The diseases caused by dermatophytes are common among several other infections which cause serious threat to human health. It is evident that enzyme squalene epoxidase is responsible for prolonged dermatophyte infection and it is appealing to note that this enzyme is also responsible for fatty acid synthesis in these groups of fungi. In the present study, terbinafine drug which targets enzyme squalene epoxidase has been explored to design its various novel analogues. The present study suggests that many more prominent drug analogues could be constituted which may be crucial towards designing new drug candidates. In the present study, we have designed a series of such analogues viz. [(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)(naphthalen-1-ylmethyl)amine, N-[8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]-2-(sulfoamino) acetamide, {[4-(dihydroxyamino)-8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]sulfanyl}methanol and (R)-{[4-({[(2E,6R)-6,7-dimethyloct-2-en-4-yn-1-yl](methyl)amino}methyl)-5-[(hydroxysulfamoyl)amino]naphthalen-1-yl]amino}sulfinic acid. Moreover, further by molecular docking approach the binding between enzyme and designed analogues was further analysed. The present preliminary report suggested a considerably good docking interaction score of −338.75 kcal/mol between terbinafine and squalene epoxidase from Trichophyton rubrum. This preliminary study implies that few designed candidate ligands can be effectual towards the activity of this enzyme and can play crucial role in pathogenesis control of T. rubrum.     

Synthesis and structure-activity relationships of N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide derivatives as novel CCR3 antagonists

A novel class of potent CCR3 receptor antagonists were designed and synthesized starting from N-{1-[(6-fluoro-2-naphthyl)methyl]piperidin-4-yl}benzamide (1),which was found by subjecting our chemical library to high throughput screening (HTS). The CCR3 inhibitory activity of the synthesized compounds against eotaxin-induced Ca(2+) influx was evaluated using CCR3-expressing preB cells. Systematic chemical modifications of 1 revealed that the 6-fluoro-2-naphthylmethyl moiety was essential for CCR3 inhibitory activity in this new series of CCR3 antagonists. Further structural modifications of the benzamide and piperidine moieties of 1 led to the identification of exo-N-{8-[(6-fluoro-2-naphthyl)methyl]-8-azabicyclo[3.2.1]oct-3- yl}biphenyl-2-carboxamide [corrected] (31) as a potent CCR3 antagonist with an IC(50) value of 0.020 microM.     

Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group

Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays. Compound 12c also exhibited reduction of hepatic de novo fatty acid synthesis in rats after oral administration.     

The role of the oximes HI-6 and HS-6 inside human acetylcholinesterase inhibited with nerve agents: a computational study

The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.     

Vanillin-derived antiproliferative compounds influence Plk1 activity

We synthesized a series of vanillin-derived compounds and analyzed them in HeLa cells for their effects on the proliferation of cancer cells. The molecules are derivatives of the lead compound SBE13, a potent inhibitor of the inactive conformation of human polo-like kinase 1 (Plk1). Some of the new designs were able to inhibit cancer cell proliferation to a similar extent as the lead structure. Two of the compounds ((({4-[(6-chloropyridin-3-yl)methoxy]-3-methoxyphenyl}methyl)(pyridin-4-ylmethyl)amine) and (({4-[(4-chlorophenyl)methoxy]-3-methoxyphenyl}methyl)(pyridin-4-ylmethyl)amine)) were much stronger in their capacity to reduce HeLa cell proliferation and turned out to potently induce apoptosis and reduce Plk1 kinase activity in vitro.     

An efficient synthesis of a heterobifunctional coupling agent

An efficient synthesis of 4-[(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl]-N-(6-[[6-([6-[(2,5-dioxopyrrolidin-1-yl)oxy]-6-oxohexyl]amino)-6-oxohexyl]amino]-6-oxohexyl)cyclohexanecarboxamide (12), a heterobifunctional coupling agent, was developed, which is critical for chemoselective conjugation of proteins and enzymes. The synthesis involved seven steps starting from 6-{[(benzyloxy)carbonyl]amino}hexanoic acid (1), and multigram quantities of coupling agent (12) were prepared using this protocol in excellent overall yield and 99.6% purity by reversed phase HPLC. The new method is suitable for the synthesis of coupling agent 12, consistently with purity >99%, and is useful for the preparation of other analogous coupling agents.     

A remarkable anion effect on the crystal packing of two analogous copper complexes from a thiophene-containing phenol-based ligand

The new asymmetric phenol-based N,O,S-ligand Hpy2th1as was prepared by the straightforward reductive amination of 3-{[bis(pyridin-2-ylmethyl)amino]methyl}-2-hydroxybenzaldehyde with (thiophen-2-yl)methylamine. This potentially hexadentate ligand was used to coordinate to copper(II) chloride. Two dinuclear copper complexes were thus synthesised and fully characterized. Although the two coordination compounds exhibit identical complex cations, the crystal packings of both molecules significantly differ, which is most likely induced by the distinct, but geometrically related anions, namely tetrachlorocuprate(II) and perchlorate.     

Novel semicarbazones based 2,5-disubstituted-1,3,4-oxadiazoles: One more step towards establishing four binding site pharmacophoric model hypothesis for anticonvulsant activity

A series of novel N¹-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N⁴-(4-substitutedbenzaldehyde)-semicarbazone, N¹-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N⁴-[1-(4-substitutedphenyl)ethanone]-semicarbazone and N¹-{5-[(naphthalene-2-yloxy)methyl]-1,3,4-oxadiazol-2-yl}-N⁴-[1-(4-substitutedphenyl) (phenyl) methanone]-semicarbazone were designed and synthesized on the basis of semicarbazone based pharmacophoric model to meet the structural requirements necessary for anticonvulsant activity. The anticonvulsant activities of the compounds were investigated using maximal electroshock seizure (MES), subcutaneous pentylenetrtrazole (scPTZ) and subcutaneous strychnine (scSTY) models. Some of the selected active compounds were subjected to GABA assay to confirm their mode of action. The efforts were also made to establish structure activity relationships among synthesized compounds. The results of the present studying validated that the pharmacophoric model with four binding sites is essential for anticonvulsant activity.     

Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation

Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl-glutamate-pyridine as a P2Y₁₂ antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation as measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized leading to compound (4S)-4-[({4-[4-(methoxymethyl)piperidin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 22J with good human PRP potency, selectivity, in vivo efficacy and oral bioavailability.     

Modelling the sulfoxygenation activity of vanadate-dependent peroxidases

Vanadate-dependent peroxidases contain, in their active center, vanadate covalently attached to histidine in an overall trigonal-bipyramidal array. We describe here the synthesis and characterization of optically active amino alcohols and their vanadium(V) complexes, and we show that the structural models of the active center thus obtained are also functional models for the sulfide-peroxidase activity of the enzyme in heterogeneous catalysis. The heterogeneous systems were obtained by immobilizing the complexes on silica gel and mesoporous silicas, and by aggregation. The following ligands, ligand precursors, and V compounds have been structurally characterized: (R)-(2-phenylethanol)-(R)-1-phenylethylamine (HL(A)), (R,R)-bis[2-phenyl(ethylmethylether)]ammonium chloride ([L(D)]+Cl(-)), the carbasilatranes (R,R)-methoxy{N,N',N'-2,2',3-[bis(1-phenylethanolato)propyl]amino}silane ((R,R)-Si(OMe)L(E)), (R,R)-methoxy-{N,N',N'-1,2',3-[(1-phenylethanolato)-(2-phenylethanolato)propyl]amino}silane ((R,R)-Si(OMe)L(E')), and [VO(L(F))(OSiMe2(t)Bu)], where H2L(F)=ethylbis(2-hydroxy-2-phenylethyl)amine.     

Synthesis and reactions of O-acetylated benzyl alpha-glycosides of 6-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-N-acetylmuramoyl-L- alanyl-D-isoglutamine esters: the base-catalysed isoglutamine in equilibrium glutamine rearrangement in peptidoglycan-related structures

Condensation of benzyl 2-acetamido-6-O-(2-acetamido-3,4,6-tri-O-acetyl-2- deoxy-3-O-[(R)-1-carboxyethyl]-alpha-D-glucopyranoside (2) and its 4-acetate (4) with L-alanyl-D-isoglutamine benzyl ester via the mixed anhydride method yielded N-(2-O-[benzyl 2-acetamido-6-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D- glucopyranosyl)-2,3-dideoxy-alpha-D-glucopyranosid-3-yl]-(R)-lacto yl)-L- alanyl-D-isoglutamine benzyl ester (5) and its 4-acetate (6), respectively. Condensation by the dicyclohexylcarbodi-imide-N-hydroxysuccinimide method converted 2 into benzyl 2-acetamido-6-O-(2-acetamido-3,4,6-tri-O-acetyl- 2-deoxy-beta-D-glucopyranosyl)-3-O-[(R)-1-carboxyethyl]-2-deoxy-alpha-D- glucopyranoside 1',4-lactone (7). In the presence of activating agents, 7 underwent aminolysis with the dipeptide ester to give 5. Zemplén O-deacetylation of 5 and 6 led to transesterification and alpha----gamma transamidation of the isoglutaminyl residue to give N-(2-O-[benzyl 2-acetamido-6-O-(2- acetamido-2-deoxy-beta-D-glucopyranosyl)-2,3-dideoxy-alpha-D-glucopyr anosid-3- yl]-(R)-lactoyl)-L-alanyl-D-isoglutamine methyl ester (8) and -glutamine methyl ester (9). Treatment of 6 with MgO-methanol caused deacetylation at the GlcNAc residue to give a mixture of N-(2-O-[benzyl 2-acetamido-6-O-(2-acetamido-2- deoxy-beta-D-glucopyranosyl)-4-O-acetyl-2,3-dideoxy-alpha-D-glucopyra nosid-3- yl]-(R)-lactoyl)-L-alanyl-D-isoglutamine methyl ester (11) and -glutamine methyl ester (12). Benzyl or methyl ester-protection of peptidoglycan-related structures is not compatible with any of the reactions requiring alkaline media. Condensation of 2 with L-alanyl-D-isoglutamine tert-butyl ester gave N-(2-O-[benzyl 2-acetamido- 6-O-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranosyl)-2,3-d ideoxy- alpha-D-glucopyranosid-3-yl]-(R)-lactoyl-L-alanyl-D-isoglutamine tert-butyl ester (16), deacetylation of which, under Zemplén conditions, proceeded without side-reactions to afford N-(2-O-[benzyl 2-acetamido-6-O-(2-acetamido-2-deoxy-beta-D- glucopyranosyl)-2,3-dideoxy-alpha-D-glucopyranosid-3-yl]-(R)-la cotyl)-L- alanyl-D-isoglutamine tert-butyl ester (17).     

Microwave-assisted synthesis of 4'-azaflavones and their N-alkyl derivatives with biological activities

4'-Azaflavone (=2-(pyridin-4-yl)-4H-1-benzopyran-4-one; 4) and 3-[(pyridin-4-yl)methyl]-4'-azaflavone (5) were synthesized by a simple environmentally friendly microwave-assisted one-pot method through the cyclization of 3-hydroxy-1-(2-hydroxyphenyl)-3-(pyridin-4-yl)propan-1-one (1), (E)-2'-hydroxy-4-azachalcone (2; chalcone=1,3-diphenylprop-2-en-1-one), and 2'-hydroxy-2-[(hydroxy)(pyridin-4-yl)methyl]-4'-azachalcone (3) under solventless conditions using silica-supported NaHSO(4), followed by treatment with base. In addition, N-alkyl-substituted 4'-azaflavonium bromides 6 and 7 were prepared from compounds 4 and 5, respectively. The antimicrobial and antioxidant activities of compounds 1-7 were tested. The N-alkyl-substituted 4'-azaflavonium bromides 6 and 7 showed high antimicrobial activity against the Gram-positive bacteria and the fungus tested, with MIC values close to those of reference antimicrobials ampicilline and fluconazole. The alkylated compounds 6 and 7 also showed a good antioxidant character in the two antioxidant methods, DPPH (=1,1-diphenyl-2-picrylhydrazyl) radical-scavenging and ferric reducing/antioxidant power (FRAP) tests.