Assessing site-isolation of amine groups on aminopropyl-functionalized SBA-15 silica materials via spectroscopic and reactivity probes

The average degree of separation and the accessibility of aminopropyl groups on SBA-15 silica materials prepared using different silane grafting approaches are compared. Three specific synthetic approaches are used: (1) the traditional grafting of 3-aminopropyltrimethoxysilane in toluene, (2) a protection/deprotection method using benzyl- or trityl-spacer groups, and (3) a cooperative dilution method where 3-aminopropyltrimethoxysilane and methyltrimethoxysilane are co-condensed on the silica surface as a silane mixture. The site-isolation and accessibility of the amine groups are probed via three methods: (a) evaluation of pyrene groups adsorbed onto the solids using fluorescence spectroscopy, (b) the reactions of chlorodimethyl(2,3,4,5-tetramethyl-2,4-cyclopentadien-1-yl)silane (Cp′Si(Me)₂Cl) and chloro(cyclopenta-2,4-dienyl)dimethylsilane (CpSi(Me)₂Cl) with the tethered amine sites, and (c) comparison of the reactivity of zirconium constrained-geometry-inspired catalysts (CGCs) prepared using the Cp′Si(Me)₂-modified aminosilicas in the catalytic polymerization of ethylene to produce poly(ethylene). The spectroscopic probe of site-isolation suggests that both the protection/deprotection method and the cooperative dilution method yield similarly isolated amine sites that are markedly more isolated than sites on traditional aminosilica. In contrast, both reactivity probes show that the protection/deprotection strategy leads to more uniformly accessible amine groups. It is proposed that the reactivity probes are more sensitive tests for accessibility and site-isolation in this case.     

N-(2-alkylaminoethyl)-4-(1,2,4-oxadiazol-5-yl)piperazine-1-carboxamides as highly potent smoothened antagonists

Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.     

4-[6-(2-Aminoethyl)naphthalen-2-yl]benzonitriles are potent histamine H3 receptor antagonists with high CNS penetration

4-[6-(2-Tertiaryaminoethyl)naphthalen-2-yl]benzonitriles are conformationally constrained histamine H3 receptor antagonists with high potency and selectivity. The analogs were designed around a naphthalene core, with the goal of enhancing lipophilicity and CNS penetration, as compared to a previously reported benzofuran series. The SAR of the tertiary amine moiety is similar to that reported for the benzofuran series, with analogs bearing a 2-methylpyrrolidine substituent possessing the greatest rat and human H3 receptor binding affinities.     

Synthesis and antimetabolite properties of 5-substituted 2'-deoxyuridines. Anomeric 5-(2-aminohexafluoroprop-2-yl)- and 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)-2'-deoxyuridine

Alkylation of 2,4-bis-O-(trimethylsilyl)uracil with hexafluoroacetone trifluoroacetylimine gave 5-(2-trifluoroacelylaminohexafluoroprop-2-yl)uracil, which was transformed by alkaline hydrolysis to 5-(2-aminohexafluoroprop-2-yl)uracil. The latter was glycosytated with 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-ribofyranosyl chloride by means of various modifications of the silyl method leading to the predominant formation of beta-deoxynucleoside; after deacylation 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil was obtained. Interaction of silylated 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)uracil with acylgalogenose gave anomeric O-substitutet deoxynucleosides, which were deblocked to give 5-(2-trifluoroacetylaminohexafluoroprop-2-yl)-2'-deoxyuridine and corresponding alpha-anomer. Alkaline hydrolysis of N-trifluoroacetyl group in both individual anomers produced 1-(2-deoxy-alpha-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ur acil and the abovementioned beta-anomer. Of all compounds synthesised only 1-(2-deoxy-beta-D-ribofuranosyl)-5-(2-aminohexafluoroprop-2-yl)ura cil has a moderate inhibitory effect on replication of vaccinia virus in vitro.     

The thulium complex of 1,4,7,10-tetrakis{[N-(1H-imidazol-2-yl)carbamoyl]methyl}-1,4,7,10-tetraazacyclododecane (dotami) as a ParaCEST contrast agent

1,4,7,10-Tetrakis{[N-(1H-imidazol-2-yl)carbamoyl]methyl}-1,4,7,10-tetraazacyclododecane (dotami), a tetra(1H-imidazol-2-yl) derivative of the well-studied octadentate 1,4,7,10-tetrakis[(carbamoyl)methyl]-1,4,7,10-tetraazacyclododecane (dotam) ligand, was synthesized by reaction of 1,4,7,10-tetraazacyclododecane with N-(1H-imidazol-2-yl)chloroacetamide in high yield. Its tricationic thulium complex was isolated as a water-soluble chloride salt. The detection of the mildly acidic amide and amine protons by direct proton NMR in aqueous solution was unsuccessful, but such exchangeable protons could be detected via their chemical exchange-dependent saturation transfer (CEST) effect. The observed CEST effect was distinctly different from that found for respective dotam complexes and is, therefore, ascribed to exchangeable protons associated with the imidazole substituent.     

Discovery and initial SAR of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-ones as inhibitors of insulin-like growth factor 1-receptor (IGF-1R)

The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.     

Mononuclear and unsymmetric dinuclear complexes of the tripodal ligand 2-hydroxyethyl-bis(2-{pyrid-2-yl}ethyl)amine

Reaction of bis(2-{pyrid-2-yl}ethyl)amine with 2-bromoethanol in the presence of Na₂CO₃ yields the title ligand, LH. Treatment of LH with the CuBr₂ or Zn(O₂CMe)₂ · 2H₂O yields pure crystalline [CuBr(LH)]Br · H₂O (1 · H₂O) and [Zn₂(O₂CMe)₂(μ-O₂CMe)(μ-L)] (2). Reaction of LH with Cu(O₂CMe)₂ · H₂O affords a low yield of [Cu₂Cl₂(μ-O₂CMe)(μ-L)] (3), the Cl⁻ ligands apparently originating from the CH₂Cl₂ crystallization solvent. Compound 1 · H₂O is a near-regular square-pyramidal complex with a neutral, protonated LH ligand. In contrast, 2 and 3 are both unusual unsymmetric dinuclear complexes, with a five-coordinate [ML(O₂CMe)] (M = Zn or Cu) unit linked to a second metal ion through the deprotonated ligand alkoxide donor and O,O′-bridging acetate ligand.     

Synthesis and bioactivity of novel methyl 6-deoxy-6-(N'-alkyl/aryl-N'-benzothiazol-2-yl)guanidino-alpha-D-glucopyranosides

A series of new methyl 6-deoxy-6-[N′-alkyl/aryl-N″-(benzothiazol-2-yl)]guanidino-α-d-glucopyranosides were obtained from the reaction of an alkyl/aryl amine in the presence of HgCl₂ and sugar-thiourea derivatives, followed by the removal of protecting groups. The sugar-thiourea derivatives were obtained from the treatment of 2-aminobenzothiazole derivatives with methyl 2,3,4-tri-O-acetyl-6-deoxy-6-isothiocyanato-α-d-glucopyranoside in dry pyridine. Some of the synthesized guanidines displayed anti-influenza activity.     

The discovery of [1-(4-dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethylbutyl)-phen yl]-(3-methyl-but-2-enyl)-amine, an N-type Ca+2 channel blocker with oral activity for analgesia

Our drug discovery efforts for N-type calcium channel blockers in the 4-piperidinylaniline series led to the discovery of an orally active analgesic agent 26.1-[4-Dimethylamino-benzyl)-piperidin-4-yl]-[4-(3,3-dimethyl-but yl)-phenyl]-(3-methyl-but-2-enyl)amine (26) showed high affinity to functionally block N-type calcium channels (IC50=0.7 microM in the IMR32 assay) and exhibited high efficacy in the anti-writhing analgesia test with mice (ED50=12 mg/kg by po and 4 mg/kg by iv). In this report, the rationale for the design, synthesis, biological evaluation, and pharmacokinetics of this series of blockers is described.     

Optimization of diaryl amine derivatives as kinesin spindle protein inhibitors

Structure–activity relationship studies of diaryl amine-type KSP inhibitors were carried out. Diaryl amine derivatives with a pyridine ring or urea group were less active when compared with the parent carboline and carbazole derivatives. Optimization studies of a lactam-fused diphenylamine-type KSP inhibitor revealed that the aniline NH group and 3-CF₃ phenyl group were indispensable for potent KSP inhibition. Modification with a seven-membered lactam-fused phenyl group and a 4-(trifluoromethyl)pyridin-2-yl group improved aqueous solubility while maintaining potent KSP inhibitory activity. From these studies, we identified novel diaryl amine-type KSP inhibitors with a favorable balance of potency and solubility.     

Synthesis of bis-(methyl 3,4,6-tri-O-acetyl-D-glucopyranosid-2-yl)-oxamides

The synthesis of a new bis-(D-glucopyranosid-2-yl)oxamides via the key intermediate, N-acetyl N-(methyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranosid-2-yl) oxamic acid chloride (2alpha) is described. Treatment of compound 2alpha with methyl 3,4,6-tri-O-acetyl-2-amino-2-deoxy-beta-D-glucopyranoside afforded N-(methyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranosid-2-yl)-N'-(methyl 3,4,6-tri-O-acetyl-beta-D-glucopyranosid-2-yl)-oxamide. Reaction of 2alpha with 1,2-diaminoethane afforded 1,2-bis-[N,N'-(methyl 3',4',6'-tri-O-acetyl-alpha-D-glucopyranosid-2'-yl)]ethyloxamide as a main product, while 2-N-[N'-(methyl 3',4',6'-tri-O-acetyl-alpha-D-glucopyranosid-2'-yl)oxamide]-ethyl acetamide was formed as a side product. Reaction of 2alpha with 1,3-diamino-2-hydroxypropane gave only 1,3-bis-N,N-[N'-(methyl 3',4',6'-tri-O-acetyl-2'-deoxy-alpha-D-glucopyranosid-2'-yl)-oxamido]-2-propanol.     

Synthesis of 2-deoxy-2-(4-nitroimidazol-1-yl)-D-alditols

Small molecules possessing defined configuration at centres of chirality provide a valuable chiral pool. Among different strategies applied for modification of chiral compounds, the most common is to begin with a single stereoisomer and use a synthesis that does not affect the chiral centres. The ANRORC type reaction has been applied for conversion of unprotected 2-amino-2-deoxy-D-hexopyranoses into 2-deoxy-2-(4-nitroimidazol-1-yl)-D-hexopyranoses in a reaction of some 2-aminosugars with 1,4-dinitroimidazoles. The reaction occurs with retention of configuration at C-2 of sugar ring. The products of the reaction were obtained as anomeric mixtures and separated into anomers after acetylation followed by column chromatography. 2-Deoxy-2-(4-nitroimidazol-1-yl)-D-hexopyranoses treated with sodium borohydride in methanolic solution gave the corresponding 2-deoxy-2-(4-nitroimidazol-1-yl)-D-hexitols, characterised as per-O-acetylated derivatives.     

Synthesis, pharmacological evaluation and docking studies of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs as COX-2 inhibitors

The existing NSAIDs having number of toxicities emphasises the need for discovery of new non-toxic anti-inflammatory agents. In this Letter, we present the simple two step chemical synthesis, in vivo pharmacological screening and docking study of few N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs. Different amino benzothiazoles were chloroacetylated and further reacted with substituted piperazines in presence of a base to get N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs (A1-C4). These compounds were evaluated for anti-inflammatory activity by carragenan induced paw oedema method. Promising compounds were screened for toxicity by evaluating the ulcerogenic potential. Molecular docking experiments were carried out against COX-2 enzyme using Surflex-Dock GeomX programme of Sybyl software on Dell T-1500 workstation to confirm the mechanism of action of active compounds among the series. In silico study reveal the binding interactions of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs with COX-2 protein and is in agreement with the in vivo anti-inflammatory activity.     

Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR,synthesis and modeling evaluation

The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analogs containing the new scaffolds. In addition, the structure–activity relationship (SAR) of the 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives and their biological activities were reported. The complex structure of compound 18 with PHD2 was also obtained for the purpose of more efficient lead optimization.     

Synthesis of imidazol-2-yl amino acids by using cells from alkane-oxidizing bacteria

Sixty-one strains of alkane-oxidizing bacteria were tested for their ability to oxidize N-(2-hexylamino-4-phenylimidazol-1-yl)-acetamide to imidazol-2-yl amino acids applicable for pharmaceutical purposes. After growth with n-alkane, 15 strains formed different imidazol-2-yl amino acids identified by chemical structure analysis (mass and nuclear magnetic resonance spectrometry). High yields of imidazol-2-yl amino acids were produced by the strains Gordonia rubropertincta SBUG 105, Gordonia terrae SBUG 253, Nocardia asteroides SBUG 175, Rhodococcus erythropolis SBUG 251, and Rhodococcus erythropolis SBUG 254. Biotransformation occurred via oxidation of the alkyl side chain and produced 1-acetylamino-4-phenylimidazol-2-yl-6-aminohexanoic acid and the butanoic acid derivative. In addition, the acetylamino group of these products and of the substrate was transformed to an amino group. The product pattern as well as the transformation pathway of N-(2-hexylamino-4-phenylimidazol-1-yl)-acetamide differed in the various strains used.     

3-[2-Amino-2-imidazolin-4-yl] alanine, 2-[2-amino-2-imidazolin-4-yl] acetic acid, 2-aminoimidazole and other guanidine derivatives in the tephrosieae

The distribution of enduracididine, 2-[2-amino-2-imidazolin-4-yl] acetic acid, 2-aminoimidazole, canavanine, homoarginine, γ-hydroxyhomoarginine and other unidentified guanidino compounds in seeds of spp. of the Tephrosieae is described. Within Lonchocarpus enduracididine and 2-[2-amino-2-imidazolin-4-yl] acetic acid were found only in American spp. and canavanine only in African spp.     

4,5-bis(ethoxycarbonyl)-[1,3]dioxolan-2-yl as a new orthoester-type protecting group for the 2'-hydroxyl function in the chemical synthesis of RNA

We wish to report 4,5-bis(ethoxycarbonyl)-[1,3]dioxolan-2-yl as a new protecting for the 2'-hydroxyl function. Our cyclic orthoester-type group is compatible with the DMTr strategy for oligonucleotide synthesis. This group was introduced to the 2'-hydroxyl group of appropriately protected nucleoside derivatives in good yields under mild acidic conditions. Post-synthetic conversion of the moiety of this protecting group with an amine resulted in formation of a new amide moiety that is more stable to acid deprotection in aqueous solution, but it can still be easily removed by treatment with acids in organic solvents. In this article, we also describe the stability of not only the original and modified protecting groups but also internucleotidic phosphate linkages of protected RNA intermediates under deprotection conditions.     

Furanyl-1,3-thiazol-2-yl and benzoxazol-5-yl acetic acid derivatives: novel classes of heparanase inhibitor

Using a furanylthiazole acetic acid as a starting point, a novel series of benzoxazol-5-yl acetic acid derivatives have been identified as heparanase inhibitors. Several compounds possess an IC50 of approximately 200 nM against heparanase, for example, trans 2-[4-[3-(3,4-dichlorophenylamino)-3-oxo-1-propenyl]-2-fluorophenyl]benzoxazol-5-yl acetic acid (16e). Several of the compounds show anti-angiogenic properties. Improvement to the DMPK profile of compounds has provided compounds of potential use in in vivo models.     

Synthesis and antibacterial activity of N-[2-(5-bromothiophen-2-yl)-2-oxoethyl] and N-[(2-5-bromothiophen-2-yl)-2-oximinoethyl] derivatives of piperazinyl quinolones

A series of N-[2-(5-bromothiophen-2-yl)-2-oxoethyl] and N-[2-(5-bromothiophen-2-yl)-2-oximinoethyl]derivatives of piperazinyl quinolones were synthesized and evaluated for antimicrobial activity against Gram-positive and Gram-negative microorganisms. Some of these derivatives exhibit comparable or better activity against Gram-positive bacteria, Staphylococcus aureus, Staphylococcus epidermidis and Bacillus subtilis, than ciprofloxacin, norfloxacin and enoxacine as reference drugs.