Triamide Derivatives Research Articles

Discovery of benzothiazole derivatives as efficacious and enterocyte-specific MTP inhibitors

A series of triamide derivatives bearing a benzothiazole core is shown to be potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize liver toxicity, these compounds have been optimized to have activity only in the enterocytes and have limited systemic bioavailability. Upon oral administration, selected analogs within this series have been further demonstrated to reduce food intake along with body weight and thereby improve glucose homeostasis and insulin sensitivity in a 28-day mice diet-induced obesity (DIO) model.

Structural diversity in phosphoramidate’s chemistry: Syntheses, spectroscopic and X-ray crystallography studies

Novel phosphorus compounds of bisphosphoramidate, phosphoramidate and phosphoric triamide derivatives were synthesized using the starting materials PCl 5 and POCl 3. The products were then characterized by 1H, 13C, 31P, 19F NMR, IR spectroscopy and CHN elemental analysis. It is noticeable that the reaction of 4-aminobenzamide with PCl 5 in different molar ratios yields different products, bisphosphoramides and phosphoric triamides. Moreover, we were taken by surprise that the interaction of POCl 3 with the first-type aromatic amines gave bisphosphoramidates with P–N–P linkages that exhibited 2 J(P,P) ≈ 20.0 Hz in the 31P NMR spectra. In fact, two simple one-pot pathways are presented here for the synthesis of new bisphosphoramidates, and to the best of our knowledge these are the first instances of bisphosphoramidates that have been obtained up until now. The structures of compounds I (4-OCH 3–C 6H 4–CH 2–C 9H 13–NH 2Cl), 34 and 44 were further determined by X-ray crystallography. All of these structures produced three dimensional polymeric chains through strong- and weak hydrogen bonds. The presence of chiral aminoacidester moieties in the phosphoric triamides lead to chiral molecules that showed two sets of signals for the two groups. Interestingly, in phosphoric triamides containing cyanoacetamide moieties, the existence of aromatic amine substituents on the P atoms created central chiral phosphorus atoms, i.e. the two aromatic groups revealed two sets of peaks in the 1H and 13C NMR spectra, while compounds with aliphatic moieties did not display this effect.

Spermidine and Flavonoid Conjugates from Peanut (Arachis hypogaea) Flowers

A new spermidine triamide derivative has been isolated from peanut flowers and identified as N (1)-acetyl- N (5), N (10)-di- p-( EE)-coumaroylspermidine on the basis of detailed analysis of NMR, MS, and UV data. Two other spermidine conjugates, N (1), N (5), N (10)-tri- p-( EEE)-coumaroylspermidine and di- p-( EE)-coumaroylspermidine, as well as four flavonoid conjugates (quercetin-3-glucoside, quercetin-3-glucuronide, isorhamnetin-3-glucoside, and isorhamnetin-3-glucuronide) that have been previously reported in organs of other plants, have been found in this study in peanut ( Arachis hypogaea L.), a representative of the Leguminosae family, for the first time. The dynamics of photoisomerization in the spermidine conjugates have been investigated.

Synthesis and amino acid extraction abilities of chiral calix[4]arene triamides containing amino alcohol units

Herein the synthesis and extraction abilities of new d-/l-phenylalaninol substituted p-tert-butylcalix[4]arene triamide derivatives (3 and 4) towards amino acids are reported. These compounds (3 and 4) have been easily synthesized via aminolysis of p-tert-butylcalix[4]arene trimethylester (2) with d-/l-phenylalaninol in methanol-toluen solvent system at one step. The extraction properties of the prepared chiral calix[4]arene triamide derivatives (3 and 4) towards some selected amino acid methylesters are studied by liquid–liquid extraction. Results show that these chiral calix[4]arene triamide derivatives (3 and 4) exhibited a good affinity towards all amino acid species without any remarkably discrimination.

Alkyl Ammonium Ion Selectivity of Hexahomotrioxacalix[3]arene Triamide Derivative having the Intramolecular Hydrogen-Bonding Group

The lower rim functionalized hexahomotrioxacalix[3]arene triamide 4 with cone-conformation was synthesized from triol 1 by a stepwise reaction. The different extractability for alkali metal ions, transition metal ions, and alkyl ammonium ions from water into dichloromethane is discussed. Due to the strong intramolecular hydrogen bonding between the neighboring NH and CO groups in triamide 4, its affinity to metal cations was weakened. Triamide 4 shows a single selectivity to n-BuNH 3 + . The anion complexation of triamide 4 was also studied by 1H NMR titration experiments. Triamide 4 binds halides through the intermolecular hydrogen bonding among the NH hydrogens of amide in a 1:1 fashion in CDCl3. The association constants calculated from these changes in chemical shifts of the amide protons are K a = 223 M−1 for Cl− and K a = 71.7 M−1 for Br−. Triamide 4 shows a preference for Cl− complexation than Br− complexation.

A nitrate-selective electrode based on a tris(2-aminoethyl)amine triamide derivative receptor

A tris(2-aminoethyl)amino triamide derivative anion receptor has been tested as electroactive material for the development of anion-selective electrodes. The receptor was incorporated in plasticized poly(vinyl chloride) membranes of different compositions. The membrane that provided the best response and selectivity towards nitrate was selected to develop a new nitrate-selective electrode. The electrode exhibited a Nernstian response over the nitrate concentration range of 1 × 10 −5 to 1 × 10 −1 mol l −1 with a slope of −54.7 mV/decade of concentration, a detection limit of 2.3 × 10 −6 mol l −1 nitrate, a wide working pH range (2–12) and a fast response time. It showed good selectivity for nitrate relative to many common anions and better selectivity relative to thiocyanate, perchlorate and nitrite than previous nitrate-selective electrodes. Quantum chemical calculations made to study the interaction between the receptor and the different anions assayed are used to explain these improvements. The proposed electrode was applied to the determination of nitrate in drinking waters.

Solution-phase combinatorial synthesis of nonpeptide bradykinin antagonists

We describe the solution-phase combinatorial synthesis and pharmacological effect of fifty N, N ′-substituted- N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide derivatives as nonpeptide B2 antagonists. The synthesized compounds were tested for their antibradykinin activity by utilizing guinea-pig ileum smooth muscle. Most of the compounds showed antagonistic effects on bradykinin induced contraction. N-acetyl- N ′-(4-methylbenzyl)- N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide ( A3B1C1) showed the 46% inhibition at 100 nM.

Solution-phase combinatorial synthesis of nonpeptide bradykinin antagonists

We describe the solution-phase combinatorial synthesis and pharmacological effect of fifty N,N′-substituted-N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide derivatives as nonpeptide B2 antagonists. The synthesized compounds were tested for their antibradykinin activity by utilizing guinea-pig ileum smooth muscle. Most of the compounds showed antagonistic effects on bradykinin induced contraction. N-acetyl-N′-(4-methylbenzyl)-N″-1-(4-chlorobenzhydryl)piperazine iminodiacetic acid triamide (A3B1C1) showed the 46% inhibition at 100 nM.

Synthesis of 3‐Aminopyrrolidines by Cyclization of Neutral C‐Centered α‐Aminoalkyl Radicals.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and biological characteristics of the Technetium‐99m triamide derivatives of mercaptoacetyltriglycine (MAG3)

AbstractA number of MAG3‐derivatives, containing the three‐amide functions modified by inverting the sequence –CO–NH– to –NH–CO– in the first‐ and/or second‐amide functions, have been labelled with 99mTc in order to study the renal characteristics of the resulting MAG3‐derivatives versus the reference 99mTc‐MAG3. The 99mTc‐MAG3‐derivatives displayed HPLC‐profiles similar to that of 99mTc‐MAG3. Furthermore, in mice they exhibited biological behaviour comparable or even superior to 99mTc‐MAG3, which indicates that the sequence of the first‐ and/or second‐amide bond in 99mTc‐MAG3 affects the biological behaviour only to a limited degree. However, in baboon the plasma clearance of the 99mTc‐MAG3‐derivatives was relatively slower than 99mTc‐MAG3, which underlines the inter‐species variability. Copyright © 2002 John Wiley & Sons, Ltd.

Synthesis of 3-aminopyrrolidines by cyclization of neutral C-centered α-aminoalkyl radicals

3-Aminopyrrolidines are prepared by SmI 2-promoted cyclization of neutral α-aminoalkyl radicals generated from N-(α-benzotriazolyl)alkenylamines. Appropriate manipulation of the two N-protecting groups allows further manipulation of the products, which is exemplified with the preparation of a triamide derivative.

Synthesis, Conformations and Inclusion Properties of Hexahomotrioxacalix[3]arene Triamide Derivatives having Hydrogen-bonding Groups

The lower rim functionalizedhexahomotrioxacalix[3]arene triamide derivatives4a and 4b were synthesized from triol 1by a stepwise reaction. Extraction data for alkalimetal ions, transition metal ions, and alkyl ammoniumions from water into dichloromethane are discussed.Due to the strong intramolecular hydrogen bondingbetween the neighboring NH and CO groups, theiraffinities to metal cations were weakened.cone-4a shows a single selectivity ton-BuNH3 plus while partial-cone-4aalmost has no affinity to cations. The anioncomplexation of cone-4a was studied by1H NMR titration experiments. cone-4abinds halides through the intermolecular hydrogenbonding among the NH hydrogens of amide in a 1 : 1fashion in CDCl3. The association constantscalculated from these changes in chemical shifts ofthe amide protons are Ka = 8520 M-1for Cl-1 and Ka = 1720 M-1 forBr-1. cone-4a shows a preference forCl-1 complexation over Br- complexation. Incontrast, cone-4b has good selectivity andaffinity to Agplus cation. A good Job plot proves1:1 coordination of cone-4b withAgplus cation. The complexation mode of cone-4a with n-BuNH3Cl and cone-4b with AgSO3CF3 were also demonstrated by 1H NMR titration in CDCl3.

Syntheses and ion selectivities of tri-amide derivatives of hexahomotrioxacalix[3]arene. Remarkably large metal template effect on the ratio of cone vs. Partial-cone conformers

We have found that a homotrioxacalix[3]arene (1H 3) -based ionophore with a cone conformation, which is very difficult to obtain by the reaction of 1H 3 and ethyl bromoacetate, can be synthesized quantitatively by the reaction of 1H 3 and N, N-diethylchloroacetamide in THF in the presence of NaH. The conformer distribution of the tri-amide derivative (1Am 3) between cone and partial-cone was sensitively affected in 0 ∼ 100% range by the metal template effects. Cone-1Am 3 showed the very high affinity for alkali and alkaline earth metal cations. Particularly, it formed stable complexes with alkaline earth metal cations which were scarcely bound to the tri-ester derivative. The results show that cone-1Am 3 acts as an excellent neutral ionophore owing to the three coordinative amide groups arranged in C 3-symmetry.

In the search for new anticancer drugs xi. anticancer activity of nitroxyl labeled phosphoric N,N;N′,N′;N″,N″-TRIS[1,2-ethanediyl]triamide(TEPA) and phosphorothioic N,N;N′,N′;N″,N″-TRIS[L,2-ethanediyl]triamide(THIO-TEPA) derivatives

In order to further evaluate the effect of the nitroxyl moiety on the anticancer activity of nitroxyl labeled analogues of phosphoric N,N;N',N';N",N"-tris[1,2-ethanediyl]triamide (TEPA) and phosphorothioic N,N;N',N';N",N"-tris[1,2-ethanediyl]triamide (thio-TEPA), the activity of these compounds was compared in vivo, using murine lymphoid leukemia L1210, with the reduced forms of the drugs, i.e. the hydroxylamines and amine congeners. At optimum dose, all compounds were active. However, the nitroxyl containing compounds were more active than the corresponding reduced forms. An admixture of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl had no effect on the activity of thio-TEPA. Consequently, the nitroxyl moiety must be an integral part of the anticancer drug's structure in order to influence that drug's performance.

In the search for new anticancer drugs. 9. Synthesis and anticancer activity of spin-labeled analogues of N,N:N',N':N",N"-Tri-1,2-ethanediylphosphoric triamide and N,N:N',N':N",N"-tri-1,2-ethanediylphosphorothioic triamide.

A number of N,N:N',N':N",N"-tri-1,2- ethanediylphosphoric triamide (TEPA) and N,N:N',N':N",N"-tri-1,2- ethanediylphosphorothioic triamide (thio-TEPA) derivatives containing either two aziridine moieties (1a) or two (2-chloroethyl)amino functions (1b) and either a 2,2,6,6-tetramethylpiperidine, 1-oxy-2,2,6,6-tetramethylpiperidine or 1-hydroxy-2,2,6,6-tetramethylpiperidine component were synthesized and tested against lymphocytic leukemia P388 in mice. In a structure-activity comparison it was found that at optimum dose all compounds containing the nitroxyl radical were more active than the corresponding hydroxylamine derivatives. The open-chain compounds (1b) were less active than the corresponding aziridine ring compounds (1a). The replacement of the X = bridge in 1a with the X = N(CH3) group resulted in lowering of the anticancer activity.