Carboxamide Substituents Research Articles

Singlet Oxygen Photooxidation of Peptidic Oxazoles and Thiazoles.

Oxazoles and thiazoles are commonly found moieties in nonribosomal peptides (NRPs) and ribosomally synthesized post-translationally modified peptides (RiPPs), which are important biomolecules present in the environment and in natural waters. From previous studies, they seem susceptible to oxidation by singlet oxygen (1O2); therefore, we designed and synthesized model oxazole- and thiazole-peptides and measured their 1O2 bimolecular reaction rate constants, showing slow photooxidation under environmental conditions. We reasoned their stability through the electron-withdrawing effect of the carboxamide substituent. Reaction products were elucidated and support a reaction mechanism involving cycloaddition followed by a series of rearrangements. The first 1O2 bimolecular reaction rate constant for a RiPP, the thiazole-containing peptide Aerucyclamide A, was measured and found in good agreement with the model peptide's rate constant, highlighting the potential of using model peptides to study the transformations of other environmentally relevant NRPs and RiPPs.

Novel 5-oxo-hexahydroquinoline derivatives: design, synthesis, in vitro P-glycoprotein-mediated multidrug resistance reversal profile and molecular dynamics simulation study.

Overexpression of the efflux pump P-glycoprotein (P-gp) is one of the important mechanisms of multidrug resistance (MDR) in many tumor cells. In this study, 26 novel 5-oxo-hexahydroquinoline derivatives containing different nitrophenyl moieties at C4 and various carboxamide substituents at C3 were designed, synthesized and evaluated for their ability to inhibit P-gp by measuring the amount of rhodamine 123 (Rh123) accumulation in uterine sarcoma cells that overexpress P-gp (MES-SA/Dx5) using flow cytometry. The effect of compounds with highest MDR reversal activities was further evaluated by measuring the alterations of MES-SA/Dx5 cells’ sensitivity to doxorubicin (DXR) using MTT assay. The results of both biological assays indicated that compounds bearing 2-nitrophenyl at C4 position and compounds with 4-chlorophenyl carboxamide at C3 demonstrated the highest activities in resistant cells, while they were devoid of any effect in parental nonresistant MES-SA cells. One of the active derivatives, 5c, significantly increased intracellular Rh123 at 100 µM, and it also significantly reduced the IC50 of DXR by 70.1% and 88.7% at 10 and 25 µM, respectively, in MES-SA/Dx5 cells. The toxicity of synthesized compounds against HEK293 as a noncancer cell line was also investigated. All tested derivatives except for 2c compound showed no cytotoxicity. A molecular dynamics simulation study was also performed to investigate the possible binding site of 5c in complex with human P-gp, which showed that this compound formed 11 average H-bonds with Ser909, Thr911, Arg547, Arg543 and Ser474 residues of P-gp. A good agreement was found between the results of the computational and experimental studies. The findings of this study show that some 5-oxo-hexahydroquinoline derivatives could serve as promising candidates for the discovery of new agents for P-gp-mediated MDR reversal.

Solvation State of Nicotinamide in Binary Solvents by 13C NMR Probing at Different Temperatures

Solvation state of pyridine-3-carboxamide (nicotinamide) was studied by means of different temperature nuclear magnetic resonance spectroscopy at different compositions of water–dimethyl sulfoxide solvent. The breaking of hydrogen bonds between heteronitrogen and water molecules takes place at X DMSO ~ 0.2–0.3 m.f. Changes in carboxamide substituent solvation consisting in the disappearance of water molecules occur at X DMSO ~ 0.4 m.f. The quantum chemical modeling of some nicotinamide solvates was performed along with NBO analysis and chemical shift calculations.

Synthesis of Chlorins by Diels–Alder Cycloadditions of Pheophorbide a and Its Derivatives

The Diels–Alder reaction was exploited for the preparation of novel long-wavelength chlorin photodynamic therapy photosensitizers. The styryl group and furan carboxamide substituents were used as diene components in [4+2] cycloaddition functionalizations.

(4-Phenoxyphenyl)tetrazolecarboxamides and related compounds as dual inhibitors of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)

Inhibitors of the enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the principle enzymes involved in the degradation of endogenous cannabinoids like anandamide and 2-arachidonoylglycerol, have potential utility in the treatment of several disorders including pain, inflammation and anxiety. In the present study, the effectivity and selectivity of eight known FAAH and MAGL inhibitors for inhibition of the appropriate enzyme were measured applying in vitro assays, which work under comparable conditions. Because many of the known FAAH and MAGL inhibitors simply consist of a lipophilic scaffold to which a heterocyclic system is bound, furthermore, different heterocyclic structures were evaluated for their contribution to enzyme inhibition by attaching them to the same lipophilic backbone, namely 4-phenoxybenzene. One of the most active compound synthesized during this investigation was N,N-dimethyl-5-(4-phenoxyphenyl)-2H-tetrazole-2-carboxamide (16) (IC50 FAAH: 0.012 μM; IC50 MAGL: 0.028 μM). This inhibitor was systematically modified in the lipophilic 4-phenoxyphenyl region. Structure–activity relationship studies revealed that the inhibitory potency against FAAH and MAGL, respectively, could still be increased by replacement of the phenoxy residue of 16 by 3-chlorophenoxy (45) or pyrrol-1-yl groups (49). Finally, the tetrazolecarboxamide 16 and some related compounds were tested for metabolic stability with rat liver S9 fractions showing that these kind of FAAH/MAGL inhibitors are readily inactivated by cleavage of the bond between the tetrazole ring and its carboxamide substituent.

Towards the Discovery of a Novel Class of Monoamine Oxidase Inhibitors: Structure–Property–Activity and Docking Studies on Chromone Amides

Strong bonds! Theoretical and experimental data provide evidence of the existence of a strong O⋅⋅⋅HN hydrogen bond in chromones with carboxamide substituents located at position 3 of the γ-pyrone ring. The results suggest that the hydrogen-bond interaction is essential to the stabilization of the chromone folded stage and is strictly related to the potency and selectivity observed in monoamine oxidase-B biological assays.

Hypoxia-Activated Prodrugs: Substituent Effects on the Properties of Nitro seco-1,2,9,9a-Tetrahydrocyclopropa[c]benz[e]indol-4-one (nitroCBI) Prodrugs of DNA Minor Groove Alkylating Agents

Nitrochloromethylbenzindolines (nitroCBIs) are a new class of hypoxia-activated prodrugs for antitumor therapy. The recently reported prototypes undergo hypoxia-selective metabolism to form potent DNA minor groove alkylating agents and are selectively toxic to some but not all hypoxic tumor cell lines. Here we report a series of 31 analogues that bear an extra electron-withdrawing substituent that serves to raise the one-electron reduction potential of the nitroCBI. We identify a subset of compounds, those with a basic side chain and sulfonamide or carboxamide substituent, that have consistently high hypoxic selectivity. The best of these, with a 7-sulfonamide substituent, displays hypoxic cytotoxicity ratios of 275 and 330 in Skov3 and HT29 human tumor cell lines, respectively. This compound (28) is efficiently and selectively metabolized to the corresponding aminoCBI, is selectively cytotoxic under hypoxia in all 11 cell lines examined, and demonstrates activity against hypoxic tumor cells in a human tumor xenograft in vivo.

(E)-3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-N-(2-naphthyl)cyclopropanecarboxamide

The title compound, C19H17ClF3NO, was synthesized from 3-[(E)-2-chloro-3,3,3-trifluoro­prop-1-en­yl]-2,2-dimethyl­cyclopropane­carboxylic acid and 2-aminona­phthalene. There are two molecules in the asymmetric unit. The dihedral angle between the naphthalene and cyclo­propane units is 111.6 (5)°. Molecules are connected into chains by intermol­ecular N—H⋯O hydrogen bonds. One of the Cl atoms is disordered over two positions with occupancies 0.653 (15) and 0.347 (15).

(E)-3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-N-(3-methoxyphenyl)-2,2-dimethylcyclopropanecarboxamide

The title compound, C16H17ClF3NO2, was synthesized from 3-[(E)-2-chloro-3,3,3-trifluoro­prop-1-en­yl]-2,2-dimethyl­cyclo­propane­carboxylic acid and 3-methoxy­benzenamine. The propenyl and carboxamide substituents lie on the same side of the cyclo­propane ring plane, with the two methyl substituents on either side of the plane. The benzene ring makes a dihedral angle of 76.4 (3)° with the plane of the cyclo­propane ring. The crystal structure involves intermolecular N—H⋯O hydrogen bonds.

(E)-3-(2-Chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethyl-N,N-diphenylcyclopropanecarboxamide

The title compound, C21H19ClF3NO, was synthesized from 3-[(E)-2-chloro-3,3,3-trifluoro­prop-1-en­yl]-2,2-dimethyl­cyclo­propane­carboxylic acid and diphenyl­amine. The propenyl and carboxamide substituents lie on the same side of the cyclo­propane ring plane, with the two methyl substituents on either side of the plane. The phenyl rings of the carboxamide are inclined at an angle of 84.6 (3)° to one another. The F atoms are disordered over two positions; the site occupancy factors are ca 0.6 and 0.4.

(E)-Methyl 3-[3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxamido]thiophene-2-carboxylate

The title compound, C15H15ClF3NO3S, was synthesized from 3-[(E)-2-chloro-3,3,3-trifluoro­prop-1-en­yl]-2,2-dimethyl­cyclo­propane­carboxylic acid and methyl 3-amino­thio­phene-2-carboxyl­ate. The propenyl and carboxamide substituents lie on the same side of the cyclo­propane ring plane, with the two methyl substituents on either side of the plane. The mol­ecular conformation is stabilized by an N—H⋯O hydrogen bond and the crystal packing shows C—H⋯O hydrogen bonds.

New Polar Pyrazolylborate Ligands and Their Basic Zinc Complex Chemistry

AbstractBy refinement of Trofimenko’s procedures, four new tris(pyrazolyl)borate (Tp) ligands bearing pyridyl and carboxamide substituents at the 3‐positions of the pyrazole rings, were obtained. Two of them were identified by structure determinations of their potassium salts. Their coordinative properties were explored by preparing Tp*Zn‐X complexes, with X = Cl, Br, I, NO3, OAc, phenolate, thiophenolate and diorganophosphate, including the cationic complexes [Tp*Zn·L]+ with L = methanol and pyrazole. From the spectra and structure determinations of these complexes it has become evident that the polar Tp* ligands favor coordination numbers higher than four for zinc, either by inducing bidentate coordination of the coligands X and L, using the carboxamide oxygen atoms for coordination, or by linking two Tp*Zn‐X units through the pyridyl nitrogen atoms. As a result, the structural chemistry of these complexes is quite varied, and includes coordination dimers and polymers.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

New Polar Pyrazolylborate Ligands and Their Basic Zinc Complex Chemistry (Eur. J. Inorg. Chem. 19/2006)

AbstractThe cover picture shows the Alhambra in Granada, the home town of the Spanish author of this paper. The Moors in their desert dreamt of palaces abundant with water, and that is why they built the Alhambra. Likewise, the water‐soluble encapsulating pyrazolylborate ligand, shown as an (aqua)zinc complex set in one of Alhambra's gardens, is the realization of a long‐standing dream of the Freiburg group, whose biomimetic zinc complex chemistry was previously confined by the hydrophobicity of the model complexes, typically the zinc hydroxide complex shown in the background. The abundance of red (carbonyl oxygen) and green (amide nitrogen) atoms in the foreground complex visualizes its hydrophilicity due to the carboxamide substituents on the tripod ligand. Details are discussed in the article by H. Vahrenkamp et al. on p. 3869 ff.

An atom-economical approach to conformationally constrained tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder reaction of pyrrole.

An efficient approach to rigid tricyclic nitrogen heterocycles via sequential and tandem Ugi/intramolecular Diels-Alder (IMDA) cycloaddition of pyrrole is described. The one-pot Ugi four-component condensation (4CC) reaction was used as the key transformation to prepare trienes with a carboxamide substituent on the tether. The use of acrylic acid (21) and N-propyl- and N-benzylmaleamic acids (24b and 24C) as the acid components provided trienes 22, 25b, and 25c, respectively, which upon heating at 120 degrees C for 12 h yielded the corresponding [4 + 2] cycloaddition products. In the case of maleic acid derivative 24a, heating the reaction mixture at 60 degrees C for 6 h promoted the cycloaddition reaction and provided the desired product 26a in 78% yield. In contrast, fumaric acid monoethyl ester (27a) and 3-acetyl- and 3-(4-methylbenzoyl) acrylic acids (27b-c) directly yielded the corresponding Ugi/IMDA cycloaddition products 29a-c in high yields at room temperature without any trace of initially formed trienes 28a-c. The IMDA cycloaddition reactions proceed with excellent stereoselectivity with the formation of five stereogenic centers and three rings.

Acid-amide calixarene ligands for uranyl and lanthanide ions: synthesis, structure, coordination and extraction studies

The synthesis of a series of calix[4]arene ligands bearing lower rim 1,3-acid-amide functionality for the two-phase solvent extraction of lanthanide and uranyl ions from aqueous wastes is described. X-Ray crystal structure studies demonstrate binding of lanthanide ions at the calixarene lower rim through phenolate, carboxylate and carboxamide oxygen atoms. The crystal structures of a centrosymmetric, dimeric lanthanum(III) and non-centrosymmetric dimeric sodium(I) complexes of a 1,3-acid-dihexylamidecalix[4]arene ligand are detailed. Electrospray mass spectrometry confirms retention of this 2 ∶ 2 dimeric structure for large lanthanide ions and that the smaller lanthanide ions e.g. Lu3+ form monomeric 1 ∶ 1 calixarene ∶ lanthanide complexes in solution. Extraction studies demonstrate a pH dependent uptake of lanthanide and uranyl cations by 1,3-acid-amide ligands with the nature of the carboxamide substituent largely irrelevant to extraction efficiency. Upper rim modified 1,3-dinitro and de-tert-butylcalix[4]arene ligands were prepared and NMR and ES-MS studies confirm uranyl coordination by these novel acid-amide ligands. The 1,3-dinitro and de-tert-butyl ligands exhibit superior and more efficient extraction of uranyl cations at lower pH values.

Self-assembly of polymer and sheet structures from palladium(II) complexes by hydrogen bonding between carboxamide substituents.

The self-assembly of supramolecular structures from either neutral or cationic palladium(II) complexes containing primary or secondary carboxamide groups as substituents on pyridine ligands has been explored. The displacement of PhCN in trans-[PdCl(2)(PhCN)(2)] by L = N-methylnicotinamide (MNA), isonicotinamide (INA), or nicotinamide (NA) gave the corresponding complexes trans-[PdCl(2)L(2)] 1-3, respectively. Complex 1.H(2)O forms a 2D sheet network via amide-amide hydrogen bonding supported by chloride ligand-to-water hydrogen-bonding interactions. Several cationic complexes, [Pd(L'L')L(2)](2+) 4-9 and 11-16, containing the above ligands and with PPh(3), dppp, dppm, or bu(2)bipy as ancillary ligand(s) were prepared. Complex 4 (L = MNA, L'L' = dppp) forms dimers through amide-amide hydrogen bonding, forming macrocycles which further propagate to form chains via weak C-H...O=C hydrogen bonding. Complex 6 (L = NA, L'L' = dppp) forms zigzag chains connected by amide head-to-head hydrogen bonds. Complex 8 (L = INA, L'L' = dppm) gives interesting double-stranded ribbons linked by two types of amide--amide hydrogen-bonding interactions. Complex 13 (L' = PPh(3), L = NA) forms an infinite chain via complementary amide-amide hydrogen bonds. Complex 14 (L = MNA, L'L' = bu(2)bipy) forms infinite ribbons via the combination of amide hydrogen bonding mediated by a BF(4) anion and weak C-H...O=C hydrogen bonding. Complex 15 (L = INA, L'L' = bu(2)bipy) gives a ladder polymer formed through amide--amide hydrogen bonds. The structure of cis-[Pd(PPh(3))(2)(OH(2))(2)] (OTf)(2) (10) is also reported.

Structure–property relationships on histamine H 3-antagonists: binding of phenyl-substituted alkylthioimidazole derivatives to rat plasma proteins

The binding of a series of H 3-antagonists to rat plasma proteins was investigated by dialysis experiments, with RP-HPLC measurement of the free ligand. The series was composed of 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazoles having, on the phenyl ring, meta- and para-substituents, with different physico-chemical characteristics. As high protein binding had been proposed as being one of the features limiting brain access for the reference H 3-antagonist thioperamide, the title series was employed to test the possibility of achieving lower protein binding by modulation of lipophilicity, while maintaining good receptor affinity. The compounds tested showed quotas of bound drug ranging from 60 to 97.5%, while for thioperamide a 78% bound drug quota was observed at high total concentrations, with a steep increase in bound percentage at lower concentrations. Two of the tested compounds, having a carboxamide substituent, showed lower protein binding compared to thioperamide over a wide range of total concentration, without a significant loss in affinity with respect to the parent compound. A strict dependence of protein binding on lipophilicity was observed, and a QSPR model was derived which could also account for the protein binding observed for thioperamide, while receptor affinity had been reported to be quite insensitive to phenyl ring substitution. It is therefore possible to modulate protein binding of these H 3-antagonists, through lipophilicity adjustment, without losing receptor affinity; this finding could help in the design of new compounds with improved brain access.

Formation and structural properties of 1,1′,2,2′-tetra(tert-butylcarbamoyl)-ferrocene and -ruthenocene †

Sodium cyclopentadienide adds two molar equivalents of tert-butylisocyanate to yield the 1,2-bis(N-tert-butylcarbamoyl)cyclopentadienide reagent 1. This reacts with RuCl2(PPh3)4 3 in a 2∶1 stoichiometry to yield the metallocene [η5-C5H3(CONHCMe3)2]2Ru 5. Complex 5 was characterized by an X-ray crystal structure analysis. It shows a near to eclipsed C2-symmetric metallocene conformation with the carboxamide substituents pairwise connected by intramolecular hydrogen bridges between –CONHR groups attached to different Cp ligands. The intermediate of the substitution reaction sequence, the complex [η5-C5H3(CONHCMe3)2]RuCl(PPh3)2 4, was also isolated and characterized by X-ray diffraction. Treatment of 1 with FeCl2 (2∶1) yields 1,1′,2,2′-tetra(N-tert-butylcarbamoyl)ferrocene 6. The X-ray crystal structure analysis of 6 features a staggered Ci metallocene conformation.

Addition of silyloxydienes to 2-substituted 1,4-benzoquinones and 1,4-naphthoquinones

Abstract Addition of 1-trimethylsilyloxybuta-1,3-diene 2 to the quinones 4,5,6,17,18,19,20 bearing formyl, acetyl, methoxycarbonyl or carboxamide substituents at C-2, afforded the Diels-Alder adducts 11,12,13,25,26,27,28 whereas addition of 2-trimethylsilyloxyfuran 3 afforded the fragmentation products 29,30,31,35,36,37,38. Quinones 7,21 bearing a carboxyl group at C-2 afforded 1,4-naphthoquinone and 9,10-anthracenedione with 2 and no adducts were isolated from reaction with 3. Benzoquinone-sulfide 8 afforded Diels-Alder adduct 14 and fragmentation product 32 with 2 and 3 respectively whereby reaction occurred on the less substituted double bond. No adducts were isolated upon treatment of naphthoquinone-sulfide 22 with either 2 or 3. The Diels-Alder adducts of benzoquinone-sulfoxide 9 and naphthoquinone-sulfoxide 23 with 2 underwent facile aromatisation to 1,4-naphthoquinone and 9,10-anthracenedione with 2. Addition of 3 to 9 afforded fragmentation product 33 whereas analogous reaction with 23 was unsucccessful. Addition of dienes 2,3 to benzoquinone-sulfone 10 afforded fragmentation products 16,34 respectively, whereas naphthoquinone-sulfone 24 afforded 9,10-anthracendione with 2 and no products with 3.

ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes

Acyl-CoA:cholesterol acyltransferase (ACAT) is the enzyme largely responsible for intracellular cholesterol esterification. A systemic inhibitor of ACAT is believed to be able to slow or even reverse the atherosclerotic process. Towards that goal, a series of cyclic sulfides, derived from the hetero-Diels-Alder reaction of thioaldehydes with 1,3-dienes, and bearing carboxamide substituents, were prepared and evaluated for in vitro (in several tissues and species) and ex vivo ACAT inhibition. Minor changes in subsequent structure were found to have a significant effect in optimization of the biological activity of this series of compounds.