N-benzoyl Derivatives Research Articles

Phenylalanine-derived β-lactam TRPM8 antagonists: revisiting configuration and new benzoyl derivatives

Aim: To expand the understanding of the structure-activity relationship within a family of amino acid-derived β-lactam TRPM8 (transient receptor potential melastatin channel, subtype 8) antagonists, this work investigated both the configuration-dependence of potency and selectivity, and explored strategies for increasing total polar surface area (TPSA). Methods: Diastereoisomeric compounds derived from H-Phe-OtBu, and analogues incorporating differently substituted benzoyl groups, were synthesized by stereoselective solution pathways. Ca2+ microfluorometry assays were used for TRPM8 antagonist activity assessment, and then confirmed through electrophysiology (patch-clamp assay). The pharmacological activity in vivo was studied on a mice model of oxaliplatin-induced peripheral neuropathy. Results: For OtBu derivatives, a 3S,4S-configuration was preferred, while compounds with 2'R chiral centers show higher selectivity for TRPM8 versus transient receptor potential vanilloid, subtype 1 (TRPV1) than their 2'S-counterparts. N-terminal benzoyl derivatives, which increased TPSA values, resulted in equipotent compounds as previous prototypes, but also showed activity in other pain-related targets [TRPV1 and cannabinoid receptor, subtype 2 (CB2R)]. A selected N-benzoyl derivative displays antinociceptive activity in vivo. Conclusions: The potency and selectivity of these β-lactam TRPM8 antagonists developed from amino acid derivatives depend not only on the configuration but also on the substituents at the 4-carboxy and at the N-benzoyl groups. Dual and multitarget compounds were discovered within this family of TRPM8 antagonists.

Catalyst-free ring opening of azlactones in water microdroplets.

A catalyst-free method was developed for the ring opening of azlactones (also known as oxazolones) in water microdroplets. Azlactone was dissolved in a water : acetonitrile (1 : 1) mixture, and the solution is sprayed by using nitrogen gas at a pressure of 120 psi to generate microdroplets. This method promoted selective cleavage of the lactone bond to afford the corresponding N-benzoyl derivatives in up to 94% isolated yield with no epimerization. Our method produces the ring-opening products in milliseconds (up to 94 μmol for 33.3 minutes), and may have utility for high-throughput synthesis applications.

Acid-induced hydrolysis of 1-(methoxydiphenylmethyl)-2-methyldiazene: interception of methyldiazenium ion with 1,3-dienes affording 1-methyl-1,2,3,6-tetrahydropyridazine Diels–Alder products

The conversion of benzophenone methylhydrazone with bromine and pyridine into 1-[(methyldiazenyl)diphenylmethyl]pyridin-1-ium bromide followed by the solvolysis with methanol provides a facile synthesis of 1-(methoxydiphenylmethyl)-2-methyldiazene. The acid-induced hydrolysis of this N,O-ketal releases the methyldiazenyl moiety as the putative intermediate methyldiazenium ion. Reacting as a heterodienophile, methyldiazenium ion is intercepted with 1,3-dienes in [4 + 2+] cycloaddition reactions affording 1-methyl-1,2,3,6-tetrahydropyridazine Diels–Alder products which are transformed into stable and isolated N-benzoyl derivatives.Graphical abstract

Halolactonization of N-Acyl-N-(2-cyclohex-1-en-1-yl-6-methylphenyl)glycines: Towards Production of 4,1-Benzoxazoheterocycles

AbstractA significant influence of the nature of the acyl substituent at the nitrogen atom on the direction of the reaction in the interaction of N-acyl-N-(2-cyclohex-1-en-1-yl-6-methylphenyl)glycines with bromine was found. In the case of the N-benzoyl derivative, along with benzoxazocinone, which is formed through the stages of pseudoallyl halogenation and subsequent lactonization due to the replacement of the bromine atom by the oxygen atom of the carboxyl group, a mixture of axially chiral isomers of spiro-fused 2′-bromocyclohexane-benzoxazepin-3-ones was also obtained. The aR*,R*,R*-isomer of benzoxazepinone, which initially is four times predominant in the reaction mixture, upon dissolution in deuterochloroform, slowly transforms into aS*-conformer until a ratio of 2:1 is established. In the case of the N-acetyl analogue of this glycine, the only heterocycle is the product of 7-exo-halogenlactonization, the benzoxazepinone spiro-fused with 2′-bromocyclohexane and an undetermined configuration of the axial chirality.

Synthesis, vibrational analysis, molecular property investigation, and molecular docking of new benzenesulphonamide-based carboxamide derivatives against Plasmodium falciparum

Zinc chloride mediated synthesis, density functional theory (DFT) studies and molecular docking of new carboxamide derivatives containing sulphonamide functionality is reported. The synthesis of benzenesulphonamide (3a-d) was achieved from the reaction of benzenesulphonyl chlorides (1a) and amino acids (2a-d) and the yields were characterized using FT-IR and NMR spectroscopy. The reaction of compounds (3a-d) with benzoyl chloride (4) provided the N-benzoylated derivatives (5a-d) which upon reaction with 4-nitroaniline (6) using zinc chloride as a catalyst afforded the new carboxamides; 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl-N-(4-nitrophenyl)pentanamide (BSPFMNPP), 2-[N-(benzenesulfonyl)-1-phenylformamido]-3-methyl-N-(4-nitrophenyl)butanamide, (BSPFMNPB), 1-(benzenesulfonyl)-4-hydroxy-N-(4-nitrophenyl)pyrrolidine-2-carboxamide (BSHNPPC) and 1-(benzenesulfonyl)-N-(4-nitrophenyl)pyrrolidine-2-carboxamide (BSNPPC) in excellent yields. Theoretical calculations on the newly synthesized carboxamides were conducted at the B3LYP/6-311++G(d,p) level of theory to investigate the reactivity, stability, bonding nature, along with vibrational functional groups assignment and correlation with experimental values. From the docking result, the binding affinities obtained from the docking score were in the order; -7.3 > -7.2 > -6.1 > -5.8 kcal/mol for BSPFMNPB, BSPFMNPP, BSNPPC and BSHNPPC respectively while the standard drug, atovaquone scored -7.7 kcal/mol. There were no significant differences between the docking score by the standard drug and the studied compounds. However, results showed that the 2-[N-benzoylated]-alkane derivatives (pentanamide and butanamide); BSPFMNPB and BSPFMNPP are better anti-malaria drug candidates than their 1-[N-benzoylated]-pyrollidine derivatives; BSNPPC and BSHNPPC.

Electrochemical and theoretical study on enhanced pseudocapacitance performance of poly orthoaminophenol film in the presence of different derivatives of phenylglycine

We have successfully synthesized three derivative of phenylglycine by Schotten-Baumann method denoted as 2-[(4-methylbenzoyl) amino] phenyl acetic acid (B-Me), 2-(benzoyl amino) phenyl acetic acid (B-H) and 2-[(4-chlorobenzoyl) amino] phenyl acetic acid (B-Cl). Afterward, dealing with improving electrochemical properties of the poly ortho aminophenol (POAP), we fabricated POAP/B-Me, POAP/B-H and POAP/B-Cl films through electro-polymerization of POAP by employing of N-benzoyl derivatives of phenylglycine to consider as the active electrode for SCs. Analysis of electronic wave function (DFT-method) results show that the atomic-scale electronic properties are generally depend on the bonding and electronic molecular structures and electron donating group on the N-benzoyl derivatives has main important effect rather than electron withdrawing group. The electrochemical properties of electrodes and the capacitive behavior of the resulting capacitors were systematically studied using cyclic voltammetry (CV), ac impedance and constant current charge–discharge tests. The specific capacitance of POAP/B-Me electrode was exhibited as high as 614.3 F/g, in comparison with a value of 261 F/g for POAP film. These results make POAP/B-Me it a promising candidate for supercapacitor applications.

Synthesis, characterization and anthelmintic activity evaluation of pyrimidine derivatives bearing carboxamide and sulphonamide moieties

Pyrimidines, sulphonamides and carboxamides have shown a large number of pharmacological properties against different types of diseases including helminthiasis. Seventeen new pyrimidine derivatives bearing sulphonamide and carboxamide were synthesized and investigated for their in vitro anthelmintic properties. Substituted benzenesulphonyl chlorides 15a?c were treated with various amino acids (16a?h) to obtain benzenesulphonamide derivatives 17a?l. Compounds 17a?f were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives 19a?f. Further reactions of compounds 19a?f and 17g?l with 4- or 2-aminopyrimidine (20) using boric acid as a catalyst gave the required sulphonamide carboxamide derivatives 21a?q in excellent yields. The compounds were isolated in their analytical grade and characterized using FTIR, 1H-NMR, 13C-NMR and HRMS. The in vitro anthelmintic studies showed that all the synthesized compounds possessed anthelmintic property. Compounds 21a?c, e, g, m and p showed mean paralyzing times of 15, 19, 14, 18, 19, 19 and 18 min, respectively, at 100 mg mL-1 compared to 10 min for albendazole. Compounds 21a?c, g and m had mean death times of 18, 24, 16, 20 and 25 min, respectively, at 100 mg mL-1 compared to 13 min for albendazole.

Structure-activity relationship study and optimisation of 2-aminopyrrole-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile as a broad spectrum metallo-β-lactamase inhibitor

A SAR study on derivatives of 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile 5a revealed that the 3-carbonitrile group, vicinal 4,5-diphenyl and N-benzyl side chains of the pyrrole are important for the inhibitory potencies of these compounds against members representing the three main subclasses of metallo-β-lactamases (MBLs), i.e. IMP-1 (representing the B1 subgroup), CphA (B2) and AIM-1 (B3). Coupling of 5a with a series of acyl chlorides and anhydrides led to the discovery of two N-acylamide derivatives, 10 and 11, as the two most potent IMP-1 inhibitors in this series. However, these compounds are less effective towards CphA and AIM-1. The N-benzoyl derivative of 5a retained potent in vitro activity against each of MBLs tested (with inhibition constants in the low μM range). Importantly, this compound also significantly enhanced the sensitivity of IMP-1, CphA- or AIM-1-producing cell cultures towards meropenem. This compound presents a promising starting point for the development of a universal MBL inhibitor, targeting members of each of the major subgroups of this family of enzymes.

Synthesis, characterization, molecular docking and in vitro antimalarial properties of new carboxamides bearing sulphonamide

Sulphonamides and carboxamides have shown large number of pharmacological properties against different types of diseases among which is malaria. Twenty four new carboxamide derivatives bearing benzenesulphonamoyl alkanamides were synthesized and investigated for their in silico and in vitro antimalarial and antioxidant properties. The substituted benzenesulphonyl chlorides (1a-c) were treated with various amino acids (2a-h) to obtain the benzenesulphonamoyl alkanamides (3a-x) which were subsequently treated with benzoyl chloride to obtain the N-benzoylated derivatives (5a-f, i-n and q-v). Further reactions of the N-benzoylated derivatives or proline derivatives with 4-aminoacetophenone (6) using boric acid as a catalyst gave the sulphonamide carboxamide derivatives (7a-x) in excellent yields. The in vitro antimalarial studies showed that all synthesized compounds had antimalarial property. Compound 7k, 7c, 7l, 7s, and 7j had mean MIC value of 0.02, 0.03, 0.05, 0.06 and 0.08 μM respectively comparable with chloroquine 0.06 μM. Compound 7c was the most potent antioxidant agent with IC50 value of 0.045 mM comparable with 0.34 mM for ascorbic acid. In addition to the successful synthesis of the target molecules using boric acid catalysis, the compounds were found to have antimalarial and antioxidant activities comparable with known antimalarial and antioxidant drugs. The class of compounds reported herein have the potential of reducing oxidative stress arising from malaria parasite and chemotherapeutic agent used in the treatment of malaria.

Synthesis of marine alkaloids leucettamines B and C by β-lactam ring rearrangement

ABSTRACTA new method for the synthesis of marine alkaloids leucettamines B and C from Leucetta sp. sponges is described. The key step is the base-promoted rearrangement of β-lactam into imidazolone ring. Leucettamines B and C as well as their N-benzoyl derivatives were obtained in high yields. Single-crystal structures of both leucettamines B and C were determined by X-ray diffraction confirming Z-configuration of double bond at 4-position of imidazolone.

Chemistry of Amide-based Axial Chirality: Elucidation of the Active Conformation Recognized by Enzymes and Receptors

Axial chirality caused by an sp(2)-sp(2) axis at Ar-N(C=O) (a conformational stereogenic axis) in pharmaceutically important seven-membered-ring benzolactams (I) and N-acyl-benzazepines and related nuclei (II) was investigated to verify the importance of the atropisomerism in the biologically active molecules. Anilide derivatives with the seven-membered-ring benzolactams (derivatives of I: 6-8) and the N-benzoyl derivatives of 1,5-benzodiazepines (derivatives of II: 11-ii-14-ii) were successfully synthesized as new, highly potent acyl-CoA:cholesterol acyltransferase inhibitors and the vaptan class of vasopressin receptor ligands, respectively. By freezing the atropisomerism at the scaffold regions, we succeeded in separating and isolating the atropisomers. The biological activities of the atropisomers were examined to reveal that the axial chirality is recognized by the enzyme and receptor when the molecules exert their activity.

N-2,4-dichlorobenzoyl phosphoric triamides: Synthesis, spectroscopic and X-ray crystallography studies

New phosphoric triamides 1–9 were synthesized by the reaction of N-2,4-dichlorobenzoyl phosphoramidic dichloride with various cyclic aliphatic amines and the products were characterized by 1H, 13C, 31P NMR, IR spectroscopy and elemental analysis. Surprisingly, the 1H NMR spectrum of 2 indicated long range 6 J (P, H) coupling constant = 1.3, 1.4 Hz and those of molecules 3, 4, 6–8 display long-range 4 J (H, H) coupling constants (1.8–1.9 Hz) for the coupling of aromatic protons in 2,4-dichlorophenyl rings. 1H NMR spectra indicated 3 J (PNCH) for enantiotopic and diastereotopic benzylic CH2 protons in compounds 7 and 8. The spectroscopic data of newly synthesized compounds were compared with those related N-benzoyl derivatives. The structures of compounds 5, 8 and 10 (2,4-Cl2-C6H3C(O)NHP(O)[NCH2CH(CH3)2]2) have been determined by X-ray crystallography. The structures form centrosymmetric dimers through intermolecular strong -P=O…H-N-hydrogen bonds. The dimers connect to each other via rather strong and weak C-H…O plus weak C-H…Cl H-bonds to produce a 1-D network for 5 while 3-D polymeric chains for 8 and 10.

Heteropolyacids in synthesis of benzoyl hydrazone derivatives

Keggin type of heteropolyacids as green reusable and efficient catalyst was used in the synthesis of benzoyl hydrazones from reaction of benzoic acid hydrazide and aldehyde and ketone derivatives. The synthesis of N-acetyl and N-benzoyl derivatives has also been performed by the reaction of obtained benzoyl hydrazones with acylcholorides in presence of this kind of heteropolyacids.

Highlighting the possible secondary interactions in the role of balhimycin and its analogues for enantiorecognition in capillary electrophoresis

It is believed that the enantiorecognition mechanism based on macrocyclic antibiotics involves multimodal interactions via hydrogen bonding, π–π interaction, steric hindrance, hydrophobic interaction and so on. A variety of enantiomeric N-benzoylated amino acids were separated using balhimycin ( A) or its analogues bromobalhimycin ( B) and dechlorobalhimycin ( C) as chiral mobile phase additive using a CE method, which combined the partial filling technique with the dynamic coating technique and the co-EOF electrophoresis technique. The enantioresolution and the migration time were highly relevant to the structure of analytes, especially to the substitutions on the N-tagged benzoyl moiety of the amino acids. A steric effect and π–π interaction based mechanism is proposed in order to explain some observed enantioresolution differences between positional isomers. Notably dechlorobalhimycin exhibited the best enantioresolution for several N-benzoylated derivatives of leucine, which was rarely observed for N-dansylated amino acid derivatives. The hydrophobicity difference of the aglycone pocket among three chiral selectors was assumed to account for this behaviour.

An N-Aroyltransferase of the BAHD Superfamily Has Broad Aroyl CoA Specificity in Vitro with Analogues of N-Dearoylpaclitaxel

The native N-debenzoyl-2'-deoxypaclitaxel:N-benzoyltransferase (NDTBT), from Taxus plants, transfers a benzoyl group from the corresponding CoA thioester to the amino group of the beta-phenylalanine side chain of N-debenzoyl-2'-deoxypaclitaxel, which is purportedly on the paclitaxel (Taxol) biosynthetic pathway. To elucidate the substrate specificity of NDTBT overexpressed in Escherichia coli, the purified enzyme was incubated with semisynthetically derived N-debenzoyltaxoid substrates and aroyl CoA donors (benzoyl; ortho-, meta-, and para-substituted benzoyls; various heterole carbonyls; alkanoyls; and butenoyl), which were obtained from commercial sources or synthesized via a mixed anhydride method. Several unnatural N-aroyl-N-debenzoyl-2'-deoxypaclitaxel analogues were biocatalytically assembled with catalytic efficiencies (V(max)/K(M)) ranging between 0.15 and 1.74 nmol.min(-1).mM(-1). In addition, several N-acyl-N-debenzoylpaclitaxel variants were biosynthesized when N-debenzoylpaclitaxel and N-de(tert-butoxycarbonyl)docetaxel (i.e., 10-deacetyl-N-debenzoylpaclitaxel) were used as substrates. The relative velocity (v(rel)) for NDTBT with the latter two N-debenzoyl taxane substrates ranged between approximately 1% and 200% for the array of aroyl CoAs compared to benzoyl CoA. Interestingly, NDTBT transferred hexanoyl, acetyl, and butyryl more rapidly than butenoyl or benzoyl from the CoA donor to taxanes with isoserinoyl side chains, whereas N-debenzoyl-2'-deoxypaclitaxel was more rapidly converted to its N-benzoyl derivative than to its N-alkanoyl or N-butenoyl congeners. Biocatalytic N-acyl transfer of novel acyl groups to the amino functional group of N-debenzoylpaclitaxel and its 2'-deoxy precursor reveal the surprisingly indiscriminate specificity of this transferase. This feature of NDTBT potentially provides a tool for alternative biocatalytic N-aroylation/alkanoylation to construct next generation taxanes or other novel bioactive diterpene compounds.

Ortho Effect in Electron Ionization Mass Spectrometry of N-Acylanilines Bearing a Proximal Halo Substituent

Electron ionization (EI) mass spectra are not very helpful for characterizing ortho, meta, and para isomers of underivatized haloanilines since their spectra are virtually identical. In contrast, when the amino group of chloro-, bromo-, or iodoanilines is transformed to an N-formyl, N-acetyl, or N-benzoyl derivative, the spectra of the derivatives reveal a highly dramatic loss of a halogen radical, instead of an HX elimination usually expected from an "ortho effect." For example, the spectra of N-formyl, N-acetyl, and N-benzoyl derivatives of ortho isomers of chloro-, bromo-, and iodoanilines show a very prominent peak at m/z 120, 134, and 196, respectively, for the loss of the corresponding halogen atom.

On the Mechanism of the Thermal Retrocycloaddition of Pyrrolidinofullerenes (Retro-Prato Reaction)

In contrast to N-methyl or N-unsubstituted pyrrolidinofullerenes, which efficiently undergo the retrocycloaddition reaction to quantitatively afford pristine fullerene, N-benzoyl derivatives do not give this reaction under the same experimental conditions. To unravel the mechanism of the retrocycloaddition process, trapping experiments of the in-situ thermally generated azomethine ylides, with an efficient dipolarophile were conducted. These experiments afforded the respective cycloadducts as an endo/exo isomeric mixture. Theoretical calculations carried out at the DFT level and by using the two-layered ONIOM (our own n-layered integrated molecular orbital and molecular mechanics) approach underpin the experimental findings and predict that the presence of the dienophile is not a basic requirement for the azomethine ylide to be able to leave the fullerene surface under thermal conditions. Once the 1,3-dipole is generated in the reaction medium, it is efficiently trapped by the dipolarophile (maleic anhydride or N-phenylmaleimide). However, for N-unsubstituted pyrrolidinofullerenes, the participation of the dipolarophile in assisting the 1,3-dipole to leave the fullerene surface throughout the whole reaction pathway is also a plausible mechanism that cannot be ruled out.

Crystal structures and mass spectral fragmentation studies of some new carbacylamidophosphate compounds

Twenty new carbacylamidophosphates R′ 2P(O)NHC(O)R, where R = acetyl and benzoyl derivatives, R′ = 3, 5, 6 and 7 membered ring amines, were synthesized and characterized by IR, 1H, 13C and 31P NMR spectroscopy, and elemental analysis. The crystal structures of CCl 3C(O)NHP(O)[N(C 5H 10)] 2 ( 1d), CHCl 2C(O)NHP(O)[N(C 5H 10)] 2 ( 2d), Cl–C 6H 4C(O)NHP(O)[NH(C 5H 9)] 2 ( 5b) and Cl–C 6H 4C(O)NHP(O)[N(C 4H 8)O] 2 ( 5e) have been determined. All four compounds indicate the formation of intermolecular –P O…H–N– hydrogen bonds which give dimeric aggregates. They were centrosymmetric in 5b and 5e. Also, the mass spectra of these compounds, in addition to our previously synthesized 29 carbacylamidophosphates, were recorded and the observed fragmentation behaviors were studied. The main pathways of fragmentation of N-acetyl and N-benzoyl phosphoric amide derivatives indicated that the molecular ions involve mainly a radical cationic center at the carboxyl oxygen. All the N-benzoyl and N-acetyl phosphoramidates rearranged to the O-phosphorylated benz- or acetamides, and those readily lost the (R′) 2PO 2 radicals and yielded N-protonated nitrilium ions R–C NH + and ▪. The greater intensities for the ▪ ions in the N-benzoyl derivatives relative to R–C NH + for the N-acetyl derivatives may due to differences in the P O, C O, P–N amide and C–N amide bond lengths and their different specific properties in the parent molecules.

The effect of substitution of the N-acetyl groups of N-acetylgalactosamine residues in chondroitin sulfate on its degradation by chondroitinase ABC

Chondroitinase ABC is a lyase that degrades chondroitin sulfate, dermatan sulfate and hyaluronic acid into disaccharides. The purpose of this study was to determine the ability of chondroitinase ABC to degrade chondroitin sulfate in which the N-acetyl groups are substituted with different acyl groups. The bovine tracheal chondroitin sulfate A (bCSA) was N-deacetylated by hydrazinolysis, and the free amino groups derivatized into N-formyl, N-propionyl, N-butyryl, N-hexanoyl or N-benzoyl amides. Treatment of the N-acyl or N-benzoyl derivatives of bCSA with chondroitinase ABC and analysis of the products showed that the N-formyl, N-hexanoyl and N-benzoyl derivatives are completely resistant to the enzyme. In contrast, the N-propionyl or N-butyryl derivatives were degraded into disaccharides with slower kinetics compared to that of unmodified bCSA. The rate of degradation of bCSA derivatives by the enzyme was found to be in the order of N-acetyl>N-propionyl>>N-butyryl bCSA. These results have important implications for understanding the interaction of N-acetyl groups of glycosaminoglycans with chondroitinase ABC.

Synthesis and characterization of some new cobalt(II) and nickel(II) ternary complexes of N-acetyl, N-benzoyl and N-tosyl derivatives of amino acids

A series of some new cobalt(II) and nickel(II) ternary complexes of N-(acetyl)phenylalaninate (acphe), N-(acetyl)tyrosinate (actyr), N-(benzoyl)leucinate (bzleu), N-(benzoyl)phenylalaninate (bzphe), N-(tosyl)glutamic acid (tsglu), N-(tosyl)arginine (tsarg) with certain N-heterocyclic ligands such as imidazole (imi), methylimidazole (mimi), 2,2′-bipyridyl (bipy) 1,10-phenanthroline (phen) have been synthesized and characterized by elemental analyses, IR and electronic spectra. as well as thermogravimetry. The structure of the cobalt(II) N-phthaloylglycinate complex was also characterized by X-ray single crystal. It was found that the cobalt atom coordinates a 1,10-phenanthroline molecule and four water oxygen atoms, forming a distorted octahedral conformation. A molecule of N-phthaloylglycinate is connected by van der Waals contact and H-bonds.