Showing papers by "Justo Cobo published in 2013"

Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration.

Abstract: A molecular modeling study on dihydrofolate reductase (DHFR) inhibitors was carried out. By combining molecular dynamics simulations with semiempirical (PM6), ab initio, and density functional theory (DFT) calculations, a simple and generally applicable procedure to evaluate the binding energies of DHFR inhibitors interacting with the human enzyme is reported here, providing a clear picture of the binding interactions of these ligands from both structural and energetic viewpoints. A reduced model for the binding pocket was used. This approach allows us to perform more accurate quantum mechanical calculations as well as to obtain a detailed electronic analysis using the quantum theory of atoms in molecules (QTAIM) technique. Thus, molecular aspects of the binding interactions between inhibitors and the DHFR are discussed in detail. A significant correlation between binding energies obtained from DFT calculations and experimental IC50 values was obtained, predicting with an acceptable qualitative accuracy t...

The renin-angiotensin system: new insight into old therapies.

Abstract: Although the renin-angiotensin system (RAS) is already an old acquaintance, there are often exciting discoveries that improve our knowledge of it and open new therapeutic possibilities. Moreover, well-established drugs, such as angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), or beta-blockers, show that their mechanism of action may be the result of parallel pathways other than the ones initially established. A detailed analysis of the RAS can be carried out in part through the study of the enzymes, named angiotensinases, involved in its cascade, whose activity is a reflection of the functionality of their peptide substrates. The study of these enzymes offers the possibility of controlling the effects of angiotensins through various pharmacological manipulations. For example, angiotensinase inhibitors or activators are being used or have been proposed as antihypertensive agents. They have also been suggested as analgesic and antidepressant drugs or targets for drug development against different pathologies such as Alzheimer's disease, epilepsy or ischemia. On the other hand, the analysis of brain asymmetry has revealed surprising results about the laterality of central and peripheral components of the RAS. Such studies indicate that the neurovisceral integration, already proposed by Claude Bernard (1867) should also be analyzed from a bilateral perspective. In this review, the RAS and the role of various angiotensinases implicated in the cascade are revisited. Therapeutic strategies involving some components of the RAS with an unusual vision resulting from a bilateral perspective added to their study are discussed.

Efficient Catalyst-Free Four-Component Synthesis of Novel γ-Aminoethers Mediated by a Mannich Type Reaction

Abstract: Herein, it is provided an efficient and one-pot procedure for the synthesis of novel and diversely substituted γ-aminoethers in good yields through a four-component process by treatment of benzylamines with polyformaldehyde and activated alkenes in aliphatic alcohols acting both as solvent and as etherificant agents. Reactions proceeded via a Mannich-type reaction, where the formation of iminium ions and aminals was identified as the key intermediates to obtain the target products.

Synthesis, antifungal and antitumor activity of novel (Z)-5-hetarylmethylidene-1,3-thiazol-4-ones and (z)-5-ethylidene-1,3-thiazol-4-ones.

Abstract: New hetaryl- and alkylidenerhodanine derivatives 3a – d , 3e , and 4a – d were prepared from heterocyclic aldehydes 1a – d or acetaldehyde 1e . The treatment of several rhodanine derivatives 3a – d and 3e with piperidine or morpholine in THF under reflux, afforded ( Z )-5-(hetarylmethylidene)-2-(piperidin-1-yl)thiazol-4(5 H )-ones and 2-morpholinothiazol-4(5 H )-ones 5a – d , 6a – d , and ( Z )-5-ethylidene-2-morpholinothiazol-4(5 H )-one ( 5e ), respectively, in good yields. Structures of all compounds were determined by IR, 1D and 2D NMR and mass spectrometry. Several of these compounds were screened by the U.S. National Cancer Institute (NCI) to assess their antitumor activity against 60 different human tumor cell lines. Compound 3c showed high activity against HOP-92 (Non-Small Cell Lung Cancer), which was the most sensitive cell line, with GI 50 = 0.62 μM and LC 50 > 100 μM from the in vitro assays. In vitro antifungal activity of these compounds was also determined against 10 fungal strains. Compound

Synthesis, Antifungal and Antitumor Activity of Novel (Z)-5-Hetarylmethylidene-1,3-thiazol-4-ones and (Z)-5-Ethylidene-1,3-thiazol-4-ones

Abstract: New hetaryl- and alkylidenerhodanine derivatives 3a – d , 3e , and 4a – d were prepared from heterocyclic aldehydes 1a – d or acetaldehyde 1e . The treatment of several rhodanine derivatives 3a – d and 3e with piperidine or morpholine in THF under reflux, afforded ( Z )-5-(hetarylmethylidene)-2-(piperidin-1-yl)thiazol-4(5 H )-ones and 2-morpholinothiazol-4(5 H )-ones 5a – d , 6a – d , and ( Z )-5-ethylidene-2-morpholinothiazol-4(5 H )-one ( 5e ), respectively, in good yields. Structures of all compounds were determined by IR, 1D and 2D NMR and mass spectrometry. Several of these compounds were screened by the U.S. National Cancer Institute (NCI) to assess their antitumor activity against 60 different human tumor cell lines. Compound 3c showed high activity against HOP-92 (Non-Small Cell Lung Cancer), which was the most sensitive cell line, with GI 50 = 0.62 μM and LC 50 > 100 μM from the in vitro assays. In vitro antifungal activity of these compounds was also determined against 10 fungal strains. Compound

Ultrasonics Promoted Synthesis of 5-(Pyrazol-4-yl)-4,5-Dihydropyrazoles Derivatives

Abstract: A series of new 1,3-diaryl-5-(1-phenyl-3-methyl-5-chloropyrazol-4-yl)-4,5-dihydropyrazole derivatives have been synthesized under sonication conditions in ethanol or methanol/glacial acetic acid mixture (5/1 ratio) with two equivalents of hydrazines and seven kinds of chalcone-like heteroanalogues obtained from 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carbaldehyde. The structures were established on the basis of NMR, IR, MS and element analysis. This method provides several advantages over current reaction methodologies, including a simple work-up procedure, shorter reaction times (2–20 min) and good yields (65%–80%).

1-(2-Allylaryl)-1H-pyrroles as Building Blocks for Novel 4-Methyl-4,5-di­hydropyrrolo[1,2-a]quinoline Derivatives

Abstract: Novel substituted 4-methyl-4,5-dihydropyrrolo[1,2- a ]-quinolines were prepared by a simple two-step approach involving a Clauson-Kaas reaction of a substituted ortho -allylaniline followed by acid-catalyzed regioselective intramolecular Friedel–Crafts alkylation of the resulting 1-(2-allylaryl)-1 H -pyrroles. All the synthetized compounds were fully characterized by IR, 1 H and 13 C NMR spectroscopy, and mass spectrometry.

Three closely related thienyl-substituted 1,4-epoxynaphtho[1,2-b]azepines: hydrogen-bonded assembly in one, two and three dimensions.

Abstract: (2R,4S)-2-(3-Methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, C19H17NOS, (I), crystallizes with a single enantiomer in each crystal, whereas its geometrical isomer (2RS,4SR)-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-naphtho[1,2-b]azepine, (II), and (2RS,4SR)-2-(5-bromothiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxynaphtho[1,2-b]azepine, C18H14BrNOS, (III), both crystallize as racemic mixtures. A combination of one C-H...O hydrogen bond and two C-H...π(arene) hydrogen bonds links the molecules of (I) into a three-dimensional framework; the molecules of (II) are linked into a C(4)C(4)[R2(2)(7)] chain of rings by a combination of C-H...N and C-H...O hydrogen bonds; and in (III), where Z' = 2, a combination of four C-H...π(arene) hydrogen bonds and two C-H...π(thienyl) hydrogen bonds links the molecules into complex sheets. Comparisons are made with the assembly patterns in some aryl-substituted 1,4-epoxynaphtho[1,2-b]azepines.

Microwave-Assisted Synthesis of Pyrimido[4,5-b][1,6]naphthyridin-4(3H)-ones with Potential Antitumor Activity.

Abstract: A catalyst-free, microwave-assisted synthesis of various pyrimidonaphthyridinone derivatives is developed.

A chain of π-stacked molecules in 4-(2-chlorophenyl)pyrrolo[1,2-a]quinoxaline and a hydrogen-bonded sheet in (4RS)-4-(1,3-1,3-benzodioxol-6-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline.

Abstract: In the mol­ecule of 4-(2-chloro­phenyl)­pyrrolo­[1,2-a]­quinoxa­line, C17H11ClN2, (I), the bond lengths are consistent with electron delocalization in the two outer rings of the fused tricyclic system, with a localized double bond in the central ring. The mol­ecules of (I) are linked into chains by a π–π stacking inter­action. In (4RS)-4-(1,3-benzo­dioxol-6-yl)-4,5-di­­hydro­pyrrolo­[1,2-a]­quinoxaline, C18H14N2O2, (II), the central ring of the fused tricyclic system adopts a conformation inter­mediate between screw-boat and half-chair forms. A combination of N—H⋯O and C—H⋯π(arene) hydrogen bonds links the mol­ecules of (II) into a sheet. Comparisons are made with related compounds.

A hydrogen-bonded tetramer in (2RS,4SR)-7-bromo-2-(2-methylphenyl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol and a three-dimensional hydrogen-bonded framework in (2RS,4SR)-2-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol.

Abstract: (2RS,4SR)-7-Bromo-2-(2-methylphenyl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol, C21H20BrNO, (I), and (2RS,4SR)-2-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-naphtho[1,2-b]azepin-4-ol, C19H19NOS, (II), both crystallize with Z' = 2 in the space groups P2(1)/c and Cc, respectively; compound (II) crystallizes as a nonmerohedral twin, with twin fractions 0.183 (2) and 0.817 (2). The molecules of (I) are linked by O-H···O and O-H···N hydrogen bonds to form a cyclic centrosymmetric R4(4)(16) tetramer. The molecules of (II) are linked by O-H···O hydrogen bonds to form a C2(2)(4) chain and these chains are weakly linked by a single C-H···π(thienyl) interaction to form a three-dimensional array. Comparisons are made with some related compounds.

3,3'-[(1RS,3SR)-2-oxocyclohexane-1,3-diyl]bis[(3RS,3'SR)-3-hydroxyindolin-2-one] dihydrate: organic layers of R2(2)(8), R2(2)(16) and R6(6)(40) rings linked by tetrameric water aggregates.

Abstract: The organic component of the title compound, C22H20N2O5·2H2O, exhibits approximate but noncrystallographic mirror symmetry. The molecules of the organic component are linked by a combination of one O-H...O hydrogen bond and two N-H···O hydrogen bonds to form sheets containing R2(2)(8), R2(2)(16) and R6(6)(40) rings. These sheets are linked into a continuous three-dimensional framework structure by cyclic centrosymmetric R4(2)(8) water tetramers. Comparisons are made with some simpler analogues.

(E)-2-(1,3-benzothiazol-2-yl)-3-(4-fluorophenyl)acrylonitrile: a chain of π-stacked hydrogen-bonded rings.

Abstract: The title compound, C16H9FN2S, crystallizes as a nonmerohedral twin with twin rotation about the reciprocal-lattice vector [10\overline{1}]*. The mol­ecules are nearly planar and the dihedral angle between the planes of the two aryl rings is only 4.4 (2)°. The mol­ecules are linked by pairs of C—H⋯N hydrogen bonds to form cyclic centrosymmetric R22(18) dimers, which are linked into chains by an aromatic π–π stacking inter­action. Com­parisons are made with some related 3-aryl-2-thienylacrylo­nitriles.

Four related esters: two 4-(aroylhydrazinyl)-3-nitrobenzoates and two 3-aryl-1,2,4-benzotriazine-6-carboxylates.

Abstract: The molecules of both methyl 4-[2-(4-chlorobenzoyl)hydrazinyl]-3-nitrobenzoate, C15H12ClN3O5, (I), and methyl 4-[2-(2-fluorobenzoyl)hydrazinyl]-3-nitrobenzoate, C15H12FN3O5, (II), contain an intramolecular N-H···O hydrogen bond, and both show electronic polarization in the nitrated aryl ring. In both compounds, molecules are linked by a combination of N-H···O and C-H···O hydrogen bonds to form sheets, which are built from R4(3)(18) rings in (I) and from R4(4)(28) rings in (II). In each of methyl 3-phenyl-1,2,4-benzotriazine-6-carboxylate, C15H11N3O2, (III), and methyl 3-(4-methylphenyl)-1,2,4-benzotriazine-6-carboxylate, C16H13N3O2, (IV), the benzotriazine unit shows naphthalene-type delocalization. There are no hydrogen bonds in the structures of compounds (III) and (IV), but in both compounds, the molecules are linked into chains by π-π stacking interactions involving the benzotriazine units. The mechanism of chain formation is the same in both (III) and (IV), and the different orientations of the two chains can be related to the approximate relationship between the unit-cell metrics for (III) and (IV).

Stereoselective Synthesis of Novel 2‐Alkenyl‐2,3,4,5‐tetrahydro‐1,4‐epoxy‐1‐benzazepines and 2‐Alkenyl‐2,3,4,5‐tetrahydro‐1H‐1‐benzazepin‐4‐ols.

Abstract: New series of polyfunctionalized 2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepines and 2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols substituted at C2 with 2-methylprop-1-enyl, (E)-styryl, and (E)-pent-1-enyl were synthesized starting from the corresponding N-alkenyl-substituted [prenyl, trans-cinnamyl, (E)-hex-2-enyl] 2-allylanilines by a three-step sequence consisting of selective oxidation of aromatic secondary amines, intramolecular nitrone–olefin 1,3-dipolar cycloaddition, and reductive cleavage The intramolecular 1,3-dipolar cycloaddition is stereoselective favoring the exo-cycloadducts (ratio exo/endo 2–3:1) The stereochemistry was determined by exhaustive NMR analysis and X-ray diffraction

(E)-3-tert-butyl-4-(4-chlorobenzyl)-N-(4-chlorobenzylidene)-1-phenyl-1H-pyrazol-5-amine: sheets built from π-stacked hydrogen-bonded dimers.

Abstract: The title compound, C27H25Cl2N3, is an unexpected but high-yield product from the microwave-mediated reaction between 3-tert-butyl-N-4-chloro­benzyl-1-phenyl-1H-pyrazol-5-amine and 4-chloro­benzaldehyde. Inversion-related pairs of mol­ecules are linked by C—H⋯π(arene) hydrogen bonds to form cyclic centrosymmetric dimers, and dimers of this type are linked into sheets by two independent π–π stacking inter­actions.

Hydrogen-bonded bilayers in 7-benzyl-3-tert-butyl-1-phenyl-4,5,6,7-tetrahydro-1H-spiro[pyrazolo[3,4-b]pyridine-5,2'-indan]-1',3'-dione.

Abstract: In the title compound, C31H29N3O2, the reduced pyridine ring adopts a conformation inter­mediate between the envelope and half-chair forms. The aryl rings of the benzyl and phenyl substituents are nearly parallel and overlap, indicative of an intra­molecular π–π stacking inter­action. A combination of two C—H⋯O hydrogen bonds and one C—H⋯N hydrogen bond links the mol­ecules into a bilayer having tert-butyl groups on both faces.

Hydrogen-bonded dimers in 3-amino-4-anilino-1H-isochromen-1-one and a hydrogen-bonded sheet in 3-amino-4-[methyl(phenyl)amino]-1H-isochromen-1-one.

Abstract: The mol­ecules of 3-amino-4-anilino-1H-isochromen-1-one, C15H12N2O2, (I), and 3-amino-4-[methyl(phenyl)amino]-1H-isochromen-1-one, C16H14N2O2, (II), adopt very similar conformations, with the substituted amino group PhNR, where R = H in (I) and R = Me in (II), almost orthogonal to the adjacent heterocyclic ring. The mol­ecules of (I) are linked into cyclic centrosymmetric dimers by pairs of N—H⋯O hydrogen bonds, while those of (II) are linked into complex sheets by a combination of one three-centre N—H⋯(O)2 hydrogen bond, one two-centre C—H⋯O hydrogen bond and two C—H⋯π(arene) hydrogen bonds.

(Z)-5-[4-(dimethylamino)benzylidene]-2-(piperidin-1-yl)-1,3-thiazolidin-4(5H)-one.

Abstract: The mol­ecules of the title compound, C17H21N3OS, are characterized by a wide C—C—C angle at the methine C atom linking the aryl and thia­zolidine rings, associated with a short repulsive intra­molecular S⋯H contact between atoms in these two rings. A single piperidine–arene C—H⋯π hydrogen bond links pairs of mol­ecules into centrosymmetric dimers.

Two methyl 3-(1H-pyrazol-4-yl)octahydropyrrolo[3,4-c]pyrrole-1-carboxylates form different hydrogen-bonded sheets.

Abstract: In the molecules of both methyl (1RS,3SR,3aRS,6aSR)-1-methyl-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-4,6-dioxo-5-phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate, C₂₅H₂₄N₄O₄, (I), and methyl (1RS,3SR,3aRS,6aSR)-5-(4-chlorophenyl)-1-methyl-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate, C₂₅H₂₃ClN₄O₄, (II), the two rings of the pyrrolopyrrole fragment are both nonplanar, with conformations close to half-chair forms. The overall conformations of the molecules of (I) and (II) are very similar, apart from the orientation of the ester function. The molecules of (I) are linked into sheets by a combination of an N-H∙∙∙π(pyrrole) hydrogen bond and three independent C-H∙∙∙O hydrogen bonds. The molecules of (II) are also linked into sheets, which are generated by a combination of an N-H∙∙∙N hydrogen bond and two independent C-H∙∙∙O hydrogen bonds, weakly augmented by a C-H∙∙∙π(arene) hydrogen bond.

Six closely related 4,6‐disubstituted 2‐amino‐5‐formylpyrimidines: different ring conformations, polarized electronic structures, and hydrogen‐bonded assembly in zero, one, two and three dimensions

Abstract: In each of ethyl N-{2-amino-5-formyl-6-[meth­yl(phen­yl)amino]­pyrimidin-4-yl}glycinate, C16H19N5O3, (I), N-{2-amino-5-formyl-6-[meth­yl(phen­yl)amino]­pyrimidin-4-yl}glycin­amide, C14H16N6O2, (II), and ethyl 3-amino-N-{2-amino-5-formyl-6-[meth­yl(phen­yl)amino]­pyrimidin-4-yl}propionate, C17H21N5O3, (III), the pyrimidine ring is effectively planar, but in each of methyl N-{2-amino-6-[benz­yl(meth­yl)amino]-5-formyl­pyrimidin-4-yl}glycinate, C16H19N5O3, (IV), ethyl 3-amino-N-{2-amino-6-[benz­yl(meth­yl)amino]-5-formylpyrimidin-4-yl}propionate, C18H23N5O3, (V), and ethyl 3-amino-N-[2-amino-5-formyl-6-(piperidin-4-yl)pyrimidin-4-yl]propionate, C15H23N5O3, (VI), the pyrimidine ring is folded into a boat conformation. The bond lengths in each of (I)–(VI) provide evidence for significant polarization of the electronic structure. The mol­ecules of (I) are linked by paired N—H⋯N hydrogen bonds to form isolated dimeric aggregates, and those of (III) are linked by a combination of N—H⋯N and N—H⋯O hydrogen bonds into a chain of edge-fused rings. In the structure of (IV), mol­ecules are linked into sheets by means of two hydrogen bonds, both of N—H⋯O type, in the structure of (V) by three hydrogen bonds, two of N—H⋯N type and one of C—H⋯O type, and in the structure of (VI) by four hydrogen bonds, all of N—H⋯O type. Mol­ecules of (II) are linked into a three-dimensional framework structure by a combination of three N—H⋯O hydrogen bonds and one C—H⋯O hydrogen bond.

Synthesis of Novel Pyrimido[4,5‐b]quinolin‐4‐ones with Potential Antitumor Activity.

Abstract: The novel heterocycles (III) and (V) as well as their corresponding chloranil oxidation products (not shown) are evaluated against a panel of cancer cell lines.

Solvent‐Free Microwave‐Assisted Synthesis of Novel 4‐Hetarylpyrazolo[1,5‐a][1,3,5]triazines.

Abstract: A series of novel 4-hetaryl substituted pyrazolo[1,5-a][1,3,5]triazines were synthesized by microwave assisted reaction betweenO,S-diethyl hetaroylimidothiocarbonates and 5-amino-3-aryl-1H-pyrazoles under solvent-free conditions. This procedure led to the formation of mixtures of two new pyrazolotriazine derivatives in a 1:4 ratio, which were separated by column chromatography being their corresponding structures unambiguously established by spectroscopic and analytical techniques. Comparison of the reactions mediated by microwave irradiation and by conventional heating in solution of DMF showed that both procedures afforded the same mixtures of products, but thefirst approach required shorter reaction times and gave higher yields than the second one.

Dibenzylammonium hydrogen maleate and a redetermination at 120 K of bis(dibenzylamino)methane.

Abstract: In di­benzyl­ammonium hydrogen maleate [or di­benzyl­am­monium (2Z)-3-carb­oxy­prop-2-enoate], C14H16N+·C4H3O4−, (I), the anion contains a fairly short and nearly linear O—H⋯O hydrogen bond, with an O⋯·O distance of 2.4603 (16) A, but with the H atom clearly offset from the mid-point of the O⋯O vector. The counter-ions in (I) are linked by two N—H⋯O hydrogen bonds to form C22(6) chains and these chains are weakly linked into sheets by a C—H⋯O hydrogen bond. Bis(di­benzyl­amino)­methane, C29H30N2, (II), crystallizes with two independent mol­ecules lying across twofold rotation axes in the space group C2/c, and the mol­ecules are conformationally chiral; there are no direction-specific inter­molecular inter­actions in the crystal structure of (II).

Hydrogen-bonded sheet structures in methyl 4-(4-chloroanilino)-3-nitrobenzoate and methyl 1-benzyl-2-(4-chlorophenyl)-1H-benzimidazole-5-carboxylate.

Abstract: In methyl 4-(4-chloro­anilino)-3-nitro­benzoate, C14H11ClN2O4, (I), there is an intra­molecular N—H⋯O hydrogen bond and the intra­molecular distances provide evidence for electronic polarization of the o-quinonoid type. The mol­ecules are linked into sheets built from N—H⋯O, C—H⋯O and C—H⋯π(arene) hydrogen bonds, together with an aromatic π–π stacking inter­action. The mol­ecules of methyl 1-benzyl-2-(4-chloro­phenyl)-1H-benzimidazole-5-carboxyl­ate, C22H17ClN2O2, (II), are also linked into sheets, this time by a combination of C—H⋯π(arene) hydrogen bonds and aromatic π–π stacking inter­actions.

Three Practical Approaches for the Synthesis of Novel 4,7‐Dihetarylpyrazolo[1,5‐a][1,3,5]triazines.

Abstract: Best results are achieved by reaction of S,S-diethyl thiocarbonates (I) with aminopyrazoles (II) under neat conditions and microwave irradiation.

5,5'-Methylenebis[6-amino-3-methyl-2-methylsulfanylpyrimidin-4(3H)-one]: an unusual molecular geometry within a hydrogen-bonded molecular ribbon.

Abstract: The mol­ecules of the title compound, C13H18N6O2S2, lie across twofold rotation axes in the space group C2/c. Although the pyrimidine ring is effectively planar, the bridging methyl­ene C atom is displaced from the plane of the pyrimidine ring by 0.213 (2) A, while the C—C—C angle at the bridging C atom is 120.3 (2)°. The mol­ecule contains two symmetry-related N—H⋯O hydrogen bonds, generating S(8) motifs, and inter­moecular N—H⋯O hydrogen bonds link the mol­ecules into a ribbon of edge-fused rings.