Benzamide Group Research Articles

Microwave-Assisted Facile Synthesis, Anticancer Evaluation and Docking Study of N-((5-(Substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl) Benzamide Derivatives.

In the present work, 12 novel Schiff’s bases containing a thiadiazole scaffold and benzamide groups coupled through appropriate pharmacophore were synthesized. These moieties are associated with important biological properties. A facile, solvent-free synthesis of a series of novel 7(a–l) N-((5-(substituted methylene amino)-1,3,4-thiadiazol-2-yl)methyl) benzamide was carried out under microwave irradiation. Structures of the synthesized compounds were confirmed by IR, NMR, mass spectral study and elemental analysis. All the synthesized hybrids were evaluated for their in vitro anticancer activity against a panel of four human cancer cell lines, viz. SK-MEL-2 (melanoma), HL-60 (leukemia), HeLa (cervical cancer), MCF-7 (breast cancer) and normal breast epithelial cell (MCF-10A) using 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. Most of the synthesized compounds exhibited promising anticancer activity, showed comparable GI50 values comparable to that of the standard drug Adriamycin. The compounds 7k, 7l, 7b, and 7a were found to be the most promising anticancer agents in this study. A molecular docking study was performed to predict the probable mechanism of action and computational study of the synthesized compounds 7(a–l) was performed to predict absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, by using QikProp v3.5 (Schrödinger LLC). The results showed the good oral drug-like behavior of the synthesized compounds 7(a–l).

Different intra- and inter-molecular hydrogen-bonding patterns in (3S,4aS,8aS)-2-[(2R,3S)-3-(2,5-X2-benzamido)-2-(2,5-X2-benzo-yloxy)-4-phenyl-butyl]-N-tert-butyldeca-hydro-iso-quinoline-3-carboxamides (X = H or Cl): compounds with moderate aspartyl protease inhibition activity.

The crystal structures of (3S,4aS,8aS)-2-[(2R,3S)-3-benzamido-2-benzo-yloxy-4-phenyl-but-yl]-N-tert-butyldeca-hydro-iso-quinoline-3-carboxamide, C38H47N3O4, (I), and (3S,4aS,8aS)-2-[(2R,3S)-3-(2,5-di-chloro-benzamido)-2-(2,5-di-chloro-benzo-yloxy)-4-phenyl-but-yl]-N-tert-butyldeca-hydro-iso-quinoline-3-carboxamide, C38H43Cl4N3O4, (II), are described. Despite their chemical similarity, they adopt different conformations in the solid state: (I) features a bifurcated intra-molecular N-H⋯(N,O) hydrogen bond from the tert-butylamide NH group to the piperidine N atom and the benzoate O atom, whereas (II) has an intra-molecular N-H⋯O link from the benzamide NH group to the tert-butyl-amide O atom. In the crystal of (I), mol-ecules are linked by C(4) amide N-H⋯O hydrogen bonds into chains propagating in the [010] direction, with both donor and acceptor parts of the benzamide group. In the extended structure of (II), C(11) N-H⋯O chains propagating in the [010] direction arise, with the donor being the tert-butylamide NH group and the acceptor being the O atom of the benzamide group.

Preparation of thermochromic polymer nanocomposite films from polymerizable organogels of oligothiophene-based organogelators

Thermochromic polymer nanocomposite films were prepared from polymerizable organogels. Organogelator 1 had a structure which 3,4,5-tris(ω-decenyl)benzamide groups were attached to a quarterthiophene core through amide bonds. Organogelator 2 had the same structure except that tris(ω-decenyl) groups were replaced by tris(n-decanyl) groups. The PMMA nanocomposite films were prepared by the photopolymerization of the organogels formed in methyl methacrylate (MMA). The film containing 1 (0.5 wt%) showed reversible thermochromism. The emission under 365 nm irradiation was changed to bright green from orange by heating up to 120 °C and returned to its initial orange by cooling. To the contrary, the PMMA composite film prepared from the organogel of 2 (0.5 wt%) did not show a reversible thermochromic property. Organogelator 1 with polymerizable terminal vinyl groups was covalently embedded in the PMMA matrix, but 2 was not. The reversible thermochromism was likely caused by the thermally reversible conformational change of quarterthiophene units in the polymer fibers.

Lithium ion conductivity of polymers containing N-phenyl-2,6-dimethoxybenzamide framework in their side chains: Possible role of bond rotation in polymer side chain substituents for efficient ion transport

A new carbon–carbon main chain polymer with N-phenyl-2,6-dimethoxybenzamide on its each main chain carbon atom is prepared by Pd-initiated polymerization of diazoacetate containing the benzamide group, and the Li ion conductivity of the polymer doped with lithium bis(trifluoromethylsulfonyl)imide is evaluated along with its vinyl polymer counterparts with the same benzamide substituent. Although the expected high ion conductivity at low temperatures derived from a unique ion transport mechanism based on the bond rotation in the benzamide moiety reported in a literature is not observed, it is revealed that the dense packing of the benzamide group along the polymer main chain results in the enhanced ion conductivity. In addition, investigation of the correlation between ion conductivity and glass transition temperature of these solid polymer electrolytes (SPEs) reveals that other ion transport mechanism would operate in the benzamide containing SPEs than that derived from segmental motion of polymer chains observed in PEO-based SPEs.

Selective non-zinc binding MMP-2 inhibitors: Novel benzamide Ilomastat analogs with anti-tumor metastasis

Novel Ilomastat analogs with substituted benzamide groups, instead of hydroxamic acid groups, were designed, synthesized and evaluated against MMP-2 and MMP-9. Among these analogs, the most potent compound 10a exhibited potent inhibitory activity against MMP-2 with IC50 value of 0.19nM, which is 5 times more potent than that of Ilomastat (IC50=0.94nM). Importantly, 10a exhibited more than 8300 fold selectivity for MMP-2 versus MMP-9 (IC50=1.58μM). Molecular docking studies showed that 10a bond to the catalytic active pocket of MMP-2 by a non-zinc-chelating mechanism which was different from that of Ilomastat. Furthermore, the invasion assay showed that 10a was effective in reducing HEY cells invasion at 84.6% in 50μM concentration. For 10a, the pharmacokinetic properties had been improved and especially the more desirable t1/2z was achieved compared with these of the lead compound Ilomastat.

Synthesis and properties of novel brominated chiral polyamides derived from 5-[4-(2-tetrabromophthalimidylpropanoylamino)benzoylamino]isophthalic acid and aromatic diamines

A novel aromatic chiral dicarboxylic acid, 5-[4-(2-tetrabromophthalimidylpropanoylamino)benzoylamino]isophthalic acid was synthesized in three steps in high yield and purity starting from tetrabromophthalic anhydride and l-alanine. A series of new soluble, thermally stable and optically active polyamides (PA)s having pendent tetrabromophthalimide, flexible asymmetrical and benzamide groups with flame retardancy properties have been successfully prepared using triphenyl phosphite/pyridine in the presence of calcium chloride and N-methyl-2-pyrrolidone (NMP). The resulting new polymers were obtained in good yields, inherent viscosities ranging between 0.36 and 0.63 dL g−1 and were characterized with FT-IR, 1H NMR, specific rotation and thermogravimetric analysis techniques. Bulky pendent groups of the polymer chains disturb interchain and intrachain interactions and make these polymers readily soluble in various solvents, such as NMP, N,N-dimethylacetamide, dimethyl sulfoxide, and N,N-dimethylformamide. The resulting PAs were thermally stable, with 10 % weight loss recorded at 432 and 478 °C in the nitrogen atmosphere. In addition, due to existence of chiral center and optical activity of these polymers, they have potential to be utilized as chiral stationary phase in chromatography technique for the separation of racemic mixtures.

Cinchona Alkaloid Catalyzed Sulfa-Michael Addition Reactions Leading to Enantiopure β-Functionalized Cysteines.

Sulfa-Michael additions to α,β-unsaturated N-acylated oxazolidin-2-ones and related α,β-unsaturated α-amino acid derivatives have been enantioselectively catalyzed by Cinchona alkaloids functionalized with a hydrogen bond donating group at the C6' position. The series of Cinchona alkaloids includes known C6' (thio)urea and sulfonamide derivatives and several novel species with a benzimidazole, squaramide or a benzamide group at the C6' position. The sulfonamides were especially suited as bifunctional organocatalysts as they gave the products in very good diastereoselectivity and high enantioselectivity. In particular, the C6' sulfonamides catalyzed the reaction with the α,β-unsaturated α-amino acid derivatives to afford the products in a diastereomeric ratio as good as 93:7, with the major isomer being formed in an ee of up to 99%. The products of the organocatalytic sulfa-Michael addition to α,β-unsaturated α-amino acid derivatives were subsequently converted in high yields to enantiopure β-functionalized cysteines suitable for native chemical ligation.

Synthesis of 5,6‐dihydro‐4H‐benzo[d]isoxazol‐7‐one and 5,6‐dihydro‐4H‐isoxazolo[5,4‐c]pyridin‐7‐one Derivatives as Potential Hsp90 Inhibitors

A novel class of 5,6-dihydro-4H-benzo[d]isoxazol-7-ones and 5,6-dihydro-4H-isoxazolo[5,4-c]pyridin-7-ones was designed, synthesized, and assayed to investigate the affinity toward Hsp90 protein. The synthetic route was based on a 1,3-dipolar cycloaddition of nitriloxides, generated insitu from suitable benzaldoximes, with 2-bromocyclohex-2-enones or 3-bromo-5,6-dihydro-1H-pyridin-2-ones. Whereas all the compounds bearing a benzamide group on the bicyclic scaffold were devoid of activity, the derivatives carrying a resorcinol-like fragment showed a remarkable inhibitory effect on Hsp90. Docking calculations were performed to investigate the orientation of the new compounds within the binding site of the enzyme.

Identification of MK-8133: An orexin-2 selective receptor antagonist with favorable development properties.

Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.

ChemInform Abstract: Asymmetric Synthesis of Tetrahydroquinolines Through a [3 + 2] Cycloaddition Controlled by Dienamine Catalysis.

A dienamine-mediated enantioselective 1,3-dipolar cycloaddition catalyzed by a chiral prolinol silyl ether catalyst has been developed. Removal of the benzamide group of the intermediates could furnish chiral C-1 substituted tetrahydroisoquinolines (see scheme) in high yields and excellent stereoselectivities.

Asymmetric synthesis of tetrahydroquinolines through a [3+2] cycloaddition controlled by dienamine catalysis.

A dienamine-mediated enantioselective 1,3-dipolar cycloaddition catalyzed by a chiral prolinol silyl ether catalyst has been developed. Removal of the benzamide group of the intermediates could furnish chiral C-1 substituted tetrahydroisoquinolines (see scheme) in high yields and excellent stereoselectivities.

Design and synthesis of novel quinazoline derivatives and their evaluation as PI3Ks inhibitors.

The aim of this work was to synthesize 4-acetamido-, 4-amino- and 4-oxo-6-substituted aminoquinazolines and to evaluate them as phosphoinositide 3-kinases (PI3Ks) inhibitors. The respective chemotype was designed based on combining the structural features of two previously reported scaffolds acting as potent PI3Kγ inhibitors, which are quinazoline derivatives and amino-heterocyclic derivatives. In vitro enzymatic assay at 10 µM against all the eight human PI3K isoforms showed that an unsubstituted benzamide group at position 6 and an acetyl group at N(4) gave the best inhibitory activity on PI3Kγ. Interestingly, compounds 5a and 5e showed a significant, inhibitory effect on Class II PI3K-C2γ. This is of high value since there are very few inhibitors for this isoform reported in the literature.

Divergence between Organometallic and Single-Electron-Transfer Mechanisms in Copper(II)-Mediated Aerobic C–H Oxidation

Copper(II)-mediated C-H oxidation is the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions are poorly understood. Here, we observe different products from Cu(II)-mediated oxidation of N-(8-quinolinyl)benzamide, depending on the reaction conditions. Under basic conditions, the benzamide group undergoes directed C-H methoxylation or chlorination. Under acidic conditions, the quinoline group undergoes nondirected chlorination. Experimental and computational mechanistic studies implicate an organometallic C-H activation/functionalization mechanism under the former conditions and a single-electron-transfer mechanism under the latter conditions. This rare observation of divergent, condition-dependent mechanisms for oxidation of a single substrate provides a valuable foundation for understanding Cu(II)-mediated C-H oxidation reactions.

3,3′-{[(Biphenyl-2,2′-diyl)bis(methylene)]bis(oxy)}bis[N-(4-chlorophenyl)benzamide

In the title compound, C40H30Cl2N2O4, the two benzene rings of the biphenyl unit are twisted with respect to each other, making a dihedral angle of 73.07 (4)°. The benzene rings of the benzamide groups form dihedral angles of 77.09 (5) and 55.48 (6)° with the central biphenyl moiety. In the crystal, mol­ecules are linked through N—H⋯O hydrogen bonds to form a fused R 2 2(38) ring motif which forms a supermolecular ribbon network extending along the [100] plane. In the two 4-chloro­phenyl rings, the five C atoms and their attached H atoms are disordered over two sets of sites, with site-occupancy factors of 0.657 (15):0.343 (15) and 0.509 (13):0.491 (13).

N-(4,4′-Dibromo-[1,1′-biphenyl]-2-yl)benzamide

In the title compound, C19H13Br2NO, the dihedral angle between the rings of the biphenyl group is 53.59 (14)°. The ring of the benzamide group is inclined to the phenyl rings of the biphenyl group by 23.87 (15) and 75.89 (15)°. There are no significant inter­molecular inter­actions in the crystal structure.

Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192

Histone deacetylase inhibitors (HDACIs) are in advanced clinical development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliphatic compounds with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clinical trials, such as the benzamide group compounds MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compound named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukaemic origin. When tested in culture against the acute myeloid leukaemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukaemia.

Effect of carboxylic acid on micelles of a neutral amphiphilic dendro-calix[4]arene

An amphiphilic calix[4]arene bearing branched 3,4,5-tris(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)benzamide groups at the upper rim was synthesized and could increase the solubility of naproxen and ibuprofen in water through hydrogen bonding and π-π stacking interactions. The interactions between amphiphilic calix[4]arene and carboxylic acids such as naproxen and ibuprofen could reverse the direction of the branched substituents and change the shape and size of calixarene micelles from solid to hollow or linear ones.

Synthesis and preliminary evaluation of a modified estradiol-core bearing a fused γ-lactone as non-estrogenic inhibitor of 17β-hydroxysteroid dehydrogenase type 1

A non-estrogenic inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) was designed based on a modified 3-hydroxy-estra-1,3,5(10)-triene core having an additional five-member lactone ring and a benzamide group. The inhibitor was synthesized, fully characterized and tested for its ability to inhibit the enzyme activity. Estrogenicity was also investigated and tested on estrogen-dependent T-47D cell line. Interestingly, this steroid derivative showed inhibitory potency towards 17β-HSD1 and did not present residual unwanted estrogenic activity.

Bis(2-{2-[2-(benzylcarbamoyl)phenoxy]acetamido}ethyl)ammonium nitrate ethanol disolvate

In the title compound, C36H40N5O6 +·NO3 −·2C2H5OH, the nitrate anion is disordered over the two orientations of equal occupancy while the solvent mol­ecule reveals large displacement parameters. The cation is formed by protonation of the N atom of a secondary amine in the middle of the flexible chain and the whole compound has crystallographically imposed C-2 symmetry with the crystallographic b axis. An O atom of the nitrate anion links the acidic H atoms of the cation via N—H⋯O hydrogen bonding. In addition, neighbouring cations are connected by inter­molecular N—H⋯O hydrogen bonds and π–π inter­actions between the benzamide groups of the cations [centroid–centroid distance = 4.000 (3) Å], forming a chain along [001]. The ethanol solvent mol­ecules are arranged on the side of the chain through O—H⋯O hydrogen bonds.

Amisulpride versus moclobemide in treatment of clozapine-induced hypersalivation

Objectives. Previous publications demonstrated substitute benzamides as effective agents in treatment of clozapine-induced sialorrhea (CIS). The aim of this study was to compare efficacy of amisulpride and moclobemide (both from the substitute benzamide group) in controlling, or at least minimizing, CIS. Methods. The study was designed as a 6-week, two-center, fixed-dose, comparison study of 400 mg/day of amisulpride versus 300 mg/day of moclobemide as an adjunctive treatment in 53 schizophrenia and schizoaffective disorder patients (diagnosed according to DSM-IV) suffering from CIS. The patients were treated with each medication during 2 weeks, followed by a washout period of 2 weeks. Primary outcome measures included the reduction in the five-point Nocturnal Hypersalivation Rating Scale (NHRS). Secondary outcomes included the Positive and Negative Syndrome Scale (PANSS), Manic State Assessment Scale, and Extrapyramidal Symptom Rating Scale (ESRS). Results. Both amisulpride and moclobemide were very effective in reducing CIS. Almost 74% of patients treated with amisulpride and 83% of patients treated with moclobemide showed some level of improvement on NHRS. Only in one patient treated with amisulpride, CIS worsened. Conclusions. Both medications were safe and effective as treatment of CIS. Although moclobemide exceeded amisulpride in antisalivation activity, treatment of CIS with amisulpride leads to improvement in psychotic symptoms.