Inhibition of Ehrlich ascites cancer, hypoxia-inducible factor-1 alpha, and the kinase insert domain-containing receptor/fms-like tyrosine kinase-binding domains of vascular endothelial growth factor by Thiazole Acetamide Derivatives.

BACKGROUND: Tumor cells that have the ability to express vascular endothelial growth factor (VEGF) are more competent to growth and metastasize by the adequate amount of blood and oxygen supply by the blood vessels to the growing mass of cells. Hypoxic tumors are known for its aggressiveness and resistance to the treatment. Targeting VEGF and hypoxia-inducible factor-1 alpha (HIF-1α) is an attractive strategy to interrupt the multiple pathways crucial for tumor growth. In the present study, two thiazole acetamide derivative's anticancer property, anti VEGF and HIF-1α inhibitory property were investigated. METHODOLOGY: Two thiazole acetamide compounds were synthesized, TA1 and TA2 and its anticancer property was studied in Erlich's ascites cancer cells. To evaluate the anticancer property the assays such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, DNA diffusion assay for apoptosis, and lactate dehydrogenase leakage assay were carried out. The cell culture media was used to assess the secreted VEGF level. Molecular docking studies were performed to analyze the binding efficiency of the study compounds to the kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase (FLT)-binding domains of VEGF protein. HIF-1α inhibitory study was performed by flow cytometry analysis using HUVEC cell line. RESULTS: The study compounds inhibited HIF-1α and VEGF secretion, these data shown positive prop up for the anticancer property of the derivatives. The docking studies showed moderate binding of study compounds to KDR and FLT-binding domains of VEGF protein. CONCLUSION: These results conclude the anticancer and anti-angiogenic property of the synthesized thiazole-acetamide derivatives.

Infrared spectrum, NBO, HOMO-LUMO, MEP and molecular docking studies (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-1-one.

FT-IR spectrum of (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-1-one was recorded and analyzed. The vibrational wavenumbers were computed using HF and DFT quantum chemical calculations. The data obtained from wavenumber calculations are used to assign IR bands. Potential energy distribution was done using GAR2PED software. The geometrical parameters of the title compound are in agreement with the XRD results. NBO analysis, HOMO-LUMO, first and second hyperpolarizability and molecular electrostatic potential results are also reported. The possible electrophile attacking sites of the title molecule is identified using MEP surface plot study. Molecular docking results predicted the anti-leishmanic activity for the compound.

FT-IR, molecular structure, first order hyperpolarizability, NBO analysis, HOMO and LUMO and MEP analysis of 1-(10H-phenothiazin-2-yl)ethanone by HF and density functional methods.

FT-IR spectrum of 1-(10H-phenothiazin-2-yl)ethanone was recorded and analyzed. The equilibrium geometry, bonding features and harmonic vibrational wavenumbers were investigated with the help of HF and DFT methods. The normal modes are assigned with the help of potential energy distribution analysis. The observed vibrational wavenumbers were compared with the calculated results. The geometrical parameters of the title compound obtained from XRD studies are in agreement with the calculated (DFT) values. The first hyperpolarizability value is also reported. Natural bond orbital analysis confirms the presence of intra-molecular charge transfer and hydrogen bonding interaction. The HOMO-LUMO gap explains the charge transfer interaction taking place within the molecule. The N-H stretching frequency is red shifted in the IR spectrum with a strong intensity from the computed frequency, which indicates weakening of the N-H bond resulting in proton transfer to the neighboring units. From the MEP analysis it is evident that the negative charge covers the carbonyl and benzene and the positive region is over the NH group.

FT-IR, molecular structure, first order hyperpolarizability, MEP, HOMO and LUMO analysis and NBO analysis of 4-[(3-acetylphenyl)amino]-2-methylidene-4-oxobutanoic acid.

4-[(3-Acetylphenyl)amino]-2-methylidene-4-oxobutanoic acid is synthesized and the structure of the compound was confirmed by IR, (1)H NMR and single crystal X-ray diffraction studies. FT-IR spectrum of 4-[(3-acetylphenyl)amino]-2-methylidene-4-oxobutanoic acid was recorded and analyzed. The crystal structure is also described. The vibrational wavenumbers were computed using HF and DFT methods are assigned with the help of potential energy distribution analysis. The NH stretching frequency is red shifted in the IR spectrum with a strong intensity from the computed frequency, which indicates the weakening of the NH bond resulting in proton transfer to the neighboring oxygen atom. The first hyperpolarizability and infrared intensities are also reported. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. Molecular electrostatic potential map was performed by the DFT method. The geometrical parameters of the title compound obtained from XRD studies are in agreement with the calculated (DFT) values.

Synthesis, structural and vibrational investigation on 2-phenyl-N-(pyrazin-2-yl)acetamide combining XRD diffraction, FT-IR and NMR spectroscopies with DFT calculations.

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 2-phenyl-N-(pyrazin-2-yl)acetamide have been investigated experimentally and theoretically using Gaussian09 software package. The title compound was optimized by using the HF/6-31G(6D,7F) and B3LYP/6-31G(6D,7F) calculations. The geometrical parameters are in agreement with the XRD data. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. Gauge-including atomic orbital (1)H-NMR chemical shifts calculations were carried out and compared with experimental data. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. Molecular electrostatic potential was performed by the DFT method. First hyperpolarizability is calculated in order to find its role in non linear optics. From the XRD data, in the crystal, molecules are held together by strong C-H⋯O and N-H⋯O intermolecular interactions.

(2E)-3-(6-methoxynaphthalen-2-yl)-1-(pyridin-3-yl)prop-2-en-1-one and its cyclocondensation product with guanidine, (4RS)-2-amino-4-(6-methoxynaphthalen-2-yl)-6-(pyridin-3-yl)-3,4-dihydropyrimidine monohydrate: two types of hydrogen-bonded sheet.

The structures of a chalcone and of its cyclocondensation product with guanidine are reported. In (2E)-3-(6-methoxynaphthalen-2-yl)-1-(pyridin-3-yl)prop-2-en-1-one, C19H15NO2, (I), the planes of the pyridine and naphthalene units make dihedral angles with that of the central spacer unit of 23.61 (13) and 23.57 (15)°, respectively, and a dihedral angle of 47.24 (9)° with each other. The molecules of (I) are linked into sheets by a combination of C-H···O and C-H···π(arene) hydrogen bonds. In the cyclocondensation product (4RS)-2-amino-4-(6-methoxynaphthalen-2-yl)-6-(pyridin-3-yl)-3,4-dihydropyrimidine monohydrate, C20H18N4O·H2O, (II), the dihydropyrimidine ring adopts a conformation best described as a shallow boat. The molecular components are linked by two N-H···O hydrogen bonds, two O-H···N hydrogen bonds and one N-H···N hydrogen bond to form complex sheets, with the methoxynaphthalene interdigitated between inversion-related pairs of sheets.

Halogenated C,N-diarylacetamides: molecular conformations and supramolecular assembly.

The structures of four halogenated N,2-diarylacetamides are reported and compared with a range of analogues. N-(4-Chloro-3-methylphenyl)-2-phenylacetamide, C(15)H(14)ClNO, (I), and N-(4-bromo-3-methylphenyl)-2-phenylacetamide, C(15)H(14)BrNO, (II), are isostructural in the space group P-1. The molecules of (I) and (II) are linked into chains of rings by a combination of N-H...O and C-H...π(arene) hydrogen bonds. The molecules of N-(4-chloro-3-methylphenyl)-2-(2,4-dichlorophenyl)acetamide, C(15)H(12)Cl(3)NO, (III), and N-(4-bromo-3-methylphenyl)-2-(2-chlorophenyl)acetamide, C(15)H(13)BrClNO, (IV), are linked into simple C(4) chains by N-H...O hydrogen bonds, but significant C-H...π(arene) interactions are absent. The N-aryl groups in compounds (III) and (IV) adopt a different orientation, by ca 180°, from that of the corresponding groups in compounds (I) and (II), but otherwise the conformations of (I)-(IV) are very similar. Comparisons are drawn between compounds (I) and (IV) and a range of analogues of the type R(1)CH(2)CONHR(2), where R(2) represents a halogenated aryl ring and R(1) represents either another halogenated aryl ring or a naphthalen-1-yl unit.

4-[(4-Acetyl-phen-yl)amino]-2-methyl-idene-4-oxo-butanoic acid.

In the title compound, C13H13NO4, the N-C(=O) bond length of 1.354 (2) Šis indicative of amide-type resonance. The dihedral angle between the mean planes of the benzene ring and oxo-amine group is 36.4 (3)°, while the mean plane of the 2-methyl-idene group is inclined by 84.2 (01)° from that of the oxo-amine group. In the crystal, classical O-H⋯O hydrogen bonds formed by the carb-oxy-lic acid groups and weak N-H⋯O weak inter-actions formed by the amide groups and supported by weak C-H⋯O inter-actions between the 2-methyl-idene, phenyl and acetyl groups with the carb-oxy-lic acid, oxo-amine and acetyl O atoms, together link the mol-ecules into dimeric chains along [010]. The O-H⋯O hydrogen bonds form R 2 (2)(8) graph-set motifs.

4-[(4-Bromo-phenyl)amino]-2-methyl-idene-4-oxo-butanoic acid.

In the title compound, C11H10BrNO3, two independent mol-ecules (A and B) crystallize in the asymmetric unit. The dihedral angles between the mean planes of the 4-bromo-phenyl ring and amide group are 24.8 (7) in mol-ecule A and 77.1 (6)° in mol-ecule B. The mean plane of the methyl-idene group is further inclined by 75.6 (4) in mol-ecule A and 72.5 (6)° in mol-ecule B from that of the amide group. In the crystal, N-H⋯O hydrogen bonds formed by amide groups and O-H⋯O hydrogen bonds formed by carb-oxy-lic acid groups are observed and supported additionally by weak C-H⋯O inter-actions between the methyl-idene and amide groups. Together, these link the mol-ecules into chains of dimers along [110] and form R 2 (2)(8) graph-set motifs.

2-(2-Methyl-phen-yl)-N-(1,3-thia-zol-2-yl)acetamide.

In the title compound, C12H12N2OS, the dihedral angle between the benzene and thia-zole rings is 83.5 (7)°. The acetamide group is almost coplanar with the thia-zole ring, being twisted from it by 4.2 (9)°. In the crystal, pairs of N-H⋯N hydrogen bonds link mol-ecules into inversion dimers, generating R 2 (2)[8] loops; the dimers are stacked along [001].

2-(4-Bromo-phen-yl)-N-(pyrazin-2-yl)acetamide.

In the title compound, C12H10BrN3O, the dihedral angle between the mean planes of the 4-bromo-phenyl and pyrazin-2-yl rings is 54.6 (3)°. An intra-molecular C-H⋯O hydrogen bond generates an S(6) graph-set motif. In the crystal, weak N-H⋯N hydrogen bonds link the mol-ecules into chains along [100]. The chains are linked via C-H⋯N and C-H⋯O hydrogen bonds, forming two-dimensional networks lying parallel to the ab plane.

2-(3,4-Dichloro-phen-yl)-N-(1,3-thia-zol-2-yl)acetamide.

In the title compound, C11H8Cl2N2OS, the mean plane of the dichloro-phenyl ring is twisted by 61.8 (1)° from that of the thia-zole ring. In the crystal, mol-ecules are linked via pairs of N-H⋯N hydrogen bonds with an R 2 (2)(8) graph-set motif, forming inversion dimers which stack along the a-axis direction.

2-(2,4-Di-chloro-phen-yl)-N-(1,3-thia-zol-2-yl)acetamide.

In the title compound, C11H8Cl2N2OS, the mean plane of the di-chloro-phenyl ring is twisted by 72.4 (1)° from that of the thia-zole ring. In the crystal, mol-ecules are linked via pairs of N-H⋯N hydrogen bonds with an R 2 (2)(8) graph-set motif and weak C-H⋯O inter-actions, forming inversion dimers which stack along the c-axis direction.

2-(2,6-Dichloro-phen-yl)-N-(1,3-thia-zol-2-yl)acetamide.

In the title compound, C11H8Cl2N2OS, the mean plane of the dichloro-phenyl ring is twisted by 79.7 (7)° from that of the thia-zole ring. In the crystal, molecules are linked via pairs of N-H⋯N hydrogen bonds, forming inversion dimers which stack along the a-axis direction.

A second monoclinic polymorph of 4-[(E)-(4-benzyl-oxybenzyl-idene)amino]-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one.

In the title compound, C25H23N3O2, the central benzene ring makes dihedral angles of 77.14 (8) and 87.7 (2)° with the terminal benzene rings and an angle of 1.9 (1)° with the pyrazolone ring. The benzene ring and the N atom of the pyrazole ring bearing the phenyl substituent are disordered over two sets of sites with an occupancy ratio of 0.71 (2):0.29 (2). The N atoms of the pyrazole ring have a pyramidal environment, the sums of the valence angles around them being 354.6 (3) and 352.0 (6)/349.5 (15)°. In the crystal, mol-ecules are packed into layers parallel to the ac plane. The other monoclinic polymorphic form was reported recently [Dutkiewicz et al. (2012 ▶). Acta Cryst. E68, o1324].

4-(4-Iodo-anilino)-2-methyl-ene-4-oxo-butanoic acid.

In the title compound, C11H10INO3, an addition product of itaconic acid anhydride and 4-iodo-aniline, the least-squares planes defined by the atoms of the aromatic moiety and the non-H atoms of the carb-oxy-lic acid group enclose an angle of 74.82 (11)°. In the crystal, classical O-H⋯O hydrogen bonds formed by carb-oxy-lic groups, as well as N-H⋯O hydrogen bonds formed by amide groups, are present along with C-H⋯O contacts. Together, these connect the mol-ecules into dimeric chains along the b-axis direction.

2-(3,4-Dichloro-phen-yl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide.

In the title compound, C19H17Cl2N3O2, there are three mol-ecules (A, B and C) in the asymmetric unit and each differs in the conformation adopted. As a result of steric repulsion, the amide group is rotated with respect to both the dichloro-phenyl and 2,3-dihydro-1H-pyrazol-4-yl rings, making dihedral angles of 44.5 (2) and 56.2 (2)°, respectively in A, 51.1 (2) and 54.1 (2)° in B, and 53.8 (2) and 54.6 (2)° in C. The dihedral angles between the dichloro-phenyl and 2,3-dihydro-1H-pyrazol-4-yl rings are 54.8 (2), 76.2 (2) and 77.5 (2)° in mol-ecules A, B and C, respectively, while the 2,3-dihydro-1H-pyrazol-4-yl and phenyl rings make dihedral angles of 45.3 (2), 51.2 (2) and 42.8 (2)°, respectively. In the crystal, two of the mol-ecules are linked through N-H⋯O hydrogen bonding to an adjoining mol-ecule, forming dimers of the R2(2)(10) type, while the third mol-ecule forms such dimers with itself. C-H⋯O inter-actions link the dimers.

N-(1,3-Benzo-thia-zol-2-yl)acetamide.

The title compound, C9H8N2OS, crystallizes with two mol-ecules (A and B) in the asymmetric unit. The dihedral angles between the mean planes of the 1,3-benzo-thia-zol-2-yl ring system and the acetamide group are 2.7 (4) (mol-ecule A) and 7.2 (2) Š(mol-ecule B). In the crystal, pairs of N-H⋯N hydrogen bonds link the A and B mol-ecules into dimers, generating R 2 (2)(8) loops. The dimers stack along [100].

4-(3-Fluoro-4-methyl-anilino)-2-methyl-idene-4-oxo-butanoic acid.

The title compound, C12H12FNO3, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. The dihedral angle between the mean planes of the 3-fluoro-4-methyl-phenyl ring and the oxo-amine group is 25.7 (7)° in mol-ecule A and 71.3 (7)° in mol-ecule B, while the mean plane of the 2-methyl-idene-4-oxo-butanoic acid group is twisted by 76.2 (1)° from that of the oxo-amine group in mol-ecule A and by 76.2 (4)° in mol-ecule B. In the crystal, N-H⋯O and O-H⋯O hydrogen bonds [the latter forming an R 2 (2)(8) graph-set motif] link the mol-ecules into a two-dimensional network parallel to the ac plane.

N-(2-Bromo-phen-yl)-2-(naphthalen-1-yl)acetamide.

In the title compound, C(18)H(14)BrNO, the naphthalene ring system [maximum deviation = 0.015 (3) Å] forms a dihedral angle of 67.70 (10)° with the benzene ring. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds into C(4) chains propagating in [100]. A C-H⋯O inter-action reinforces the chain connectivity, generating an R(2) (1)(6) loop.