Exploring Antimicrobial Features for New Imidazo[4,5-b]pyridine Derivatives Based on Experimental and Theoretical Study.

5-bromopyridine-2,3-diamine reacted with benzaldehyde to afford the corresponding 6-Bromo-2-phenyl-3H-imidazo[4,5-b]pyridine (1). The reaction of the latter compound (1) with a series of halogenated derivatives under conditions of phase transfer catalysis solid-liquid (CTP) allows the isolation of the expected regioisomers compounds (2-8). The alkylation reaction of (1) gives, each time, two regioisomers, N3 and N4; in the case of ethyl bromoactate, the reaction gives, at the same time, the three N1, N3 and N4 regioisomers. The structures of synthesized compounds were elucidated on the basis of different spectral data (1H NMR, 13C NMR), X-Ray diffraction and theoretical study using the DFT method, and confirmed for each compound. Hirshfeld surface analysis was used to determine the intermolecular interactions responsible for the stabilization of the molecule. Density functional theory was used to optimize the compounds, and the HOMO-LUMO energy gap was calculated, which was used to examine the inter/intra molecular charge transfer. The molecular electrostatic potential map was calculated to investigate the reactive sites that were present in the molecule. In order to determine the potential mode of interactions with DHFR active sites, the three N1, N3 and N4 regioisomers were further subjected to molecular docking study. The results confirmed that these analogs adopted numerous important interactions, with the amino acid of the enzyme being targeted. Thus, the most docking efficient molecules, 2 and 4, were tested in vitro for their antibacterial activity against Gram-positive bacteria (Bacillus cereus) and Gram-negative bacteria (Escherichia coli). Gram-positive bacteria were more sensitive to the action of these compounds compared to the Gram-negative, which were much more resistant.

New Pyrazole-Hydrazone Derivatives: X-ray Analysis, Molecular Structure Investigation via Density Functional Theory (DFT) and Their High In-Situ Catecholase Activity.

The development of low-cost catalytic systems that mimic the activity of tyrosinase enzymes (Catechol oxidase) is of great promise for future biochemistry technologic demands. Herein, we report the synthesis of new biomolecules systems based on hydrazone derivatives containing a pyrazole moiety (L1-L6) with superior catecholase activity. Crystal structures of L1 and L2 biomolecules were determined by X-ray single crystal diffraction (XRD). Optimized geometrical parameters were calculated by density functional theory (DFT) at B3LYP/6-31G (d, p) level and were found to be in good agreement with single crystal XRD data. Copper (II) complexes of the compounds (L1-L6), generated in-situ, were investigated for their catalytic activities towards the oxidation reaction of catechol to ortho-quinone with the atmospheric dioxygen, in an attempt to model the activity of the copper containing enzyme tyrosinase. The studies showed that the activities depend on four parameters: the nature of the ligand, the nature of counter anion, the nature of solvent and the concentration of ligand. The Cu(II)-ligands, given here, present the highest catalytic activity (72.920 µmol·L-1·min-1) among the catalysts recently reported in the existing literature.

1-(Prop-2-yn-yl)-1H-benzimidazol-2(3H)-one.

The benzimidazolone part of the title mol-ecule, C10H8N2O, is almost planar [r.m.s. deviation = 0.014 (1) Å] and the NCH2C CH group forms a dihedral angle of 67.95 (6)° with its best plane. In the crystal, mol-ecules form inversion dimers via pairs of N-H⋯O hydrogen bonds. C-H⋯O inter-actions connect the dimers, forming a two-dimensional polymeric network parallel to (100).

1-Allyl-5-nitro-1H-benzimidazol-2(3H)-one.

The benzimidazolone residue in the title mol-ecule, C10H9N3O3, is almost planar, with the largest deviation from the mean plane being 0.016 (2) Šfor the C atom linked to the nitro group. This plane is nearly perpendicular to the 1-allyl chain as indicated by the C-N-C-C torsion angle of 90.9 (3)°. The fused-ring system makes a dihedral angle of 5.6 (3)° with the nitro group, leading to a synperiplanar conformation. In the crystal, zigzag supra-molecular chains are formed along the a axis by N-H⋯O hydrogen bonds.

5-Nitro-1-(prop-2-yn-1-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one.

In the two independent mol-ecules of the title compound, C(10)H(7)N(3)O(3), the nitro substitutent is twisted slightly with respect to the benzodiazol fused-ring system [dihedral angles = 4.9 (3) and 8.5 (1)°]. The two independent mol-ecules are disposed about a pseudo inversion center and are held together by N-H⋯O hydrogen bonds. The supramolecular dimer is essentially planar [dihedral angle between the fused rings = 2.0 (1)°]. Adjacent dimers are linked by acetyl-ene-nitro C-H⋯O inter-actions, generating a ribbon motif along (110).

6-Bromo-3-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine.

The two fused five- and six-membered rings building the mol-ecule of the title compound, C(13)H(10)BrN(3), are approximately planar, the largest deviation from the mean plane being 0.004 (2) Å. The dihedral angle between the imidazo[4,5-b]pyridine mean plane and that of the phenyl ring is 41.84 (11)°. The structure is held together by slipped π-π stacking between symmetry-related mol-ecules, with an inter-planar distance of 3.583 (1) Šand a centroid-centroid vector of 3.670 (2) Å.

1-Benzyl-1H-benzimidazol-2(3H)-one.

The fused five- and six-membered rings in the title compound, C(14)H(12)N(2)O, are essentially planar, the largest deviation from the mean plane being 0.023 (2) Å. The dihedral angle between the benzimidazole mean plane and the phenyl ring is 68.50 (6)°. In the crystal, each mol-ecule is linked to its symmetry equivalent created by a crystallographic inversion center by pairs of N-H⋯O hydrogen bonds, forming inversion dimers.

5-Nitro-1-n-octyl-1H-benzimidazol-2(3H)-one.

The benzimidazolone part of the mol-ecule of the title compound, C(15)H(21)N(3)O(3), is almost planar (r.m.s. deviation = 0.007 Å) with its mean plane aligned at a dihedral angle of 10.4 (3)° with respect to the mean plane of the nitro substituent. In the crystal, two mol-ecules are disposed about a center of inversion, generating an N-H⋯O hydrogen-bonded cyclic dimer with R(2) (2)(8) graph-set motif.

1-n-Decyl-5-nitro-1H-benzimidazol-2(3H)-one.

The benzimidazolone part of the title mol-ecule, C(17)H(25)N(3)O(3), is almost planar (r.m.s. deviation = 0.016 Å) and its mean plane is aligned at 7.9 (4) ° with respect to the mean plane of the nitro substituent. In the crystal, two mol-ecules are disposed about a center of inversion, generating a N-H⋯O hydrogen-bonded cyclic dimer with a R(2) (2)(8) graph-set motif.

1-Nonyl-1H-benzimidazol-2(3H)-one.

The crystal structure of the title compound, C(16)H(24)N(2)O, is built up from two fused six- and five-membered rings linked to C(9)H(19) chains. The fused-ring system is essentially planar, the largest deviation from the mean plane being 0.009 (2) Å. The chain is nearly perpendicular to this plane [dihedral angle = 80.27 (17)°]. In the crystal, inter-molecular N-H⋯O hydrogen bonds form dimers with an R(2) (2)(8) graph-set motif. These dimers are further connected through C-H⋯O hydrogen bonds, building sheets parallel to (100).

1,3-Diallyl-5-chloro-1H-benzimidazol-2(3H)-one.

The benzimidazolone part of the title mol-ecule, C(13)H(13)ClN(2)O, is almost planar (r.m.s. deviation = 0.006 Å) and its mean plane is aligned at dihedral angles of 62.5 (1) and 78.0 (1)° with respect to the mean planes of the allyl substituents.

5-Nitro-1-nonyl-1H-benzimidazol-2(3H)-one.

In the title mol-ecule, C(16)H(23)N(3)O(3), the dihedral angle between the benzimidazole and nitro group planes is 5.34 (9)° and the dihedral angle between the benzimidazole and aliphatic chain mean planes is 73.23 (5)°. The C-C-C-C torsion angles (about 176°) of the nonyl group indicate an all-anti-periplanar conformation. In the crystal, adjacent mol-ecules are linked by pairs of N-H⋯O hydrogen bonds into inversion dimers. These mol-ecules are further connected through C-H⋯O inter-actions, building tapes parallel to (22).

1,3-Bis[2-(2-oxo-1,3-oxazolidin-3-yl)eth-yl]-1H-benzimidazol-2(3H)-one.

The mol-ecular structure of the title compound, C(17)H(20)N(4)O(5), contains a central fused-ring system, comprised of six- and five-membered rings. This unit is linked by C(2) chains to two 2-oxo-1,3-oxazolidine five-membered rings. The central fused-ring system is essentially planar, with a maximum deviation of 0.008 (1) Šfrom the mean plane. Both oxazolidine five-membered rings are also nearly planar, with maximum deviations of 0.090 (1) and 0.141 (1) Å.

3-[(1-Benzyl-1H-1,2,3-triazol-5-yl)meth-yl]-6-bromo-2-phenyl-3H-imidazo[4,5-b]pyridine.

There are two crystallographically independent mol-ecules in the asymmetric unit of the title compound, C(22)H(17)BrN(6). The dihedral angles between the imidazo[4,5-b]pyridine mean plane and the phenyl rings are 20.4 (2) and 24.0 (2)° in the two mol-ecules. The orientation of triazoles compared to the imidazo[4,5-b]pyridine system is almost the same in both mol-ecules, with dihedral angles of 64.2 (2) and 65.1 (2)°. However, the main difference between the two mol-ecules lies in the arrangement of the phenyl groups compared to imidazo[4,5-b]pyridine in each mol-ecule. Indeed, in the first mol-ecule the dihedral angle between the plane of the phenyl ring and that of the imidazo[4,5-b]pyridine system is 67.7 (2)°, while in the second mol-ecule the plane of the phenyl ring is almost perpendicular to that of the imidazo[4,5-b]pyridine system with a dihedral angle of 86.0 (2)°.

1,3-Bis(prop-2-yn-yl)-1H-1,3-benzimid-azol-2(3H)-one.

In the title compound, C(13)H(10)N(2)O, the fused-ring system is essentially planar, the largest deviation from the mean plane being 0.015 (1) Å. The two propynyl groups are nearly perpendicular to the benzimidazole plane, making dihedral angles of 85 (3) and 80 (2) °, and point in opposite directions. There are two short inter-molecular C-H⋯O contacts to the carbonyl O atom, one involving the acetyl-enic H atom and the other a H atom of the methyl-ene group.

3-[2-(6-Bromo-2-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)eth-yl]-1,3-oxazolidin-2-one.

In the title mol-ecule, C(17)H(15)BrN(4)O(2), the fused-ring system is essentially planar, the largest deviation from the mean plane being 0.015 (2) Å, and forms dihedral angles of 37.8 (2) and 35.5 (2)° with the phenyl and oxazolidine rings, respectively. The conformation adopted by the mol-ecule is stabilized by an intra-molecular π⋯π inter-action [centroid-centroid distance = 3.855(2) Å] between oxazolidine and phenyl rings. The crystal packing features inter-molecular C-H⋯N and C-H⋯O inter-actions.

1-Decyl-6-nitro-1H-benzimidazol-2(3H)-one.

The title mol-ecule, C(17)H(25)N(3)O(3), is built up from fused six- and five-membered rings linked to a -C(10)H(21) chain. The fused-ring system is essentially planar, the largest deviation from the mean plane being 0.009 (2) Å. The chain is roughly perpendic-ular to this plane, making a dihedral angle of 79.5 (2)°. In the crystal, N-H⋯O hydrogen bonds build infinite chains along [010]. There are channels in the structure containing disordered hexane. The contribution of this solvent to the scattering power was suppressed using the SQUEEZE option in PLATON [Spek (2009 ▶). Acta Cryst. D65, 148-155].

3-Benzyl-6-bromo-2-(2-fur-yl)-3H-imidazo[4,5-b]pyridine.

In the title mol-ecule, C(17)H(12)BrN(3)O, the imidazopyridine ring system is almost coplanar with the furan ring [dihedral angle = 2.0 (3)°]. The benzyl phenyl ring is oriented at dihedral angles of 85.2 (2) and 85.5 (1)°, respectively, with respect to the furan ring and the imidazopyridine ring system. In the crystal, mol-ecules are linked into chains propagating along the b axis by C-H⋯N hydrogen bonds. Adjacent chains are linked via short Br⋯Br contacts [3.493 (1) Å].

4-Allyl-6-bromo-2-phenyl-4H-imidazo[4,5-b]pyridine monohydrate.

In the mol-ecule of the title compound, C(15)H(12)BrN(3)·H(2)O, the phenyl ring is coplanar with the imidazopyridine ring system [dihedral angle = 0.4 (1)°]. The water mol-ecule is disordered over two positions with occupancies of 0.58 (1) and 0.42 (1), and it is linked to the main mol-ecule via an O-H⋯N hydrogen bond.

Synthesis, crystal structure at 219†K and Hirshfeld surface analyses of 1,4,6-tri-methyl-quinoxaline-2,3(1H,4H)-dione monohydrate.

The asymmetric unit of the title compound, C11H12N2O2·H2O, contains a mol-ecule of 1,4,6-trimethyl-1,4-di-hydro-quinoxaline-2,3-dione and a solvent water mol-ecule. Four atoms of the benzene ring are disordered over two sets of sites in a 0.706 (7):0.294 (7) ratio while the N-bound methyl groups are rotationally disordered with occupancy ratios of 0.78 (4):0.22 (4) and 0.76 (5):0.24 (5). In the crystal, mol-ecules are linked by O-H⋯O and C-H⋯O hydrogen bonds into layers lying parallel to (10). The Hirshfeld surface analysis indicates that the most important contributions to the packing arrangement are due to H⋯H (51.3%) and O⋯H/H⋯O (28.6%) inter-actions. The mol-ecular structure calculated by density functional theory is compared with the experimentally determined mol-ecular structure, and the HOMO-LUMO energy gap has been calculated.