Synthesis, crystal structure determination, biological screening and docking studies of N1-substituted derivatives of 2,3-dihydroquinazolin-4(1H)-one as inhibitors of cholinesterases.

Pursuing the strategy of developing potent AChE inhibitors, we attempted to carry out the N1-substitution of 2,3-dihydroquinazolin-4(1H)-one core. A set of 32 N-alkylated/benzylated quinazoline derivatives were synthesized, characterized and evaluated for their inhibition against cholinesterases. N-alkylation of the series of the compounds reported previously (N-unsubstituted) resulted in improved activity. All the compounds showed inhibition of both enzymes in the micromolar to submicromolar range. Structure activity relationship (SAR) of the 32 derivatives showed that N-benzylated compounds possess good activity than N-alkylated compounds. N-benzylated compounds 2ad and 2af were found very active with their IC50 values toward AChE in submicromolar range (0.8µM and 0.6µM respectively). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. Computational predictions of ADMET studies reveal that all the compounds have good pharmacokinetic properties with no AMES toxicity and carcinogenicity. Moreover, all the compounds are predicted to be absorbed in human intestine and also have the ability to cross blood brain barrier. Overall, the synthesized compounds have established a structural foundation for the design of new inhibitors of cholinesterase.

Synthesis, biological evaluation and docking studies of 2,3-dihydroquinazolin-4(1H)-one derivatives as inhibitors of cholinesterases.

In search of potent inhibitors of cholinesterases, we have synthesized and evaluate a number of 2,3-dihydroquinazolin-4(1H)-one derivatives. The synthetic approach provided an efficient synthesis of the target molecules with excellent yield. All the tested compounds showed activity against both the enzymes in micromolar range. In many case, the inhibition of both enzymes are higher than or comparable to the standard drug galatamine. With the selectivity index of 2.3 for AChE, compound 5f can be considered as a potential lead compound with a feature of dual AChE/BChE inhibition with IC50=1.6±0.10µM (AChE) and 3.7±0.18µM (BChE). Binding modes of the synthesized compounds were explored by using GOLD (Genetic Optimization for Ligand Docking) suit v5.4.1. The computed binding modes of these compounds in the active site of AChE and BChE provide an insight into the mechanism of inhibition of these two enzyme.

Portulaca oleracea L. as a Prospective Candidate Inhibitor of Hepatitis C Virus NS3 Serine Protease.

Hepatitis C virus (HCV) infection is a worldwide health problem affecting about 300 million individuals. HCV causes chronic liver disease, liver cirrhosis, hepatocellular carcinoma, and death. Many side effects are associated with the current treatment options. Natural products that can be used as anti-HCV drugs are thus of considerable potential significance. NS3 serine protease (NS3-SP) is a target for the screening of antiviral activity against HCV. The present work explores plants with anti-HCV potential, isolating possible lead compounds. Ten plants, used for medicinal purposes against different infections in rural areas of Pakistan, were collected. The cellular toxicity effects of methanolic extracts of the plants on the viability of Huh-7 cells were studied through the Trypan blue dye exclusion method. Following this, the anti-HCV potential of phytoextracts was assessed by infecting liver cells with HCV-3a-infected serum inoculum. Only the methanolic extract of Portulaca oleracea L. (PO) exhibited more than 70% inhibition. Four fractions were obtained through bioassay-guided extraction of PO. Subsequent inhibition of all organic extract fractions against NS3 serine protease was checked to track the specific target in the virus. The results showed that the PO methanolic crude and ethyl acetate extract specifically abridged the HCV NS3 protease expression in a dose-dependent fashion. Hence, PO extract and its constituents either alone or with interferon could offer a future option to treat chronic HCV.

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

In the title mol-ecule, C(9)H(6)Cl(2)N(2)S, the mean planes of the benzene and thia-zole rings make a dihedral angle of 54.18 (8)°. In the crystal, mol-ecules are joined into dimers with an R(2) (2)(8) ring motif by pairs of N-H⋯N hydrogen bonds. These dimers are linked by C-H⋯Cl inter-actions into layers parallel to (011). The thia-zole rings form columns along the c-axis direction, with a centroid-centroid separation of 3.8581 (9) Å, indicating π-π inter-actions. An intra-molecular C-H⋯S contact also occurs.

4-Bromo-2-{(E)-[(3,4-dimethyl-phen-yl)imino]-meth-yl}phenol.

In the title compound, C(15)H(14)BrNO, the dihedral angle between the aromatic rings is 4.10 (11)° and the mol-ecule is close to planar (r.m.s. deviation for the non-H atoms = 0.053 Å). An intra-molecular O-H⋯N hydrogen bond closes an S(6) ring. In the crystal, very weak C-H⋯π inter-actions are observed.

N-(2,4,6-Trimethyl-phen-yl)-1,3-thia-zol-2-amine.

In the title compound, C(12)H(14)N(2)S, the dihedral angle between the 1,3,5-trimethyl-benzene and 1,3-thia-zol-2-amine groups is 73.15 (4)°. In the crystal, inversion dimers linked by pairs of N-H⋯N hydrogen bonds generate R(2) (2)(8) loops.

5-[(E)-(2-Fluoro-benzyl-idene)amino]-2-hy-droxy-benzoic acid.

In the title compound, C(14)H(10)FNO(3), the dihedral angle between the two benzene rings is 32.66 (14)°. An S(6) ring motif is formed due to an intra-molecular O-H⋯O hydrogen bond between the hy-droxy and carbonyl groups. In the crystal, mol-ecules are consolidated into dimers with R(2) (2)(8) ring motifs by pairs of O-H⋯O hydrogen bonds.

N-[(E)-3,4-Dimeth-oxy-benzyl-idene]-2,3-dimethyl-aniline.

In the title compound, C(17)H(19)NO(2), the aromatic rings are oriented at a dihedral angle of 59.27 (12)°. In the crystal, inversion dimers linked by pairs of weak C-H⋯O inter-actions generate R(2) (2)(12) loops.

(E)-1-(4-Chloro-benzyl-idene)-2-phenyl-hydrazine.

The asymmetric unit of the title compound, C(13)H(11)ClN(2), contains two geometrically distinct mol-ecules; one mol-ecule is close to planar [dihedral angle between the aromatic rings = 2.44 (18)°] and the other is twisted about the linking hydrazide group [dihedral angle = 14.08 (19)°]. In the crystal, the N-H groups do not form hydrogen bonds and the mol-ecules are linked by weak C-H⋯π inter-actions.

Methyl 2-[2-(2,6-dichloro-4-nitro-anilino)-3,5-dinitro-phen-yl]acetate.

In the title compound, C(15)H(10)Cl(2)N(4)O(8), the methyl-acetate and dichloro-anilinic groups are oriented at dihedral angles of 57.73 (8) and 62.44 (4)°, respectively to the dinitro-sustituted benzene ring. S(5) and S(7) rings are formed due to intra-molecular N-H⋯Cl and N-H⋯O hydrogen bonds, respectively. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into C(8) chains along the a axis. Further C-H⋯O and N-H⋯O hydrogen bonds link these chains in pairs, forming a polymeric network.

cyclo-Tetrakis(µ(2)-3-sulfidopropyl-κC,S:S)tetrakis[chloridocobalt(III)].

In the centrosymmetric title compound, [Co(4)Cl(4)(C(3)H(6)S)](4)], the two independent Co(III) ions are each coordinated in a distorted tetra-hedral geometry by one C, one Cl and two S atoms. The mol-ecules are stabilized by C-H⋯Cl hydrogen bonds. In the crystal, inter-molecular C-H⋯Cl and C-H⋯S hydrogen bonds with R(2) (2)(8), R(4) (2)(8) and R(2) (2)(6) ring motifs generate a polymeric network.

5-[(E)-(2,6-Dichloro-benzyl-idene)amino]-2-hy-droxy-benzoic acid.

There are two geometrically different mol-ecules in the asymmetric unit of the title compound, C(14)H(9)Cl(2)NO(3). The 5-amino-2-hy-droxy-benzoic acid units [r.m.s. deviations of 0.0323 and 0.0414 Å] and 2,6-dichloro-benzaldehyde groups [r.m.s. deviations of 0.0285 and 0.0226 Å] are roughly planar and oriented at dihedral angles of 11.69 (13) and 83.12 (6)° in the two mol-ecules. An intra-molecular O-H⋯O hydrogen bond completes an S(6) ring motif in each mol-ecule. The two mol-ecules form dimers with each other through inter-molecular O-H⋯N and C-H⋯O hydrogen bonds, completing an R(2) (2)(8) ring motif. The dimers are inter-linked via inter-molecular O-H⋯N and C-H⋯O hydrogen bonds, forming polymeric sheets.

Bis(2-carboxy-anilinium) sulfate monohydrate.

In the title hydrated mol-ecular salt, 2C(7)H(8)NO(2) (+)·SO(4) (2-)·H(2)O, each cation in the asymmetric unit is stabilized by an intra-molecular N-H⋯O hydrogen bond. The O atoms of the sulfate ion are disordered over two sets of sites with an occupancy ratio of 0.541 (13):0.459 (13), which possibly optimizes the acceptance of N-H⋯O hydrogen bonds from the cations. The crystal structure also features aromatic π-π stacking [centroid-centroid separation = 3.842 (2) Å] and a C-H⋯π inter-action.

2-Hy-droxy-5-{[(E)-4-meth-oxy-benzyl-idene]aza-nium-yl}benzoate.

In the title zwitterion, C(15)H(13)NO(4), obtained from the condensation of 5-amino-salicylic acid and 4-meth-oxy-benz-alde-hyde, the 4-hydoxyanilinic group of the 5-amino-salicylic acid moiety and the 4-meth-oxy-benzaldehyde moiety are twisted with respect to one another, making a dihedral angle of 10.37 (7)°. The carboxyl-ate group makes a dihedral angle of 5.7 (2)° with the parent 4-hydoxyanilinic group. An intra-molecular O-H⋯O hydrogen bond forms an S(6) ring motif. In the crystal, inter-molecular C-H⋯O and N-H⋯O hydrogen bonds with R(2) (1)(7) ring motifs link the mol-ecules into infinite chains extending along the c axis. The occurence of slipped π-π stacking between symmetry-related aromatic rings reinforces the packing.

N-[(E)-2,4-Dichloro-benzyl-idene]-4-methyl-aniline.

In the title compound, C(14)H(11)Cl(2)N, the dihedral angle between the 4-methyl-anilinic and 2,4-dichloro-benzaldehyde moieties is 7.37 (8)°. In the crystal, C-H⋯π inter-actions between the terminal methyl group and a symmetry-related ring of the anilinic group help to establish the packing.

2-{[(E)-1,3-Benzodioxol-5-yl]methyl-idene-amino}-benzoic acid.

In the title compound, C(15)H(11)NO(4), the dihedral angle between the aromatic rings is 23.8 (2)° and an intra-molecular O-H⋯N hydrogen bond generates an S(6) ring. In the crystal, C-H⋯O hydrogen bonds link the mol-ecules into a three-dimensional network.

2,3-Dimethyl-N-[(E)-4-nitro-benzyl-idene]aniline.

In the title compound, C(15)H(14)N(2)O(2), the aromatic rings are oriented at a dihedral angle of 24.52 (5)°. The dihedral angle between the nitro group and its parent benzene ring is 9.22 (16)°. In the crystal, mol-ecules inter-act through aromatic π-π stacking inter-actions [centroid-centroid separations = 3.8158 (14) and 3.9139 (14) Å].

N-[(E)-4-Chloro-benzyl-idene]-2,3-dimethyl-aniline.

In the title compound, C(15)H(14)ClN, the conformation about the C=N bond is trans and the dihedral angle between the aromatic rings is 51.48 (4)°. In the crystal, some very weak C-H⋯π inter-actions may help to establish the packing.

(E)-2,3-Dimethyl-N-(2-nitro-benzyl-idene)aniline.

In the title compound, C(15)H(14)N(2)O(2), the 2,3-dimethyl-anilinic and benzaldehyde groups are planar, with r.m.s. deviations of 0.0101 and 0.0241 Å, respectively, and are oriented at a dihedral angle of 11.69 (3)°. The nitro group is inclined to the benzaldehyde group by 34.02 (9)°. The mol-ecule adopts an E configuration about the C=N bond. In the crystal, mol-ecules are linked via C-H⋯O inter-actions, giving rise to the formation of zigzag polymeric chains extending along [010]. They are also linked by C-H⋯π, and π-π inter-actions [centroid-centroid distance of 3.7185 (11) Å] involving symmetry-related aniline and benzene rings. The H atoms of the ortho-methyl group are disordered over two sites with a refined occupancy ratio of 0.69 (2):0.31 (2).

(E)-1-(4-Meth-oxy-benzyl-idene)-2-phenyl-hydrazine.

In the title compound, C(14)H(14)N(2)O, the dihedral angle between the aromatic rings is 9.30 (6)°. In the crystal, mol-ecules are linked by C-H⋯π and N-H⋯π inter-actions.