Khusnutdin M. Shakhidoyatov

Discovery of diethyl 2,5-diaminothiophene-3,4-dicarboxylate derivatives as potent anticancer and antimicrobial agents and screening of anti-diabetic activity: synthesis and in vitro biological evaluation. Part 1.

Series of diethyl 2,5-diaminothiophene-3,4-dicarboxylate (DDTD) derivatives: azomethines of DDTD (2a-l) have been synthesized and screened for their anticancer, antimicrobial and anti-diabetic activities. The novel synthesized compounds were characterized by (1)H, (13)C NMR, MS and FT-IR analyses. All compounds were evaluated for their antiproliferative activity against three types of cancer cell line such as T47D and MCF-7 (human breast cancer), Hela (human cervical cancer) and Ishikawa (human endometrial cancer) lines. The results showed that most compounds exhibited significant antiproliferative activity against breast cancer cells. The majority of azomethines DDTD influenced strongly against breast cancer cells T47D and MCF-7, among them compounds 2b (2.3 μM), 2c (12.1 μM), 2e (13.2 μM), 2i (14.9 μM), 2j (16.0 μM), 2k (7.1 μM), 2l (8.6 μM) manifest potent anticancer activity against cancer cell T47D than Doxorubicin (DOX, 15.5 μM). Compound 2j has shown potent activity on all three types of cancer cells concurrently and IC50 values were considerably low in comparison with positive control DOX. In addition, all compounds were tested for antimicrobial activity against Staphylococcus aureus ATCC 6538 (Gram positive bacteria), Escherichia coli ATCC 11229 (Gram negative bacteria) and Candida albicans ATCC 10231 (Fungi) strains and 2j which contains in the ring nitrofurfural fragment, showed the highest effect on the three species of microbial pathogens simultaneously. Some compounds induced enzymatic inhibition in a concentration-dependent manner on PTP-1B inhibitor.

2-Methyl-4-oxo-6,7,8,9-tetrahydro­thieno[2′,3′:4,5]pyrimidino­[1,2-a]pyridine-3-carboxylic acid

There are two independent molecules in the asymmetric unit of the title compound, C12H12N2O3S. With the exception of the methylene groups, a mean plane fitted through all non-H atoms of each molecule has an r.m.s. deviation of 0.035 Å for one molecule and 0.120 Å for the second. In one of the independent molecules, the methylene groups was refined using a disorder model with an occupancy ratio of 0.53:0.47 (14). Each molecule features an intramolecular O—H⋯O hydrogen bond, which generates an S(7) ring.

Synthesis, Tautomeric States and Crystal Structure of (Z)-Ethyl 2-Cyano-2-(3H-Quinazoline-4-ylidene) Acetate and (Z)-Ethyl 2-Cyano-2-(2-Methyl-3H-Quinazoline-4-ylidene) Acetate

The new compounds (Z)-ethyl 2-cyano-2-(3H- and 2-methyl-3H-quinazoline- 4-ylidene) acetate (1 and 2, respectively) were synthesized by multi-step reactions. The structures in a solution have been determined by 1H-NMR spectroscopy and in the crystal form by X-ray analysis. Molecule 1 crystallized in a primitive monoclinic cell, space group Р21/c. The cell dimensions are a=7.970(6) Å, b=7.061(2) Å, c=20.537(7) Å, β=97.69(5)°, V=1145.3(10) Å3. Molecule 2 crystallized in a triclinic cell, space group P1, the cell dimensions are a=8.196(5) Å, b=8.997(6) Å, c=9.435(4) Å, α=74.22(4)°, β=89.75(4)°, γ=74.07(5)°, V=641.9(6) Å3. In both compounds the presence of intramolecular NH---O=C hydrogen bonding between the nitrogen atom in position 3 of the quinazoline ring and a carbonyl group of the ethyl cyanoacetate residue was proven by quantum-chemical, 1H-NMR and X-ray methods.

Poly[di-μ-chlorido-μ-(1,2,3,9-tetra-hydro-pyrrolo-[2,1-b]quinazolin-9-one-κN:O)-mercury(II)].

In the crystal structure of the title two-dimensional network, [HgCl2(C11H10N2O)]n, the asymmetric unit consists of HgCl2 dumbbells and one molecule of the quinazoline unit. Pseudo-octahedrally coordinated HgII cations are chloride-bridged via a crystallographic inversion centre leading to different Hg—Cl bonds (short and long) and linked by other Cl atoms via translation along the a axis. The quinazoline ligands connect the Hg—Cl—Hg—Cl chains by N and O atoms along the b axis, forming the two-dimensional network structure. The crystal structure is stabilized by weak non-classical C—H⋯Cl hydrogen bonds and aromatic π–π stacking interactions [centroid–centroid distances = 3.942 (4) and 3.621 (4) Å].

(4-Nitrophenyl)(1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-3-yl)methanol monohydrate.

In the crystal structure of the title compound, C18H17N3O3·H2O, the molecules are linked by O—H⋯O and O—H⋯N hydrogen bonds, resulting in a chain along the a axis. The crystal structure is stabilized by weak intermolecular C—H⋯π (ring) hydrogen bonds and aromatic π⋯π stacking interactions [centroid–centroid distance = 3.902 (1) Å] between the pyrimidino rings of the quinazoline system. The tricyclic quinazoline fragment is almost planar (rms deviation = 0.0139 Å) with the two methylene C atoms of the pyrrolo ring deviating by 0.148 (2) and −0.081 (3) Å from the plane through the other atoms. The 4-nitrophenyl ring makes a dihedral angle of 12.55 (7)° with the tricyclic ring system.

(E)-3-[4-(Dimethyl­amino)­benzyl­idene]-2,3-di­hydro-1H,9H-pyrrolo­[2,1-b]quinazolin-9-one

The title compound, C20H19N3O, was obtained by condensation of 2,3-dihydro-1H,9H-pyrrolo[2,1-b]quinazolin-9-one (alkaloid deoxyvasicinone, isolated from Peganum Harmala) with 4-(dimethylamino)benzaldehyde in the presence of sodium methoxide. The 2,3-dihydro-1H,9H-pyrrolo[2,1-b]quinazolin-9-one part of the molecule is roughly planar (r.m.s. deviation = 0.0178 Å) and is essentially coplanar with the benzilidene ring (r.m.s. deviation = 0.0080 Å), forming a dihedral angle of 5.0 (1)°. The crystal structure is stabilized by two aromatic π–π stacking interactions observed between the benzene rings of neighboring molecules [centroid–centroid distance = 3.7555 (19) Å.

9-Furfuryl­idene-2,3-dimethyl-6,7,8,9-tetrahydro-4H-­thieno[2′,3′:4,5]pyrimidino[1,2-a]pyridin-4-one

The title compound, C17H16N2O2S, was obtained by condensation of 2,3-dimethylthieno[2′,3′:4,5]pyrimidino[1,2-a]pyridin-4-one with furfural in the presence of sodium hydroxide. One of the methylene groups of the tetrahydropyrido ring is disordered over two positions in a 0.87 (1):0.13 (1) ratio. The thieno[2,3-d]pyrimidin-4-one unit and the furan ring are both planar (r.m.s. deviation = 0.535 Å), and coplanar with each other, forming a dihedral angle of 5.4 (1)°. Four weak intermolecular hydrogen bonds (C—H⋯O and C—H⋯N) are observed in the structure, which join molecules into a network parallel to (101).

2,3-Tri-methyl-ene-7,8-di-hydro-pyrrolo-[1,2-a]thieno[2,3-d]pyrimidin-4(6H)-one.

The title molecule, C12H12N2OS, is planar, with an r.m.s. deviation of 0.04 Å. In the crystal, the N atom adjacent to the carbonyl group is sp 2-hybridized. The crystal structure is stabilized by π–π stacking interactions observed between thiophene and pyrimidinone rings of c-glide-related molecules [centroid–centroid distance = 3.9554 (13) Å] and by C—H⋯π interactions, forming an infinite chain along the c-axis direction.

3-Methyl-2-(3,3,3-tri­chloro-2-hy­droxy­prop­yl)quinazolin-4(3H)-one

The title molecule, C12H11Cl3N2O2, contains planar quinazolin-4(3H)-one (r.m.s. deviation = 0.0257 Å) and propyl fragments, forming a dihedral angle of 10.4 (2)°. An intramolecular O—H⋯N hydorgen bond occurs. In the crystal, O—H⋯O hydrogen bonds link the molecules into an infinite chain running parallel to the b axis.

3,5,6-Trimethyl­thieno[2,3-d]pyrimidin-4(3H)-one

In the title compound, C9H10N2OS, the thienopyrimidine ring system is almost planar [greatest deviation from the mean plane = 0.0318 (13) Å for the S atom]. The crystal packing features C—H⋯O hydrogen bonds and π–π stacking interactions between inversion-related pairs of molecules with a centroid–centroid distance of 3.530 (3) Å.