Quinazoline Ring System Research Articles

Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.

Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.

ChemInform Abstract: Neosartoryadins A and B, Fumiquinazoline Alkaloids from a Mangrove‐Derived Fungus Neosartorya udagawae HDN13‐313.

AbstractIn addition to neosartoryadins A (Ia) and B (Ib), two new biogenetically related derivatives (IIa,b) are isolated.

Neosartoryadins A and B, Fumiquinazoline Alkaloids from a Mangrove-Derived Fungus Neosartorya udagawae HDN13-313.

Neosartoryadins A (1) and B (2), both with a unique 6/6/6/5 quinazoline ring system connected directly to a 6/5/5 imidazoindolone ring, together with three biogenetically related compounds 3-5, were isolated from the endophytic fungus Neosartorya udagawae HDN13-313. The absolute configurations of new compounds 1-4 were established. Compounds 1 and 2 displayed anti-influenza virus A (H1N1) activities with IC50 values of 66 and 58 μM, respectively (ribavirin as positive control, IC50 = 94 μM).

Synthesis of novel N-aryl-4-[6-(2-fluoropyridin-3-yl)quinazolin-2-yl]-piperazine-1-carboxamide or -carbothioamide derivatives and their antimicrobial activity

Quinazolines are heterocyclic compounds with an important place in the field of medicinal chemistry. The quinazoline ring system is present in the structure of approximately 150 naturally occurring pharmacologically active alkaloids, isolated from a number of families of the plant and animal kingdom, as well as various microorga- nisms. 1 Quinazoline derivatives possess diverse biological and therapeutic activities such as antibacterial, 2-4 antifun- gal, 5 anti-inflammatory, 6 anticancer, 2,7 antituberculosis, 8 A series of novel N-aryl-4-(6-(2-fluoropyridin-3-yl)quinazolin-2-yl)-piperazine-1-carboxamide or -carbothioamide derivatives was synthe- sized by cyclization of 5-bromo-2-fluorobenzaldehyde and guanidine carbonate in the presence of dimethylacetamide followed by treatment with isoamylnitrite and diiodomethane in the presence of copper iodide to afford 6-bromo-2-iodoquinazoline. The latter was treated with piperazine in the presence of triethylamine followed by (2-fluoropyridin-3-yl)boronic acid in the presence of Pd(PPh3)2Cl2 to afford 6-(2-fluoropyridin-3-yl)-2-(piperazin-1-yl)quinazoline which was further treated with various substituted arylisocyanates and arylisothio- cyanates to obtain the title compounds. The chemical structures of the synthesized compounds were confirmed by means of LC-MS, 1 H, 13 C NMR, IR, and mass spectra and elemental analysis. All the synthesized compounds were evaluated for their in vitro antibacterial activity against two Gram-positive and two Gram-negative bacterial species, as well as two different strains of antibiotic-resistant E. coli and for antifungal activity against two fungal strains. Some of the compounds have shown potential antimicrobial activity.

Crystal structure of 4-meth-oxy-quinazoline.

The title compound, C9H8N2O, is almost planar, with the C atom of the meth­oxy group deviating from the mean plane of the quinazoline ring system (r.m.s. deviation = 0.011 Å) by 0.068 (4) Å. In the crystal, mol­ecules form π–π stacks parallel to the b-axis direction [centroid–centroid separation = 3.5140 (18) Å], leading to a herringbone packing arrangement.

Synthesis and Antioxidant Properties of Novel Quinazoline Derivatives

Quinazoline derivatives have expressed a broad spectrum of biological activities, but there are few examples in literature on an antioxidant activity of different quinazolines. On the basis of literature by Chinese scientists on the effective antioxidant activity of Schiff bases containing 2-oxoquinoline and due to structural similarity of quinoline and quinazoline ring systems, the reactions of 3-aminoquinazolinone with a range of aromatic aldehydes and ethoxymethylene derivatives have been carried out and their radical scavenging activities have been studied.

Crystal structure of 4-methyl-sulfanyl-2-phenyl-quinazoline.

In the title compound, C15H12N2S, the methylthioquinazoline group is planar with the methyl C displaced by only 0.116 (3) Å from the plane of the quinazoline moiety. The dihedral angle between the phenyl ring and the quinazoline ring system is 13.95 (5)°. In the crystal, each molecule is linked by π–π stacking between to two adjacent inversion-related molecules. On one side, the inverted quinazoline groups interact with a centroid–centroid distance of 3.7105 (9) Å. On the other side, the quinazoline group interacts with the pyrimidine and phenyl rings of the second neighbour with centroid–centroid distances of 3.5287 (8) and 3.8601 (9) Å, respectively.

N-Benzyl-2-chloro-quinazolin-4-amine.

The asymmetric unit of the title compound, C15H12ClN3, contains two independent mol­ecules. The quinazoline ring system in each is essentially planar, with maximum deviations of 0.025 (16) and 0.0171 (16) Å. The dihedral angles between quinazoline ring systems and the phenyl rings are 88.25 (8) and 85.28 (16)° in the two independent mol­ecules. In the crystal, alternating independent mol­ecules are linked by N—H⋯N hydrogen bonds, forming chains along [001].

2-Ethyl-3-[(R)-2-phenyl-butanamido]-quinazolin-4(3H)-one monohydrate.

In the title compound, C20H21N3O2·H2O (EQR·H2O), the quinazoline ring system forms dihedral angles of 53.1 (1) and 85.6 (1)° with the phenyl ring and the amide link, respectively. In the crystal, O—H⋯O hydrogen bonds link two EQR and two water mol­ecules into a centrosymmetric R 4 4(18) ring motif. N—H⋯O hydrogen bonds further link these hydrogen-bonded fragments into columns extending in [010].

H3PW12O40 catalyzed synthesis of benzoxazine and quinazoline in aqueous media

A heteropolyacid efficiently catalyzed the cyclocondensation reaction of 2-aminobenzamide and salicylamide with aldehydes and ketones to afford good yields of benzoxazine and quinazoline ring systems in an aqueous medium. The method gives clean reactions, has simple workup procedure, and uses environment friendly conditions.

N-(4-Acetyl-3-methyl-1-phenyl-1H-pyrazol-5-yl)-N-methyl-2-(2-methyl-4-oxo-3,4-dihydroquinazolin-3-yl)benzamide.

In the title compound, C29H25N5O3, the dihedral angle between the benzene ring and the pendant quinazoline ring system (r.m.s. deviation = 0.036Å) is 87.60 (17)°. The equivalent angle between the pyrazole ring and the phenyl group is 70.0 (2)°. The dihedral angle between the benzene and pyrazole rings is 30.7 (2)° and overall, the mol­ecular conformation approximates to a Z shape. A short intra­molecular C—H⋯O contact occurs. In the crystal, the mol­ecules are linked by Cπ—H⋯O-type hydrogen bonds and aromatic π–π stacking inter­actions [centroid–centroid distance = 3.860 (3) Å], generating a three-dimensional network.

2-(1,3-Benzodioxol-5-yl)-3-phenylquinazolin-4(3H)-one

In the mol­ecule of the title compound, C21H14N2O3, the quinazoline ring system [maximum deviation = 0.076 (1) Å] makes dihedral angles of 40.57 (9) and 42.31 (11)°, respectively, with the phenyl and 1,3-benzodioxole rings. The dihedral angle between the phenyl ring and the 1,3-benzodioxole ring is 4.34 (10)°. In the crystal, C—H⋯O hydrogen bonds link the mol­ecules into infinite zigzag chains extending along [100].

Methyl 3-[(6-nitro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)sulfanyl]propanoate

In the title compound, C18H15N3O5S, the approximately planar quinazoline ring system [maximum deviation = 0.097 (3) Å] forms a dihedral angle of 76.53 (19)° with the phenyl ring. The terminal -C(=O)—O—C group is disordered over two sets of sites with a site-occupancy ratio of 0.811 (17):0.189 (17). In the crystal, mol­ecules are linked via weak C—H⋯O hydrogen bonds into sheets parallel to the ac plane.

7H-[1,2]Benzothiazolo[3,2-b]quinazoline 5,5-dioxide

In the title compound, C14H10N2O2S, the benzothia­zole and quinazoline ring systems are essentially planar with maximum deviations of 0.0127 (16) and 0.1588 (15) Å, respectively, and make a dihedral angleof 3.02 (5)°, which shows that the entire mol­ecule is almost planar. The O atoms deviate from the benzothia­zole ring system by 1.2231 (14) and −1.1989 (15) Å. The crystal packing features non–classical C—H⋯O hydrogen bonds and is further consolidated by π–π inter­actions [centroid–centroid distances = 3.7568 (8) and 3.8848 (9) Å].

1-{[(2,3-Dihydro-1H-inden-2-yl)-oxy]meth-yl}quinazoline-2,4(1H,3H)-dione.

In the title mol­ecule, C18H16N2O3, the five-membered ring has an envelope conformation, with the substituted C atom deviating by 0.342 (4) Å from the mean plane P calculated for the remainder of the non-H atoms of the 2,3-dihydro-1H-indene fragment. The mean planes of quinazoline-2,4(1H,3H)-dione fragment and P form a dihedral angle of 59.08 (4)°. In the crystal, pairs of N—H⋯O hydrogen bonds link mol­ecules into inversion dimers, and weak C—H⋯O hydrogen bonds and π–π inter­actions between the benzene rings of the quinazoline ring systems [centroid–centroid distance = 3.538 (3) Å] further consolidate the packing.

4-(4-Amino-2-fluorophenoxy)-7-methoxyquinazolin-6-ol methanol monosolvate

In the title compound, C15H12FN3O3·CH3OH, the dihedral angle between the quinazoline ring system and the benzene ring is 81.18 (9)°. In the crystal, mol­ecules are linked by N—H⋯O and O—H⋯N hydrogen bonds, generating [10-1] chains of alternating main mol­ecules and solvent mol­ecules. Weak C—H⋯O inter­actions are also observed.

3-Benzyl-6-methyl-2-sulfanylidene-2,3-di-hydroquinazolin-4(1H)-one.

In the title compound, C16H14N2OS, the quinazoline ring system is essentially planar, with a maximum deviation of 0.029 (3) Å. The dihedral angle between the quinazoline and benzene rings is 88.4 (2)°. In the crystal, adjacent mol­ecules are connected via pairs of N—H⋯S and C—H⋯O hydrogen bonds, which generate R 2 2(8) and R 2 2(10) graph-set motifs, respectively, resulting in a supra­molecular chain along the a axis.

3-(4-Bromophenyl)quinazolin-4(3H)-one

In the title compound, C14H9BrN2O, the quinazoline unit is essentially planar, with a mean deviation of 0.058 (2) Å from the least-squares plane defined by the ten constituent ring atoms. The dihedral angle between the mean plane of the quinazoline ring system and the 4-bromo­phenyl ring is 47.6 (1)°. In the crystal, mol­ecules are linked by inter­molecular C—H⋯N and C—H⋯O hydrogen bonds, forming infinite chains of alternating R 2 2(6) dimers and R 2 2(14) ring motifs.

3-(4-Chlorophenyl)quinazolin-4(3H)-one

In the title compound, C14H9ClN2O, the quinazoline unit is essentially planar, with a mean deviation from the least-squares plane defined by the ten constituent ring atoms of 0.027 (2) Å. The dihedral angle between the mean plane of the quinazoline ring system and the 4-chloro­phenyl ring is 44.63 (5)°. In the crystal, mol­ecules are linked by inter­molecular C—H⋯N and C—H⋯O hydrogen bonds, forming infinite chains of alternating R22(6) dimers and R22(14) ring motifs.

3-[(2-Chloro-6-methylquinolin-3-yl)methyl]quinazolin-4(3H)-one

In the title mol­ecule, C19H14ClN3O, the quinoline and quinazoline ring systems form a dihedral angle of 80.75 (4)°. In the crystal, the mol­ecules are linked by pairs of C—H⋯N hydrogen bonds into centrosymmetric dimers, generating R 2 2(6) ring motifs. The structure is further stabilized by C—H⋯π inter­actions and π–π stacking inter­actions [centroid–centroid distances = 3.7869 (8) and 3.8490 (8) Å].