Band 24, Heft 1

Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), are involved in multiple human tumors. Therefore, RTKs are attractive targets for various antitumor strategies. Two classes of tyrosine kinase antagonists were applied in the clinic for monoclonal antibodies and small-molecule tyrosine kinase inhibitors. A well-studied class of small-molecule inhibitors is represented by 4-anilinoquinazolines, exemplified by gefitinib and erlotinib as mono-targeted EGFR inhibitors, which were approved for the treatment of non-small-cell lung cancer. Mono-target drugs may result in drug resistance and the innovation of multi-target drugs has grown up to be an active field. Recent advances in research on antitumor bioactivity of 4-anilino(or phenoxy)quinazoline derivatives with multiple targets are reviewed in this paper. At the same time, synthetic methods of quinazolines were introduced from the point of building the ring skeleton and based on the types of reaction.

A convenient four-step approach to the synthesis of ( S )-4-alkyl-2-(pyrrolidin-2-yl)oxazoles starting from l -Boc-proline inspired by naturally occurring oxazole-containing peptidomimetics is described. The key step is the cyclization of 1-Boc- N -(1-oxoalkan-2-yl)pyrrolidine-2-carboxamides – aldehyde intermediates which demonstrate low to moderate stability – under Appel reaction conditions. This method furnishes the target compounds with more than 98% ee and in a 17–51% overall yield and has been used at up to a 45-g scale.

The title compounds were synthesized by a three-component reaction of 4-hydroxycoumarin, aromatic amines and α,β-epoxy ketones, catalyzed by ZnO-ZnAl 2 O 4 nanocomposite.

An efficient method for the synthesis of the title compounds by reactions of divinyl ketones with thiourea is described. This protocol has the advantages of high yields, mild reaction conditions and simple work-up procedure.

3-Carboxy-1-sulfopyridin-1-ium chloride ([CPySO 3 H] + Cl − ) was synthesized and evaluated as a recoverable catalyst for one-pot synthesis of hexahydroquinoline-3-carboxamide derivatives by a four-component reaction of an arylaldehyde, dimedone, acetoacetanilide and ammonium acetate. The [CPySO 3 H] + Cl − catalyst was characterized by infrared (IR), 1 H nuclear magnetic resonance (NMR), 13 C NMR, elemental analysis and thermal gravimetric analysis (TGA).

The reaction of 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4 H -chromene-3-carbonitriles with excess aliphatic carboxylic acids in the presence of phosphoryl chloride (POCl 3 ) afforded new 2-alkyl-5-aryl-8,8-dimethyl-8,9-dihydro-3 H -chromeno[2,3- d ]pyrimidine-4,6(5 H , 7H )-diones in high yields. The suggested mechanism involves a tandem intramolecular Pinner/Dimroth rearrangement. The synthesized compounds were characterized by infrared (IR), proton nuclear magnetic resonance ( 1 H NMR), carbon-13 nuclear magnetic resonance ( 13 C NMR) and elemental analysis.

A one-pot, three-component reaction of 4-hydroxycoumarin, arylglyoxals, and 6-aminouracil or 1,3-dimethyl-6-aminouracil in the presence of L-proline as an organocatalyst in acetic acid under reflux conditions provided a series of new pyrrolo[3,2- d ]pyrimidine derivatives in good yields.

A diversity-oriented synthesis of amide-containing thieno[2,3- d ]pyrimidin-4(3 H )-ones is reported. All compounds were tested for their influence on melanin synthesis in murine B16 cells. The azepine fragment in thieno[2,3- d ]pyrimidin-4(3 H )-one skeleton significantly increases the melanin content.

Fifteen N 4 -benzyl-substituted isatin-3-thiosemicarbazones 5a–o were synthesized and evaluated for their urease and glycation inhibitory potential. Lemna aequinocitalis growth and Artemia salina assays were also done to determine their phytotoxic and toxic effects. All compounds are potent inhibitors of the urease enzyme, displaying inhibition [half maximal inhibitory concentration (IC 50 )=1.08±0.12–11.23±0.19 μ m ] superior to that of the reference inhibitor thiourea (IC 50 =22.3±1.12 μ m ). Compounds 5c , 5d , 5h , 5j,k are potent antiglycating agents, showing glycation inhibitory activity better than that of the reference inhibitor rutin (IC 50 values 209.87±0.37–231.70±6.71 vs. 294.5±1.5 μ m ). In the phytotoxicity assay, 11 thiosemicarbazones 5a–d , 5g , 5h , 5j–l , 5n,o are active, demonstrating 5–100% growth inhibition of L. aequinocitalis at the highest tested concentrations (1000 or 500 μg/mL). In the brine shrimp ( A. salina ) lethality bioassay, three derivatives 5b , 5j and 5o are active with median lethal dose (LD 50 ) values of 3.63×10 −5 , 2.90×10 −5 and 2.31×10 −4 m , respectively.

New tetrazole-based pyrazole and pyrimidine derivatives were synthesized by an ultrasound irradiation method. All compounds were characterized by infrared spectroscopy (IR), 1 H nuclear magnetic resonance (NMR), 13 C NMR, mass spectrometry (MS) and elemental analysis and assessed in vitro for their efficacy as antimicrobial agents against four bacteria ( Staphylococcus aureus , Bacillus subtilis , Escherichia coli , Pseudomonas aeruginosa ) and two fungi ( Candida albicans , Aspergillus niger ). Compounds 8a , 8e , 9a , 9b and 9e show potent activity against the tested strains compared to the reference drugs chloramphenicol and clotrimazole.