New quinazolin-2,4-dione derivatives incorporating acylthiourea, pyrazole and/or oxazole moieties as antibacterial agents via DNA gyrase inhibition.

This article contributes to the search for new therapeutic agents for treatment of diseases caused by bacterial pathogens. In this study, a new series of compounds incorporating numerous bioactive moieties such as quinazolin-2,4-dione, acylthiourea linkage, and/or five membered nitrogen heterocycles (pyrazole and oxazole) 2-5a-c was described to identify new antibacterial drug candidates via inhibition of DNA gyrase enzyme. The precursor N-[N'-(2-cyano-acetyl)-hydrazinocarbothioyl]-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-benzamide 2 was prepared by treatment of compound 1 with ammonium thiocyanate and cyanoacetic acid hydrazide through multicomponent reaction (MCR). In addition, compounds 3a-d and 4a-b were synthesized by treatment of 2 with aromatic aldehydes and/or ketones through Knoevenagel reaction, affording high purity products in satisfactory yields. Moreover, new heterocyclic moieties such as pyrazole and/or oxazole attached to quinazolin-2,4-dione core 5a-c were synthesized by treatment of 3c with different nucleophilic reagents like hydrazine, phenyl hydrazine and hydroxyl amine, respectively. Subsequently, the obtained products were structurally characterized by IR, 1H-, 13C-NMR, and MS analyses. The minimum inhibitory concentration (MIC) and antibacterial potency of all compounds were estimated against two G-ve (E. coli and P. aeruginosa), and two G+ve bacteria (B. subtilis and S. aureus). Encouragingly, compound 3c demonstrated the best antibacterial activity against all the strains of the tested pathogenic bacteria at low concentrations compared with the standard drug, Ciprofloxacin. Electron withdrawing groups such as -NO2 and -Cl enhance the antibacterial activity. Next, a molecular docking study between the synthesized derivatives and the target enzyme, DNA gyrase enzyme (PDB: 2xct) was undertaken to investigate intermolecular interactions between the compounds and target enzyme.

Novel guanidine derivatives targeting leukemia as selective Src/Abl dual inhibitors: Design, synthesis and anti-proliferative activity.

A new series of benzene-sulfonamide derivatives 3a-i was designed and synthesized via the reaction of N-(pyrimidin-2-yl)cyanamides 1a-i with sulfamethazine sodium salt 2 as dual Src/Abl inhibitors. Spectral data IR, 1H-, 13C- NMR and elemental analyses were used to confirm the structures of all the newly synthesized compounds 3a-i and 4a-i. Crucially, we screened all the synthesized compounds 3a-i against NCI 60 cancer cell lines. Among all, compound 3b was the most potent, with IC50 of 0.018 µM for normoxia, and 0.001 µM for hypoxia, compared to staurosporine against HL-60 leukemia cell line. To verify the selectivity of this derivative, it was assessed against a panel of tyrosine kinase EGFR, VEGFR-2, B-raf, ERK, CK1, p38-MAPK, Src and Abl enzymes. Results revealed that compound 3b can effectively and selectively inhibit Src/Abl with IC500.25 µM and Abl inhibitory activity with IC500.08 µM, respectively, and was found to be more potent on these enzymes than other kinases that showed the following results: EGFR IC500.31 µM, VEGFR-2 IC500.68 µM, B-raf IC500.33 µM, ERK IC501.41 µM, CK1 IC500.29 µM and p38-MAPK IC500.38 µM. Moreover, cell cycle analysis and apoptosis performed to compound 3b against HL-60 suggesting its antiproliferative activity through Src/Abl inhibition. Finally, molecular docking studies and physicochemical properties prediction for compounds 3b, 3c, and 3 h were carried out to investigate their biological activities and clarify their bioavailability.

Eco-friendly and regiospecific intramolecular cyclization reactions of cyano and carbonyl groups in N,N-disubstituted cyanamide.

Eco-friendly, low-cost and high-yielding synthetic route toward imidazoles and oxazoles has been developed. 1-(4,6-Dimethylpyrimidin-2-yl)-2-(alkylamino)-1,5-dihydro-4H-imidazol-4-one 3a-c have been synthesized via regiospecific reaction of ethyl 2-(N-(4,6-dimethylpyrimidin-2-yl)cyanamide)acetate 1 with primary aliphatic amines in water as green solvent. While, the reaction between 4,6-dimethylpyrimidin-2-yl(2-oxo-2-phenylethyl)cyanamide 2 and primary aliphatic amines using water and/or iso-propanol as green solvents afforded 3-(4,6-dimethylpyrimidin-2-yl)-5-phenyl-1,3-oxazole-2(3H)-imine 6 and 1-(4,6-dimethylpyrimidin-2-yl)-N-alkyl-4-phenyl-1H-imidazol-2-amine 7a-d, respectively.

Crystal structure of (4Z)-4-[(di-methyl-amino)-methyl-idene]-3,5-dioxo-2-phenyl-pyrazolidine-1-carbaldehyde.

In the title compound, C13H13N3O3, the pyrazolidine ring adopts a shallow envelope conformation, with the carbonyl C atom closest to the benzene ring as the flap [deviation of 0.126 (1) Šfrom the plane through the remaining atoms (r.m.s. deviation = 0.011 Å)]. The dihedral angle between the pyrazolidine ring (all atoms) and the benzene ring is 51.09 (4)°. An extremely short (2.08 Å) intra-molecular C-H⋯O contact is seen. In the crystal, mol-ecules are linked by C-H⋯O bonds, generating [010] chains. Extremely weak C-H⋯π inter-actions are also observed.

Crystal structure of ethyl 4-(2-meth-oxy-phen-yl)-6-methyl-2-sulfanyl-idene-1,2,3,4-tetra-hydro-pyrimidine-5-carboxyl-ate.

In the title compound, C15H18N2O3S, the hydro-pyrimidine ring adopts a sofa conformation with the methine C atom as the flap. The benzene ring is almost perpendicular to the mean plane of the hydro-pyrimidine ring, making a dihedral angle of 85.51 (8)°, and the meth-oxy O atom lies over the centre of the pyrimidine ring. In the crystal, weak N-H⋯S inter-actions form a zigzag chain running along the b-axis direction.

Thieno[2,3-b]thiophenes: Part 7. Some Heterocyclization Reactions with Ethyl 3,4-diamino-5-cyanothieno[2,3-b]thiophene-2-carboxylate.

Ethyl 3,4-diamino-5-cyanothieno[2,3-b]thiophene-2-carboxylate (1) was treated with a mixture of carbon disulfide and halo compounds to give the corresponding bisthiazole and bisthiolane derivatives 2-4. Treatment of compound 1 with 2,5-dimethoxytetrahydrofuran gave the corresponding 3,4-dipyrrol-1-ylthienothiophene (5). Condensation of compound 5 with hydrazine afforded the carbohydrazide derivative 6, which was treated with CS2 or PhNCS to afford oxadiazole or triazole derivatives 7a,b. The cycloaddition reaction of compound 5 with CS2 or PhNCS under phase transfer conditions gave 1,4-thiazepino- or 1,4-diazepinothieno[2,3-b]thiophenes 8 and 9, respectively. Basic hydrolysis of compound 1 yielded 3,4-diaminothieno[2,3-b]thiophene (10), which was subjected to react with different reagents to give the corresponding bispyrido- and bispyrrolothieno[2,3-b]thiophenes, and bisarylideneaminothieno[2,3-b]thiophenes 11-15, respectively.