Synthesis of C2-Symmetrical Bis-(β-Enamino-Pyran-2,4-dione) Derivative Linked via 1,6-Hexylene Spacer: X-ray Crystal Structures, Hishfeld Studies and DFT Calculations of Mono- and Bis-(Pyran-2,4-diones) Derivatives

The synthesis of C2-symmetrical bis(β-enamino-pyran-2,4-dione) derivative 3 connected via 1,6-hexylene linker was reported for the first time. X-ray structures and Hirshfeld studies of the new bis- β-enamino-pyran-2,4-dione derivative 3 along with two structurally related pyran-2,4-dione derivatives 2a,b were discussed. A comparative analysis of the different intermolecular contacts affecting the crystal stability was presented. Generally, the H…H, O…H, and H…C interactions are common in all compounds and are considered the most abundant contacts. In addition, DFT calculations were used to compute the electronic properties as well as the 1H and 13C NMR spectra of the studied systems. All compounds (except 3) are polar where 2a (3.540 Debye) has a higher dipole moment than 2b (2.110 Debye). The NMR chemical shifts were calculated and excellent correlations between the calculated and experimental data were obtained (R2 = 0.93–0.94)

Straightforward One-Pot Synthesis of New 4-Phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one Derivatives: X-ray Single Crystal Structure and Hirshfeld Analyses

A straightforward one-pot route for the synthesis of a new 4-phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one is reported form the direct hydrazinolysis of triketo ester and hydrazine hydrate in ethanol. 4-Phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one was subjected to aza-Michael addition and N-alkylation on reaction with a set of alkylating agents in the presence of K2CO3. Hydrazinolysis of 4-phenyl-1,2,5,6-tetraazafluoranthen-3(2H)-one ester to hydrazide and conversion of hydrazide to thiosemicarbazide were successful. X-Ray single crystals analysis and 1H, 13C NMR were used for unambiguous structure confirmation. The O…H, N…H, C…N and C…C in 2, and the N…H, C…N, C…C, C…O and H…H interactions in 6 are the most important in the molecular packing based on Hirshfled analysis. Moreover, the presence of short C…C and C…N contacts in both compounds revealed the presence of π–π stacking interactions

Synthesis and Anti-Proliferative Assessment of Triazolo-Thiadiazepine and Triazolo-Thiadiazine Scaffolds

A series of triazolo-thiadiazepines 4a–k were synthesized with excellent yields using dehydrated PTSA as a catalyst in toluene. Two triazolo-thiadiazines were obtained; 8a was formed directly by reflux in ethanol, whereas, PTSA promoted the formation of 8b. The molecular structure of the formed triazolo-thiadiazepines is identical to the imine-form 4a–k and not the enamine-tautomer 6a–k. The structures of the newly synthesized triazolo-thiadiazepines 4a–k and triazolo-thiadiazines 8a–b were elucidated using NMR (1H, and 13C), 2D NMR, HRMS, and X-ray single crystal. Furthermore, 4a was deduced using X-ray single crystal diffraction analysis. These new thiadiazepine hits represent an optimized series of previously synthesized indole-triazole derivatives for the inhibition of EGFR. The cytotoxicity activity against two cancer cell lines including human liver cancer (HEPG-2) and breast cancer (MCF-7) was promising, with IC50 between 12.9 to 44.6 µg/mL and 14.7 to 48.7 µg/mL for the tested cancer cell lines respectively, compared to doxorubicin (IC50 4.0 µg/mL). Docking studies revealed that the thiadiazepine scaffold presented a suitable anchor, allowing good interaction of the various binding groups with the enzyme binding regions and sub-pockets

Synthesis of a New Series of Nitrogen/Sulfur Heterocycles by Linking Four Rings: Indole; 1,2,4-Triazole; Pyridazine; and Quinoxaline

A new series of nitrogen and sulfur heterocyclic systems were efficiently synthesized by linking the following four rings: indole; 1,2,4-triazole; pyridazine; and quinoxaline hybrids. The strength of the acid that catalyzes the condensation of 4-amino-5-(1H-indol-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 1 with aromatic aldehydes controlled the final product. Reflux in glacial acetic acid yielded Schiff bases 2–6, whereas concentrated HCl in ethanol resulted in a cyclization product at C-3 of the indole ring to create indolo-triazolo-pyridazinethiones 7–16. This fascinating cyclization approach was applicable with a wide range of aromatic aldehydes to create the target cyclized compounds in excellent yield. Additionally, the coupling of the new indolo-triazolo-pyridazinethiones 7–13 with 2,3-bis(bromomethyl)quinoxaline, as a linker in acetone and K2CO3, yielded 2,3-bis((5,6-dihydro-14H-indolo[2,3-d]-6-aryl-[1,2,4-triazolo][4,3-b]pyridazin-3 ylsulfanyl)methyl)quinoxalines 19–25 in a high yield. The formation of this new class of heterocyclic compounds in high yields warrants their use for further research. The new compounds were characterized using nuclear magnetic resonance (NMR) and mass spectral analysis. Compound 6 was further confirmed by the single crystal X-ray diffraction technique

Synthesis and Regioselectivity in the Alkylation of 1,3,4-Oxadiazolethiones with Dihaloalkanes and Epichlorohydrin

[GRAPHICS] The regioselectivity in the alkylation of 1,3,4-oxadiazolethiones with dihaloalkanes was found that it depends mainly on the length of the alkyl chain connecting the two halides; moreover, the formation of thiirane ring instead of epoxide ring during the alkylation with epichlorohydrin was surprising

Intramolecular Hydrogen Bond, Hirshfeld Analysis, AIM; DFT Studies of Pyran-2,4-dione Derivatives

Intra and intermolecular interactions found in the developed crystals of the synthesized py-ron-2,4-dione derivatives play crucial rules in the molecular conformations and crystal stabili-ties, respectively. In this regard, Hirshfeld calculations were used to quantitatively analyze the different intermolecular interactions in the crystal structures of some functionalized py-ran-2,4-dione derivatives. The X-ray structure of pyran-2,4-dione derivative namely (3E,3′E)-3,3′-((ethane-1,2-diylbis(azanediyl))bis(phenylmethanylylidene))bis(6-phenyl-2H-pyran-2,4(3H)-dione) was determined. It crystallized in the monoclinic crystal system and C2/c space group with unit cell parameters: a = 14.0869(4) Å, b = 20.9041(5) Å, c = 10.1444(2) Å and β = 99.687(2)°. Generally, the H…H, H…C, O…H and C…C contacts are the most important interactions in the molecular packing of the studied pyran-2,4-diones. The molecular structure of these compounds is stabilized by intramolecular O…H hydrogen bond. The nature and strength of the O…H hy-drogen bonds were analyzed using atoms in molecules calculations. In all compounds, the O…H hydrogen bond belongs to closed-shell interactions where the interaction energies are higher at the optimized geometry than the X-ray one due to the shortening in the A…H distance as a con-sequence of the geometry optimization. These compounds have polar characters with different charged regions which explored using molecular electrostatic potential map. Their natural charges, reactivity descriptors and NMR chemical shifts were computed, discussed and compared.peerReviewe