DNA binding studies of fluorinated bioactive heterocyclic compounds

Fluorinated heterocyclic compounds have drug like properties and possess a valuable biological activity due to their rigid chemical structures and the high solubility profile. Novel fluorinated heteroarenes have been synthesised by SNAr reaction of a range of fluorinated arenes including pentafluoropyridine, hexafluorobenzene and pentafluorotoluene to introduce a range of groups specially nitriles, benzimidazole, carbazole and benzimidazole. A number of cyclization reactions have been investigated with the aim of forming polycyclic structures that could act as DNA intercalators. The synthesised compounds have been characterized by elemental analysis, IR, 1H and 19F NMR spectroscopy and single crystal analysis. These compounds have been screened for their biological activities including DNA thermal denaturation assay, UV-Visible spectroscopy, fluorescence spectroscopy, X-ray co-crystallization and antimicrobial activity study. Some of the compounds showed potential DNA bonding activity in particular the carbazole derivatives

Novel fluorinated benzimidazole-based scaffolds and their anticancer activity in vitro

A small library of twelve, structurally diverse, fluoroaryl benzimidazoles was prepared using a simple synthetic strategy employing SNAr reactions. This allowed rapid assembly of heterocyclic structures containing linked and tethered fluoroaryl benzimidazoles. X-ray crystal structures of seven compounds were obtained including those of two macrocyclic compounds containing 21- and 24-membered rings. Three tethered fluoroaryl benzimidazole derivatives demonstrated micromolar inhibition against K-562 and MCF-7 cell lines. These compounds, in addition to 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-ylsulfanyl-1H-benzimidazole, also demonstrated micromolar inhibition against G361 and HOS cell lines. Two of the compounds were found to activate caspases leading to apoptosis

NMR spectral analysis of second-order 19F-19F, 19F-1H and 13C-19F coupling constants in pentafluorobenzene and tetrafluoro-4-(morpholino)pyridine using ANATOLIA

A new and simple to use line-shape analysis method ANATOLIA (ANAlysis of TOtal LIneshApe) optimised all and 19F19F and 19F1H coupling constants in pentafluorobenzene (AA’BB’C’H) within 10 seconds. This free and open-source NMR analysis method, which works within the Bruker Topspin-4 software and can import Bruker/JEOL/Varian data, was able to accommodate grossly inaccurate input coupling constants to provide an accurate result even for the second-order interactions 4 JAA’ and 4 JBB’. The 13C spectrum and the 19F13C-satellites share the same coupling values, but required manual intervention to achieve an acceptable fit, especially for the 19FBB’- 13C-satellites which are deceptively simple but have significant second-order effects and display Δδ 19FB – 19FB’ of ~100 Hz. A real-world analysis of a new compound, that has potential anti-cancer drug activity, tetrafluoro-4-(morpholino)pyridine molecule, is shown for the first time. The 19F spectrum consists of a spin-system of 8 coupling nuclei (AA’BB’-H4) which was analysed within 20 seconds. The 13C satellites in the 19F spectrum consist of 9-spins (AA’BB’- 13C-H4) and the carbon spectrum shows a series of 13C isotopomer multiplets consisting of 5 coupling nuclei ( 13C-AA’BB’) was optimised in less than a minute using a laptop computer. Ab initio structure optimisations were carried out using B3LYP/6-31G*, and chemical shifts and coupling constants were calculated with the basis-set B3LYP/6-311++G**. Fluorine and carbon chemical shifts were in reasonable agreement with experimental values, and n JFF and 2-4 JCF couplings were close to the experimental values, such that these were reasonable starting values for the ANATOLIA optimisation

Synthesis, molecular modeling and bioactivity of new bis-thiazole, thiazole-pyrazole, and thiazole-pyridine analogues

Several new thiazole derivatives linked pyrazole and/or pyridine rings were synthesized based on the versatile precursor 2-(5-acetyl-4-methyl-3-phenylthiazol-2(3H)-ylidene)acetonitrile (1). The synthesized derivatives were optimized using DFT approach in order to inspect the configurations and energies of the HOMO-LUMO orbitals. The data disclosed low energy gap (ΔEH-L), 0.99–2.54 eV, following the order 9 < 3 = 4 ≈ 2 ≈ 8 < 5 < 1 < 7 ≈ 6. The in vitro anticancer activity of the new thiazole hybrids was tested against three cancer cell lines (HepG2, HCT-116, and MCF-7) as well as standard fibroblast cells (WI38) using Doxorubicin as a reference drug. The thiazole-pyridine hybrids 8 and 9 exhibited high cytotoxic efficacies against the MCF-7 cell line, IC50 28.53 ± 0.39 and 25.47 ± 0.54 µM. Moreover, the synthesized hybrids were docked against the crystal structure of (PDB: 3rcd) as a representative protein for the human epidermal growth factor receptor (HER2) to approve the relationship between the in vitro cytotoxicity results and inhibitor binding interactions. The docking study showed that thiazole-pyridine hybrids 8 and 9 displayed the highest score of bindings, which was compatible with the results of the cytotoxicity results

Novel Fluorinated Benzimidazole-Based Scaffolds and their Anticancer Activity in vitro

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.A small library of twelve, structurally diverse, fluoroaryl benzimidazoles was prepared using a simple synthetic strategy employing SNAr reactions. This allowed rapid assembly of heterocyclic structures containing linked and tethered fluoroaryl benzimidazoles. X-ray crystal structures of seven compounds were obtained including those of two macrocyclic compounds containing 21- and 24-membered rings. Three tethered fluoroaryl benzimidazole derivatives demonstrated micromolar inhibition against K-562 and MCF-7 cell lines. These compounds, in addition to 1-tetrafluoropyrid-4-yl-2-tetrafluoropyrid-4-ylsulfanyl-1H-benzimidazole, also demonstrated micromolar inhibition against G361 and HOS cell lines. Two of the compounds were found to activate caspases leading to apoptosis