Benzenesulfonamide Analogs: Synthesis, Anti-GBM Activity and Pharmacoprofiling.

The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure-activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2H-inden-2-ylidene)hydrazinyl]-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC50 value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma.

Correction: Solvent-driven azide-induced mononuclear discrete versus one-dimensional polymeric aromatic Möbius cadmium(II) complexes of an N6 tetradentate helical ligand.

Correction for 'Solvent-driven azide-induced mononuclear discrete versus one-dimensional polymeric aromatic Möbius cadmium(II) complexes of an N6 tetradentate helical ligand' by Farhad Akbari Afkhami et al., Dalton Trans., 2017, 46, 14888-14896, https://doi.org/10.1039/C7DT02952G.

Evaluation of the antitumor activity of a series of the pincer-type metallocomplexes produced from isonicotinohydrazide derivative.

In this work we report on the antitumor properties of a series of pincer-type metallocomplexes [Hg2(HL-keto)Cl4]n (1), [Hg(HL-keto)I2] (2) and [Mn(HL-zwitterion)Cl2]∙MeOH (3∙MeOH), derived from N'-(1-(pyridin-2-yl)ethylidene)isonicotinohydrazide (HL) and corresponding metal salts. The Hg(II) and Mn(II) salts are chelated by the keto (HL-keto) or zwitterionic (HL-zwitterion) form of HL, respectively. The cytotoxic effects of these compounds have been accessed against lung adenocarcinoma (A549) and hepatocellular carcinoma (HepG2 and Huh7) cell lines. Complexes 1 and 2 were found to be most efficient against the cell line Huh7 with IC50 value of 2.56 and 9.90 µM, respectively, while they exhibit moderate activity towards cell lines A549 and HepG2, as evidenced from IC50 values in the range 27.98-56.99 µM. Complex 3∙MeOH is less efficient towards all the three cell lines with relatively high IC50 values. The mechanisms of the metallocomplexes killing the aforementioned cells were elucidated by flow cytometry, colony formation and polymerase chain reaction (PCR) analysis of apoptosis related expression of the genes. The results of the cytotoxic effects and antitumor activity on different cell lines are affected by the metal nature and the presence of the coordinated halide.

New iridium bis-terpyridine complexes: synthesis, characterization, antibiofilm and anticancer potentials.

This study represents synthesis, characterization, screening of antibiofilm efficacy, and cytotoxicity of iridium bis-terpyridine complexes. The complexes were characterized by NMR, MS, FTIR, UV/Visible, and fluorescence spectroscopies. The efficacy of biofilm inhibition and eradication of iridium complexes was evaluated using a crystal violet assay test and verified by fluorescence microscopy. Cytotoxicity and apoptosis analysis of iridium complexes were determined in this study. The results of our study revealed that three iridium complexes had the potential to inhibit biofilm formation and moderate the ability to destroy pre-formed biofilm of S. aureus ATCC 29,213. 250 µM concentration of synthesized complexes showed the highest antibiofilm activity (75% for Ir1, 90% for Ir2, and 71% for Ir3). The significant inhibition obtained at 6.25 µM concentration of Ir2 and Ir3 revealed the potential of our samples. Also, Ir1 and Ir2 complexes had a good capacity to destroy pre-formed biofilm. The results clearly showed that iridium complexes have cytotoxic activity towards colon cancer (Caco-2) and liver cancer (HepG2) cell lines without affecting non-cancerous cells (HEK293) at applied doses. Moreover, tested compounds induced apoptosis in these cancer cells. All of these results showed that iridium complexes had possessed the ability to inhibit or destroy pre-formed biofilm and could be developed as an effective agent against bacterial biofilms. Moreover, these pure substances may have valuable anti-cancer activity and it should be confirmed with further studies for therapeutic effects.

New class of hantaan virus inhibitors based on conjugation of the isoindole fragment to (+)-camphor or (-)-fenchone hydrazonesv.

This work presents the design and synthesis of camphor, fenchone, and norcamphor N-acylhydrazone derivatives as a new class of inhibitors of the Hantaan virus, which causes haemorrhagic fever with renal syndrome (HFRS). A cytopathic model was developed for testing chemotherapeutics against the Hantaan virus, strain 76-118. In addition, a study of the antiviral activity was carried out using a pseudoviral system. It was found that the hit compound possesses significant activity (IC50 = 7.6 ± 2 µM) along with low toxicity (CC50 > 1000 µM). Using molecular docking procedures, the binding with Hantavirus nucleoprotein was evaluated and the correlation between the structure of the synthesised compounds and the antiviral activity was established.

Hydrogen and halogen bonding in the haloetherification products in chalcone.

Cooperative action of hydrogen and halogen bonding in the reaction of 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-1-phenylprop-2-en-1-one with HCl or HBr in alcohol medium under microwave irradiation (20 W, 80 °C, 10 min) allows the isolation of the haloetherification products (2S,3S)-3-(3-tert-butyl-5-chloro-4-hydroxyphenyl)-2-chloro-3-ethoxy-1-phenylpropan-1-one, C21H24Cl2O3, (2S,3S)-2-bromo-3-(3-tert-butyl-5-bromo-4-hydroxyphenyl)-3-methoxy-1-phenylpropan-1-one, C20H22Br2O3, and (2S,3S)-2-bromo-3-(3-tert-butyl-5-bromo-4-hydroxyphenyl)-3-ethoxy-1-phenylpropan-1-one, C21H24Br2O3, in good yields. Both types of noncovalent interactions, e.g. hydrogen and halogen bonds, are formed to stabilize the obtained products in the solid state.

2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile as novel inhibitor of receptor tyrosine kinase and PI3K/AKT/mTOR signaling pathway in glioblastoma.

Nerve growth factor receptor (NGFR), a member of kinase protein, is emerging as an important target for Glioblastoma (GBM) treatment. Overexpression of NGFR is observed in many metastatic cancers including GBM, promoting tumor migration and invasion. Hydrazones have been reported to effectively interact with receptor tyrosine kinases (RTKs). We report herein the synthesis of 23 arylhydrazones of active methylene compounds (AHAMCs) compounds and their anti-proliferative activity against GBM cell lines, LN229 and U87. Compound R234, 2-(2-(2,4-dioxopentan-3-ylidene)hydrazineyl)benzonitrile, was identified as the most active anti-neoplastic compound, with the IC50 value ranging 87 µM - 107 µM. Molecular docking simulations of the synthesized compounds into the active site of tyrosine receptor kinase A (TrkA), demonstrated a strong binding affinity with R234 and concurs well with the obtained biological results. R234 was found to be a negative regulator of PI3K/Akt/mTOR pathway and an enhancer of p53 expression. In addition, R234 treated GBM cells exhibited the downregulation of cyclins, cyclin-dependent kinases and other key molecules involved in cell cycle such as CCNE, E2F, CCND, CDK6, indicating that R234 induces cell cycle arrest at G1/S. R234 also exerted its apoptotic effects independent of caspase3/7 activity, in both cell lines. In U87 cells, R234 induced oxidative effects whereas LN229 cells annulled oxidative stress. The study thus concludes that R234, being a negative modulator of RTKs and cell cycle inhibitor, may represent a novel class of anti-GBM drugs.

In vitro characterization of arylhydrazones of active methylene derivatives.

Arylhydrazones of active methylene compounds (AHAMCs) are potent chemotherapy agents for the cancer treatment. AHAMCs enhance the apoptotic cell death and antiproliferation properties in cancer cells. In this study, a series of AHAMCs, 13 compounds, was assayed for cytotoxicity, apoptosis, externalization of phosphatidylserine, heterogeneity and cellular calcium level changes. The in vitro cytotoxicity study against HEK293T cells suggests that AHAMCs have significant cytotoxic effect over the concentrations. Top 5 compounds, 5-(2-(2-hydroxyphenyl) hydrazono)pyrimidine-2,4,6(1H,3H,5H)-trione (5), 4-hydroxy-5-(2-(2,4,6-trioxo-tetrahydro-pyrimidin-5(6H) ylidene)hydrazinyl)benzene-1,3-disulfonic acid (6), 5-chloro-3-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-2-hydroxybenzenesulfonic acid (8), 5-(2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl)-4-hydroxybenzene-1,3-disulfonic acid (9) and 2-(2-sulfophenylhydrazo)malononitrile (10) were chosen for the pharmacodynamics study. Among these, compound 5 exhibited the better cytotoxic effect with the IC50 of 50.86 ±â€¯2.5 mM. DNA cleavage study revealed that 5 induces cell death through apoptosis and shows more effects after 24 and/or 48 h. Independent validation of apoptosis by following the externalization of phosphatidylserine using Annexin-V is also in agreement with the potential activity of 5. Single cell image analysis of Annexin-V bound cells confirms the presence of mixture of early, mid and late apoptotic cells in the population of the cells treated with 5 and a decreased trend in cell-to-cell variation over the phase was also identified. Additionally, intracellular calcium level measurements identified the Ca2+ up-regulation in compound treated cells. A brief inspection of the effect of the compound 5 against multiple human brain astrocytoma cells showed a better cell growth inhibitory effect at micro molar level. These systematic studies provide insights in the development of novel AHAMACs compounds as potential cell growth inhibitors for cancer treatment.

Solvent-driven azide-induced mononuclear discrete versus one-dimensional polymeric aromatic Möbius cadmium(ii) complexes of an N6 tetradentate helical ligand.

We report the synthesis and structural characterization of a heteroleptic mononuclear discrete complex [Cd(N3)2(L)(MeOH)]·MeOH (1·MeOH) and a one-dimensional coordination polymer of the composition [Cd3(N3)6(L)]n (2), fabricated from Cd(NO3)2·4H2O and the helical organic ligand benzilbis((pyridin-2-yl)methylidenehydrazone) (L) in the presence of two equivalents of NaN3. The formation of different structures is driven by the solvent. The former complex is formed in the presence of MeOH, while the latter complex is formed in EtOH. The CdII centre in 1·MeOH is trapped by the two pyridyl-imine units of the tetradentate ligand L, two azide ligands and one oxygen atom of one methanol ligand with the CdN6O coordination polyhedron yielding a square face monocapped trigonal prism. The asymmetric unit of 2 consists of three symmetrically independent atoms of CdII, six azide anions and one L. The polymeric structure of 2 is realized through chains of the Cd(N3)2 units which are decorated with Cd(N3)2L units. The CdII atoms from the backbone of the coordination polymer have a distorted octahedral coordination, while the remaining CdII atom forms a trigonal prism with two basal planes nearly parallel to each other. In both complexes, the 12π electron chelate ring of the CdL fragment is shown to be aromatic by establishing it as a Möbius object. Hirshfeld surface analysis of 1 in 1·MeOH and L in 2 showed that the structures of both species are highly dominated by HX (X = H, C and N) contacts, of which the latter two are highly favoured, as well as some contribution from highly enriched CC contacts is clearly observed.

Inter-action between maleic acid and N-R-furfuryl-amines: crystal structure of 2-methyl-N-[(5-phenyl-furan-2-yl)meth-yl]propan-2-aminium (2Z)-3-carb-oxy-acrylate and N-[(5-iodo-furan-2-yl)meth-yl]-2-methyl-propan-2-aminium (2Z)-3-carb-oxy-prop-2-enoate.

The title mol-ecular salts, C15H20NO+·C4H3O4-, (I), and C9H15INO+·C4H3O4-, (II), have very similar mol-ecular geometries for both cation and anion. The anions of both (I) and (II) are practically planar (r.m.s. deviations = 0.062 and 0.072 Å, respectively) and adopt a rare symmetrical geometry with the hy-droxy H atom approximately equidistant from the two O atoms. In their crystals, the cations and anions in both (I) and (II) form tight ionic pairs via strong N-H⋯O hydrogen bonds, with a roughly perpendicular disposition of the anion to the furan ring of the cation. This ion-pair conformation appears to correlate with the lack of reactivity of these salts in [4 + 2] cyclo-addition reactions. In the extended structures of (I) and (II), the ion pairs form hydrogen-bonded chains propagating along [010] and [001], respectively, via N-H⋯O hydrogen bonds.