Series Of Bis Research Articles

Microwave-assisted synthesis, antiproliferative, antibacterial activities, in silico, computational studies and molecular dynamics simulation of new bis-(aryl-based chalcone) derivatives

A new series of bis-(aryl-based chalcone) derivatives 9–15 derived from 4,4′-(ethane-1,2-diylbis(oxy))-bis-benzaldehyde (8) were synthesized, via Claisen–Schmidt condensation, under microwave irradiation (MWI). The newly synthesized bis-chalcones were characterized on the basis of their chemical properties and spectroscopic data. All the synthesized analogues were evaluated for their in vitro antiproliferative activity against breast adenocarcinoma of the CAL51 cell line by MTT assay. Compounds 9 and 10 exhibited the highest cytotoxic activity, with inhibitions of 78.2 % and 74.4 %, respectively, at a concentration of 10 μM. Furthermore, compounds 9–15 were evaluated for their antibacterial activity. The docking of compounds 9 and 10 with the protein kinase TTK (PDB: 7CHN, 7CIL) related to the triple negative breast cancer (TNBC) was studied to predict their possible binding modes with the kinase. The docking results were agreed with the protein kinase TKK inhibitory studies. Furthermore, the computational analysis was carried out to investigate the molecular structures of the new molecules. These results suggest that analogues 9 and 10 could be promising lead compounds for the continued development of novel antiproliferative agents. The molecular dynamics simulation with computational studies has been performed.

Bis(thiosemicarbazide)gallium(III) Complexes as Potent Anticancer Agents by ROS Induction and Mitochondrial Pathway Activation

ABSTRACTA series of bis(thiosemicarbazide)gallium (III) complexes were synthesized and characterized by infrared spectroscopy, mass spectrometry, nuclear magnetic resonance, single‐crystal x‐ray crystallography, and density functional theory (DFT) calculation. The cytotoxicity of these gallium(III) complexes (CP 1–4) was subsequently evaluated against HCT‐116, HeLa, MDA‐MB‐231, and A549 cancer cell lines, as well as the normal cell line LO2, by MTT assays. The results indicated that CP‐1 displayed potent inhibitory effects against human colorectal cancer cells (HCT‐116) (IC50 = 0.03 ± 0.01) and human breast cancer cells (MDA‐MB‐231) (IC50 = 0.02 ± 0.01), significantly outperforming cisplatin. Moreover, CP‐2 exhibited notable selectivity towards MDA‐MB‐231 cells (IC50 = 5.01 ± 0.40) with minimal toxicity towards normal cells. Mechanistic studies revealed that treatment with CP 1–2 led to elevated intracellular reactive oxygen species (ROS) levels, resulting in cell cycle arrest at different phases. Specifically, CP‐1 induced G2/M phase arrest, inhibiting cancer cell proliferation, whereas CP‐2 hindered DNA synthesis (S phase) to impede cell proliferation. Furthermore, both CP‐1 and CP‐2 caused a reduction in mitochondrial membrane potential, activating the mitochondrial apoptotic pathway and inducing apoptosis in cancer cells. Molecular docking experiments demonstrated strong interactions between CP 1–2 and protein disulfide isomerase (PDI) at the molecular level. These findings suggest that CP‐1 and CP‐2 serve as potential anticancer agents, particularly showing promising potential in the treatment of breast cancer.

Design and synthesis of bis(indolyl)-hydrazide-hydrazone derivatives and their antifungal activities against plant pathogen fungi

A series of bis(indolyl)-hydrazide-hydrazone derivatives were synthesised, and their structures were characterised using 1H-NMR and HRMS. The antifungal activity of the prepared compounds was evaluated against Pyricularia oryzae Cav., Colletotrichum ­gloeosporioides Penz., Botrytis cinerea Pers.: Fr. and Rhizoctonia solani Kühn using the mycelial growth rate method. The preliminary bioassays revealed that most of the synthesised compounds exhibited antifungal activity against the four tested fungi and displayed a remarkable inhibitory effect on the mycelium growth of R. solani. In particular, compounds 3b, 3c, and 3k demonstrated significant antifungal activity against R. solani, with EC50 values of 26.42, 20.74, and 22.41 μM, respectively, outperforming the positive control shenqinmycin (47.18 μM) and carvacrol (49.13 μM).

Synthesis and Anti‐Bacterial Evaluation of Novel Scaffolds Based on Bis‐Thiazole or bis‐1,3,4‐Thiadiazole Linked to Thieno[2,3‐b]Thiophene as New Hybrid Molecules

AbstractThe reaction of bis‐2‐(methylthiocarbonothioyl)hydrazone with the appropriate hydrazonoyl halides in 1,4‐dioxane in the presence of triethylamine at reflux yielded a novel series of bis(1,3,4‐thiadiazoles) linked to a thieno[2,3‐b]thiophene core. The reaction of the appropriate α‐ketohydrazonoyl halides or α‐haloketones with the corresponding bis(2‐carbamothioylhydrazone) in ethanol at reflux in the presence of a few drops of triethylamine produced good yields of novel bis‐thiazoles linked to the thieno[2,3‐b]thiophene core as novel hybrid molecules. Elemental analyses and spectral data were used to determine the structures of the novel compounds. The antibacterial activity of newly synthesized compounds was evaluated. The MIC determination using resazurin was studied for the most reactive compounds. The pharmacokinetic properties were evaluated by in silico ADMET analysis.

Exploring the potential of bis(thiazol-5-yl)phenylmethane derivatives as novel candidates against genetically defined multidrug-resistant Staphylococcus aureus.

Antimicrobial resistance (AMR) represents an alarming global challenge to public health. Infections caused by multidrug-resistant Staphylococcus aureus (S. aureus) pose an emerging global threat. Therefore, it is crucial to develop novel compounds with promising antimicrobial activity against S. aureus especially those with challenging resistance mechanisms and biofilm formation. Series of bis(thiazol-5-yl)phenylmethane derivatives were evaluated against drug-resistant Gram-positive bacteria. The screening revealed an S. aureus-selective mechanism of bis(thiazol-5-yl)phenylmethane derivatives (MIC 2-64 μg/mL), while significantly lower activity was observed with vancomycin-resistant Enterococcus faecalis (MIC 64 μg/mL) (p<0.05). The most active phenylmethane-based (p-tolyl) derivative, 23a, containing nitro and dimethylamine substituents, and the naphthalene-based derivative, 28b, harboring fluorine and nitro substituents, exhibited strong, near MIC bactericidal activity against S. aureus with genetically defined resistance phenotypes such as MSSA, MRSA, and VRSA and their biofilms. The in silico modeling revealed that most promising compounds 23a and 28b were predicted to bind S. aureus MurC ligase. The 23a and 28b formed bonds with MurC residues at binding site, specifically Ser12 and Arg375, indicating consequential interactions essential for complex stability. The in vitro antimicrobial activity of compound 28b was not affected by the addition of 50% serum. Finally, all tested bis(thiazol-5-yl)phenylmethane derivatives showed favorable cytotoxicity profiles in A549 and THP-1-derived macrophage models. These results demonstrated that bis(thiazol-5-yl)phenylmethane derivatives 23a and 28b could be potentially explored as scaffolds for the development of novel candidates targeting drug-resistant S. aureus. Further studies are also warranted to understand in vivo safety, efficacy, and pharmacological bioavailability of bis(thiazol-5-yl)phenylmethane derivatives.

Synthesis of bis(oxazoline)-based rare-earth metal complexes and their catalytic performance in the polymerization of isoprene and polar ortho-methoxystyrene.

A series of bis(oxazoline) rare-earth metal dialkyl complexes [(L)Ln(CH2SiMe3)2(THF)n] (L = L1 (dimethyl-substituted bis(oxazoline) ligand), Ln = Y (1-Y), Lu (1-Lu), Sc (1-Sc), n = 1; L = L2 (phenyl-substituted bis(oxazoline) ligand), Ln = Y (2-Y), Lu (2-Lu), Sc (2-Sc), n = 2) was successfully prepared. NMR spectroscopy and X-ray diffraction indicated that all the complexes ligated with a C2 symmetric bis(oxazoline) and two trimethylsilylmethyl ligands. In the presence of borate and triisobutyl aluminium, these complexes exhibited high catalytic activity for the polymerization of isoprene, yielding the polymer with high cis-1,4-regularity (up to 99.9%) and high molecular weight. Moreover, these ternary catalytic systems also served as efficient initiators for the polymerization of polar ortho-methoxystyrene. However, atactic polymers in all the cases were isolated despite the C2 symmetric geometry of bis(oxazoline) ligands.

Tunable mechanochromic luminescence of benzofuran-fused pyrazine: effects of alkyl chain length and branching pattern

Tuning the alkyl chains of bisbenzofuropyrazines allowed control over the on/off switching of mechanochromic luminescence and self-recovery rates.

PIFA Mediated Synthesis of Bis‐1,2,4‐triazoloquinazolines as Potential Anticancer Agents on MCF‐7 Cancer Cells: Characterization, Molecular Docking, Antiproliferative and ADME Profile

AbstractA novel series of bis([1,2,4]triazolo)[4,3‐a][4′,3′‐c] quinazolines derivatives 2 a–2 o has been synthesis in good to excellent yields (74–86 %) under mild reaction conditions via bis(trifluoroacetoxy)iodobenzene (PIFA) mediated oxidative‐cyclization of corresponding 2,4‐bis(2‐(E)‐arylidenehydrazinyl) quinazolines 1 a–1 o. Formation of the targeted compounds has been supported using various spectroscopic tools (IR, 1H &amp; 13 C‐NMR) and HRMS analysis. These bis([1,2,4]triazolo)[4,3‐a][4′,3′‐c] quinazolines derivatives were biologically screened for their antiproliferative activities against MCF‐7 cancer cells. Results indicate that among all synthesized derivatives, 3,7‐bis (4‐chlorophenyl) bis([1,2,4]triazolo)[4,3‐a : 4′,3′‐c]quinazoline (2 d) and 3,7‐bis(3‐methoxyphenyl)bis([1,2,4]triazolo)[4,3‐a : 4′,3′‐c]quinazoline (2 j) displayed uppermost cytotoxicity efficacy with GI50 value of 106.30 μM and 108.56 μM respectively. Furthermore, molecular docking studies have been carried out to investigate possible binding modes between active sites of the protein (PDB ID: 3 U6 J) and the target compounds. In addition to these results, ADME (adsorption, distribution, metabolism, excretion) analysis has also been carried out to study the pharmacokinetic properties of the targeted compounds.

Bis(imino)pyridine vanadium (III) and cobalt (II) complexes catalyzed selective dimerization of propylene

The high-value utilization of propylene is a topic worthy of in-depth research. In this regard, a series of bis(imino)pyridine vanadium (III) and cobalt (II) complexes have been synthesized and employed to selectively produce valuable products, such as 4-methyl-1-pentene (4M1P) and 1-hexene (1-H), through propylene dimerization with methylaluminoxane (MAO) as a cocatalyst. The study found that when halogen substituents are introduced on the pyridine group, the catalyst's activity improves significantly. A clear reaction mechanism has been proposed: to produce 4M1P, a two-step 2,1-insertion process is involved, with catalysts having lower steric hindrance proving more favorable for achieving high selectivity. On the other hand, the production of 1-H involves a one-step 1,2-insertion followed by a one-step 2,1-insertion process. Although the steric hindrance effect benefits the initial 1,2-insertion step, it hampers the subsequent 2,1-insertion step. The steric hindrance effect counteracts the impact of the central metal, leading to a decrease in selectivity.

Bis(acylthiourea) compounds as enzyme inhibitors: Synthesis, characterization, crystal structures and in silico molecular docking studies

A series of bis(acylthiourea) compounds was synthesized and characterized by various spectroscopic and analytical methods. The structures of the three compounds were determined by X-ray crystallographic method and refined to good R factors. Surface properties, and intermolecular interactions were studied by Hirshfeld surface analysis. The binding data revealed urease as one of the enzyme targets for the bis(acylthiourea) derivatives. As thiourea derivatives possess various pharmacological properties like anticancer, anti-inflammatory, antibacterial and antiviral, we have attempted to understand the binding potential of the bis(acylthiourea) derivatives with VEGFR2, EGFR (anticancer targets) and SARS-CoV-2 main protease (antiviral target) in addition to urease (antibacterial target) through in silico molecular docking tool. The results revealed good binding potential of the compounds with these enzyme targets.

Technetium Nitrido Complexes of Tetradentate Thiosemicarbazones: Kit-Based Radiolabeling, Characterization, and In Vivo Evaluation.

Bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators have demonstrated utility in nuclear medicine. In particular, the 64Cu2+ complexes have been extensively developed for hypoxia imaging and molecular imaging of peptide and protein markers of disease. However, the chemistry and application of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators in combination with 99mTc, the most widely used radionuclide in nuclear medicine, is underexplored. Herein, a series of bis(thiosemicarbazone) and pyridylhydrazone-thiosemicarbazone chelators were radiolabeled with nitrido-technetium-99m in an optimized one-pot synthesis from [99mTc]TcO4-. Optimization of the radiochemical syntheses allowed for production of the complexes in >90% radiochemical conversion with apparent molar activities of 3.3-5 GBq/μmol. Competition experiments demonstrated the excellent stability of the complexes. The nitrido-technetium-99 complexes were synthesized, and the chemical identities were investigated using mass spectrometry, spectroscopy, and density functional theory calculations. Complexation of nitrido-rhenium(V) was achieved with the N4-dialkylated bis(thiosemicarbazones). Planar imaging and ex vivo biodistribution studies of the five 99mTc complexes were conducted on healthy BALB/c mice to determine in vivo behavior. The lipophilic nature of the complexes resulted in uptake of 1.6-5.7% ID g-1 in the brain at 2 min postinjection and retention of 0.4-1.7% ID g-1 at 15 min postinjection. The stability of the complexes and the biodistribution data demonstrate that these chelators are ideal platforms for future production of radiopharmaceutical candidates.

Electronic effect of substituent groups on the oxidation and reduction of bis(2,2′:6′,2″-terpyridine)ruthenium

A series of bis(tpy)ruthenium(II) (tpy = differently substituted 2,2′:6′,2″-terpyridine) were prepared. The substituents were chosen to range from electron donating (pyrrolidinyl, hydroxy, tert-butyl, methoxy, phenyl) to electron withdrawing (Cl, Br). Electrochemistry results show that the complex with the most electron donating group in the series, [Ru(4′-(N-pyrrolidinyl)-2,2′:6′,2″-terpyridine)2]2+, oxidizes at 0.363 V vs the redox couple of ferrocene (Fc/Fc+). The oxidation of [Ru(4′-chloro-2,2′:6′,2″-terpyridine)2]2+, containing the electron withdrawing chlorine group, is much higher, 0.992 V vs Fc/Fc+. Theoretical density functional theory calculations confirmed that the oxidation and reduction of bis(tpy)ruthenium(II) are metal and ligand based, respectively. Graphs comparing the experimentally measured redox potentials and theoretically calculated energies, charges, potentials and various global and local reactivity parameters, all show linear relationships associated with the donating/withdrawing nature of the substituents as quantified by Hammett constants. All these relationships may be utilized to quantify the electronic influence of substituent groups on the redox chemistry of bis(tpy)ruthenium(II) complexes. Linear relationships obtained may also be utilized in the design of bis(tpy)ruthenium(II) type of molecules with a required oxidation or reduction potential. DFT calculations also indicate the potential utilization of these complexes as dye sensitizers in dye-sensitized solar cells.

Bis(chlorido)tin(IV)meso‐substituted Porphyrins‐Characterization and Solubility

AbstractInvestigation of the solubility behavior of para‐substituted (H, Me, t‐Bu, n‐Bu) meso‐tetraarylporphyrins as well as meso‐tetraalkylporphyrins (Me, n‐Pr, n‐Bu) were performed. An increase of solubility in chloroform and benzene is detected according to the higher functionality in para position of the phenyl ring for meso‐tetraarylporphyrins or in meso position on meso‐tetraalkylporphyrins. Furthermore, the series of bis(chlorido)tin(IV) meso‐tetraarylporphyrin and bis(chlorido)tin(IV) meso‐tetraalkylporphyrin was investigated via UV/Vis spectroscopy, 119Sn‐NMR and single crystal X‐ray diffraction.

Design, synthesis, antimicrobial activity and molecular docking study of cationic bis-benzimidazole-silver(I) complexes.

Two series of bis(1-alkylbenzimidazole)silver(I) nitrate and bis(1-alkyl-5,6-dimethylbenzimidazole)silver(I) nitrate complexes, in which the alkyl substituent is either an allyl, a 2-methylallyl, an isopropyl or a 3-methyloxetan-3-yl-methyl chain, were synthesized and fully characterized. The eight N-coordinated silver(I) complexes were screened for both antimicrobial activities against Gram-negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii) and Gram-positive (Staphylococcus aureus, Staphylococcus aureus MRSA, and Enterococcus faecalis) bacteria and antifungal activities against Candida albicans and Candida glabrata strains. Moderate minimal inhibitory concentrations (MIC) of 0.087 μmol/mL were found when the Gram-negative and Gram-positive bacteria were treated with the silver complexes. Nevertheless, MIC values of 0.011 μmol/mL, twice lower than for the well-known fluconazole, against the two fungi were measured. In addition, molecular docking was carried out with the structure of Escherichia coli DNA gyrase and CYP51 from the pathogen Candida glabrata with the eight organometallic complexes, and molecular reactivity descriptors were calculated with the density functional theory-based calculation methods.

Synthesis and Characterization of a New Series of Bis(allylic-α-aminophosphonates) under Mild Reaction Conditions.

Several bis(α-aminophosphonates) have been conveniently prepared in good yields using a straightforward multicomponent Kabachnik-Fields reaction between ethane 1,2-diamine or propane 1,3-diamine, diethylphosphite and aldehydes under catalyst-free conditions. The nucleophilic substitution reaction of bis(α-aminophosphonates) prepared and ethyl (2-bromomethyl)acrylate under mild reaction conditions afforded an original synthetic approach to a new series of bis(allylic-α-aminophosphonates).

Order-Disorder, Symmetry Breaking, and Crystallographic Phase Transition in a Series of Bis(trans-thiocyanate)iron(II) Spin Crossover Complexes Based on Tetradentate Ligands Containing 1,2,3-Triazoles.

We report herein a series of neutral trans-thiocyanate mononuclear spin crossover (SCO) complexes, [FeIIL(NCS)2] (1-4), based on tetradentate ligands L obtained by reaction of N-substituted 1,2,3-triazolecarbaldehyde with 1,3-propanediamine or 2,2-dimethyl-1,3-diaminopropane [L = N1,N3-bis((1,5-dimethyl-1H-1,2,3-triazol-4-yl)methylene)propane-1,3-diamine/-2,2-dimethylpropane-1,3-diamine, 1/2 and N1,N3-bis((1-ethyl/1-propyl-1H-1,2,3-triazol-4-yl)methylene)-2,2-dimethylpropane-1,3-diamine, 3/4]. The thermal-induced SCO behavior is characterized by abrupt transitions with an average critical temperature (ΔT1/2)/hysteresis loop width (ΔThyst) in the range 190-252/5-14 K, while the photo-generated metastable high-spin (HS) phases are characterized by TLIESST temperatures in the range 44-59 K. Single crystal analysis shows that except 1, all compounds experience reversible symmetry breaking coupled with the thermal SCO. Furthermore, 4 experiences an additional phase transition at ca. 290 K responsible for the coexistence of two HS phases quenched at 10 K through LIESST and TIESST effects. The molecules form hexagonally packed arrays sustained by numerous weak CH···S and C···C/S···C/N···C bonds involving polar coordination cores, while non-polar pendant aliphatic substituents are segregated inside, occupying hexagonal channels. Energy framework analysis of complexes with one step SCO transition (1, 2, and 4) shows a correlation between the cooperativity and the amplitude of changes in the molecule-molecule interactions in the lattice at the SCO transition.

Synthesis of New Bis(pyrazolo[1,5-a]pyrimidines) Linked to Different Spacers as Potential MurB Inhibitors.

An efficient protocol was adopted to efficiently prepare three new series of bis(pyrazolo[1,5-a]pyrimidines) linked to different spacers. The new bis(pyrazolo[1,5-a]pyrimidines) were prepared in 80-90% yields by reacting the respective bis(enaminones) and 4-(4-substituted benzyl)-1H-pyrazole-3,5-diamines in pyridine at reflux temperature for 5-7 h. The new products showed a wide spectrum of antibacterial activity against six different bacterial strains. In general, propane- and butane-linked bis(pyrazolo[1,5-a]pyrimidines), which are attached to 3-(4-methyl- or 4-methoxybenzyl) units, had the best antibacterial activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values up to 2.5 and 5.1 µM, respectively. Additionally, the previous products demonstrated promising MurB inhibitory activity with IC50 values up to 7.2 µM.

Dibenzosuberyl substituents suppressing chain transfer in Bis(imino)pyridyl Iron(II) catalyzed ethylene polymerization

It is an efficient way to introduce ortho-aryl dibenzosuberyl substituents into late-transition metal catalysts for retarding chain transfer in olefin polymerization. Here, we further found that dibenzosuberyl substituents could also suppress chain transfer and thus increase the molecular weight in ethylene polymerization with bis(imino)pyridyl Fe(II) catalysts. A series of bis(imino)pyridyl ligands with unilateral diarylmethyl or dibenzosuberyl moiety on the ortho-positions of N-aryl rings and their corresponding Fe(II) catalysts were synthesized and characterized. All these bis(imino)pyridyl Fe(II) catalysts exhibited high polymerization activity and could generate high weight-average molecular weight polyethylenes with very broad molecular weight distributions in most cases. Among them, the dibenzosuberyl Fe(II) catalysts could generate ultra-high weight-average molecular weight (Mw = 2038–2137 kg/mol) polyethylenes at low temperatures, significantly higher than the diarylmethyl catalysts. The obtained polyethylenes are all highly linear with almost no branching distribution.

Investigation of the isothermal cure kinetics of new series of bis(trimellitimide) derived epoxy-imide resins

The isothermal curing kinetics of a newly synthesized series of trimellitimide-derived epoxy-imide resins were studied compared to their previously obtained non-isothermal results. Although the minimum isothermal curing temperature was ca. 30°C above the highest glass transition temperature of the fully cured systems, the curing processes did not complete. The absolute and relative conversions (α, α')-based values of isothermal activation energy (Ea) are extremely consistent with the non-isothermal ones in the early stages of the curing processes, but the transition to the diffusion control regime at α≈0.7 leads to the dramatic increase of the α-based Ea. We also found that utilizing α' results in physically meaningful trends. Moreover, evaluation of the reactions model showed evidence of autocatalytic behavior, although the curing processes behave like an nth-order reaction in the range of 0.1<α<0.7. The difference between non-catalytic and autocatalytic activation energies indicates that more autocatalytic feature appears in the aromatic resin system.

Phosphineoxide-Chelated Europium(III) Nanoparticles for Ceftriaxone Detection.

The present work demonstrates the optimization of the ligand structure in the series of bis(phosphine oxide) and β-ketophosphine oxide representatives for efficient coordination of Tb3+ and Eu3+ ions with the formation of the complexes exhibiting high Tb3+- and Eu3+-centered luminescence. The analysis of the stoichiometry and structure of the lanthanide complexes obtained using the XRD method reveals the great impact of the bridging group nature between two phosphine oxide moieties on the coordination mode of the ligands with Tb3+ and Eu3+ ions. The bridging imido-group facilitates the deprotonation of the imido- bis(phosphine oxide) ligand followed by the formation of tris-complexes. The spectral and PXRD analysis of the separated colloids indicates that the high stability of the tris-complexes provides their safe conversion into polystyrenesulfonate-stabilized colloids using the solvent exchange method. The red Eu3+-centered luminescence of the tris-complex exhibits the same specificity in the solutions and the colloids. The pronounced luminescent response on the antibiotic ceftriaxone allows for sensing the latter in aqueous solutions with an LOD value equal to 0.974 μM.