Despite significant progress in immunotherapy and chimeric antigen receptor T cell therapy of leukemia, chemotherapy is the major treatment option for the disease. Therefore, the development of ...potent and safe drugs for standard and targeted chemotherapy of leukemia remains an important task for medicinal chemists. A library of 94 diverse 6-aryl-4-cycloamino-1,3,5-triazine-2-amines was prepared using a one-pot microwave-assisted protocol, which involves a three-component reaction of cyanoguanidine, aromatic aldehydes and cyclic amines, and subsequent dehydrogenative aromatization of the dihydrotriazine intermediates in the presence of alkali. The cytotoxic properties of prepared compounds were evaluated against the leukemic Jurkat T cell line and the selectivity of the 24 most active compounds was also assessed using a normal fibroblast MRC-5 cell line, indicating selective antiproliferative activity against leukemic cells. The structure-activity relationship was analysed, and the prepared 3D-QSAR model was found to predict the antileukemic activity of the compounds with reasonable accuracy. In the cell morphology study, both apoptosis and necrosis features were observed in Jurkat T cells after treatment with the most active compound.
New potent and selective antileukemic agents were identified in the screening of 94 compounds prepared using a convenient one-pot three-component approach.
Five new compounds of benz
e
indole pyrazolyl-substituted amides (
2a–e
) were synthesised in low to good yields via the direct amide-coupling reaction between a pyrazolyl derivative containing a ...carboxylic acid and several amine substrates. The molecular structures were determined by various spectroscopic methods, such as NMR (
1
H,
13
C and
19
F), FT-IR and high-resolution mass spectrometry (HRMS). X-ray crystallographic analysis on the 4-fluorobenzyl derivative (
2d
) reveals the amide-
O
atom to reside to the opposite side of the molecule to the pyrazolyl-
N
and pyrrolyl-
N
atoms; in the molecular packing, helical chains feature amide-N‒H⋯N(pyrrolyl) hydrogen bonds. Density-functional theory (DFT) at the geometry-optimisation B3LYP/6-31G(d) level on the full series shows general agreement with the experimental structures. While the LUMO in each case is spread over the benz
e
indole pyrazolyl moiety, the HOMO spreads over the halogenated benzo-substituted amide moieties or is localised near the benz
e
indole pyrazolyl moieties. The MTT assay showed that
2e
, exhibited the highest toxicity against a human colorectal carcinoma (HCT 116 cell line) without appreciable toxicity towards the normal human colon fibroblast (CCD-18Co cell line). Based on molecular docking calculations, the probable cytotoxic mechanism of
2e
is through the DNA minor groove binding.
Graphical abstract
The crystal chemistry of the zinc-triad binary 1,1-dithiolates, that is, compounds of xanthate −S2COR, dithiophosphate −S2P(OR)2, and dithiocarbamate −S2CNR2 ligands, is reviewed. Owing to a wide ...range of coordination modes that can be adopted by 1,1-dithiolate anions, such as monodentate, chelating, μ2-bridging, μ3-bridging, etc., there exists a rich diversity in supramolecular assemblies for these compounds, including examples of zero-, one-, and two-dimensional architectures. While there are similarities in structural motifs across the series of 1,1-dithiolate ligands, specific architectures are sometimes found, depending on the metal centre and/or on the 1,1-dithiolate ligand. Further, an influence of steric bulk upon supramolecular aggregation is apparent. Thus, bulky R groups generally preclude the close approach of molecules in order to reduce steric hindrance and therefore, lead to lower dimensional aggregation patterns. The ligating ability of the 1,1-dithiolate ligands also proves crucial in determining the extent of supramolecular aggregation, in particular for dithiocarbamate species where the relatively greater chelating ability of this ligand reduces the Lewis acidity of the zinc-triad element, which thereby reduces its ability to significantly expand its coordination number. Often, the functionalisation of the organic substituents in the 1,1-dithiolate ligands, for example, by incorporating pyridyl groups, can lead to different supramolecular association patterns. Herein, the diverse assemblies of supramolecular architectures are classified and compared. In all, 27 structurally distinct motifs have been identified.
A practical three-component method for the synthesis of pyrazolo3,4-
d
pyrimidin-4-ones was developed. The reaction was performed in a one-pot manner under controlled microwave irradiation using ...easily accessible methyl 5-aminopyrazole-4-carboxylates, trimethyl orthoformate, and primary amines. Under the optimized conditions, challenging substrates, such as N-1 unsubstituted 5-aminopyrazole-4-carboxylates with another substituted amino group in position 3, reacted selectively affording 5-substituted 3-arylamino-1,5-dihydro-4
H
-pyrazolo3,4-
d
pyrimidin-4-ones. The reaction tolerated a range of primary amines, including anilines. The advantages of the developed protocol include short reaction time, pot- and step-economy, and convenient chromatography-free product isolation. The structural features of representative products were explored by X-ray crystallography.
A practical three-component method for the synthesis of pyrazolo3,4-
d
pyrimidin-4-ones was developed.
Three highly stable, hexacoordinated nonoxidovanadium(IV), VIV(L)2, complexes (1–3) have been isolated and structurally characterized with tridentate aroylhydrazonates containing ONO donor atoms. All ...the complexes are stable in the open air in the solid state as well as in solution, a phenomenon rarely observed in nonoxidovanadium(IV) complexes. The complexes have good solubility in organic solvents, permitting electrochemical and various spectroscopic investigations. The existence of nonoxidovanadium(IV) complexes was confirmed by elemental analysis, ESI mass spectroscopy, cyclic voltammetry, EPR, and magnetic susceptibility measurements. X-ray crystallography showed the N3O3 donor set to define a trigonal prismatic geometry in each case. All the complexes show in vitro insulin mimetic activity against insulin responsive L6 myoblast cells, with complex 3 being the most potent, which is comparable to insulin at the complex concentration of 4 μM, while the others have moderate insulin mimetic activity. In addition, the in vitro antiproliferative activity of complexes 1–3 against the HeLa cell line was assayed. The cytotoxicity of the complexes is affected by the various functional groups attached to the bezoylhydrazone derivative and 2 showed considerable antiproliferative activity compared to the most commonly used chemotherapeutic drugs.
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•45 indolenine-substituted pyrazoles and pyrimido1,2-bindazoles were evaluated.•Preliminary SAR analysis in the inhibition of S. aureus biofilm is presented.•The R1-fused benzene ring ...and R2-COOH group are crucial for antibiofilm activity.•A hit compound with MBIC50 and MBEC50 values comparable to the positive standards was identified.
Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are difficult to treat with antibiotics alone. Therefore, there is a need for an effective S. aureus biofilm inhibitor to combat this public health threat. In this study, a small library of indolenine-substituted pyrazoles and pyrimido1,2-bindazole derivatives were synthesised, of which the hit compound exhibited promising antibiofilm activities against methicillin-susceptible S. aureus (MSSA ATCC 29213) and methicillin-resistant S. aureus (MRSA ATCC 33591) at concentrations significantly lower than the planktonic growth inhibition. The hit compound could prevent biofilm formation and eradicate mature biofilms of MSSA and MRSA, with a minimum biofilm inhibitory concentration (MBIC50) value as low as 1.56 µg/mL and a minimum biofilm eradication concentration (MBEC50) value as low as 6.25 µg/mL. The minimum inhibitory concentration (MIC) values of the hit compound against MSSA and MRSA were 50 µg/mL and 25 µg/mL, respectively, while the minimum bactericidal concentration (MBC) values against MSSA and MRSA were >100 µg/mL. Preliminary structure-activity relationship analysis reveals that the fused benzene ring and COOH group of the hit compound are crucial for the antibiofilm activity. Additionally, the compound was not cytotoxic to human alveolar A549 cells, thus highlighting its potential as a suitable candidate for further development as a S. aureus biofilm inhibitor.
The X-ray structural chemistry of zinc and cadmium 1,1-dithiolates (for example, xanthate, dithiophosphate and dithiocarbamate) with potentially bridging bipyridyl-type ligands (for example, ...4,4′-bipyridine) is reviewed. For zinc, the xanthates and dithiophosphates uniformly form one-dimensional coordination polymers, whereas the zinc dithiocarbamates are always zero-dimensional, reflecting the exceptional chelating ability of dithiocarbamate ligands compared with xanthates and dithiophosphates. For cadmium, one-dimensional coordination polymers are usually found, reflecting the larger size of cadmium compared with zinc, but zero-dimensional aggregates are sometimes found. Steric effects associated with the 1,1-dithiolate-bound R groups are shown to influence supramolecular aggregation and, when formed, polymer topology in order to reduce steric hindrance; the nature of the bipyridyl-type ligand can also be influential. For the dithiocarbamates of both zinc and cadmium, in instances where the dithiocarbamate ligand is functionalised with hydrogen bonding potential, extended supramolecular architectures are often formed via hydrogen bonding interactions. Of particular interest is the observation that the bipyridyl-type ligands do not always bridge zinc or cadmium 1,1-dithiolates, being monodentate instead, often in the presence of hydrogen bonding. Thus, hydroxyl-O–H…N(pyridyl) hydrogen bonds are sometimes formed in preference to M←N(pyridyl) coordinate-bonds, suggesting a competition between the two modes of association.
The Cambridge Structural Database was surveyed for crystals featuring I⋯Br secondary-bonding in their supramolecular assemblies occurring independently of other obvious supramolecular synthons and ...devoid of other halogen bonding interactions. In all, 41 crystals satisfied these criteria, with nine examples of zero-dimensional aggregation (uniformly two-molecule aggregates) and 30 one-dimensional chains of varying topology (linear, zigzag and helical). There is one example each of two- and three-dimensional patterns. Type-I, type-II and intermediate bonding situations are apparent; for type-II bonding, the ratio of iodide:bromide functioning as the electrophile is 2:1. Most molecules participated, on average, in one I⋯Br contact, although smaller numbers of half (zero-dimensional) or two contacts (two- and three-dimensional) were observed. The propensity of the formation of related halogen bonding interactions in congeners of the 41 investigated crystals was also studied. Congeners were apparent for 11 crystals, with seven of these exhibiting isostructural relationships, in terms of space-group symmetry and unit-cell parameters. Isostructural relationships do not ensure the formation of analogous aggregation patterns, particularly and in accord with expectation, for the lighter halides. When formed, often distinct aggregation patterns are observed despite the isostructural relationships. Hetero-atomic halogen bonding offers surprises and opportunities in crystal engineering endeavours.
A series of indolenine and barbituric acid zwitterion scaffolds were synthesized with a maximum yield of 98%
via
the formation of C-C single bonds. The structures were unambiguously elucidated by ...various spectroscopic techniques such as
1
H,
13
C NMR (1D and 2D), FT-IR and high-resolution mass spectrometry (HRMS). Single crystal X-ray crystallography analysis on
22
, as the
22.DMF
1 : 1 solvate, confirms the presence of well-separated iminium and enolate centres, and also confirms that the BA ring is highly twisted with respect to the indolenine ring due to steric hindrance. The presence of N-H O
−
and N-H O
−
groups favours 1D-supramolecular assembly in the solid-state. The orange or yellow solutions of the zwitterion exhibit an intense molar absorption coefficient,
, ranging between 0.21 × 10
4
and 2.93 × 10
4
M
−1
cm
−1
in the UV-vis region. Furthermore, the Intramolecular Charge Transfer (ICT) peak of the zwitterion displays a hypsochromic shift in the absorption behavior when the polarity of the solvent increases. Moreover, treatment with a small amount of trifluoroacetic acid (TFA) with the DMF solution of
19
resulted in the protonation of the enolate of the BA ring. This fundamental work provides valuable structural design and information for the construction of supramolecular chemistry and synthetic dyes based on indolenine substituted BA derivatives.
The intermolecular hydrogen bonding of barbiturates assists in the supramolecular aggregation and a hypsochromic shift is shown in protic solvents.
Pyridyl- and indoleninyl-substituted pyrimido1,2-bindazole were synthesised in good to high yields from the condensation reaction of 1,3-dialdehydes with 3-aminoindazoles. The structural features of ...the compounds were determined by NMR (1H, 13C and 19F), FT-IR and HR-MS. The spectroscopic assignments were confirmed by X-ray crystallography for two derivatives, i.e., 9-Bromo-3-(pyridin-4-yl)pyrimido1,2-bindazole (1b) and 10-Methoxy-3-(pyridin-4-yl)pyrimido1,2-bindazole (1c), which further provides support for significant delocalisation of π-electron density over the entire fused ring system. The molecular packing was assessed by conventional methods together with Hirshfeld surface analyses. In 1b, the molecular packing features pyrimidyl-N–H···N(pyrimidyl), π(pyrazolyl)···π(pyrimidyl) and Br···N interactions within a two-dimensional array. In 1c, pyrimidyl-C–H···N(pyrazolyl) and pyridyl-C–H···O(methoxy) interactions feature within a three-dimensional architecture.
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