A series of novel 2,6-diphenyl substituted imidazo4,5-bpyridines was designed and synthesized using optimized Suzuki cross coupling to evaluate their biological activity in vitro. The conditions of ...the Suzuki coupling were evaluated and optimized using a model reaction. To study the influence of the substituents on the biological activity, we prepared N-unsubstituted and N-methyl substituted imidazo4,5-bpyridines with different substituents at the para position on the phenyl ring placed at position 6 on the heterocyclic scaffold. Antiproliferative activity was determined on diverse human cancer cell lines, and the selectivity of compounds with promising antiproliferative activity was determined on normal peripheral blood mononuclear cells (PBMC). Pronounced antiproliferative activity was observed for p-hydroxy substituted derivatives 13 and 19, both displaying strong activity against most of the tested cell lines (IC50 1.45–4.25 μM). The unsubstituted N-methyl derivative 19 proved to be the most active derivative. There was a dose-dependent accumulation of G2/M arrested cells in several cancer cell lines after exposure to compound 19, implying a cell cycle-phase-specific mechanism of action. Additionally, the novel series of derivatives was evaluated for antiviral activity against a broad panel of viruses, yet the majority of tested compounds did not show antiviral activity.
Herein, we present the design and synthesis of novel
-substituted benzimidazole-derived Schiff bases, and the evaluation of their antiviral, antibacterial, and antiproliferative activity. The impact ...on the biological activity of substituents placed at the N atom of the benzimidazole nuclei and the type of substituents attached at the phenyl ring were examined. All of the synthesized Schiff bases were evaluated in vitro for their antiviral activity against different viruses, antibacterial activity against a panel of bacterial strains, and antiproliferative activity on several human cancer cell lines, thus enabling the study of the structure-activity relationships. Some mild antiviral effects were noted, although at higher concentrations in comparison with the included reference drugs. Additionally, some derivatives showed a moderate antibacterial activity, with precursor
being broadly active against most of the tested bacterial strains. Lastly, Schiff base
a 4-
,
-diethylamino-2-hydroxy-substituted derivative bearing a phenyl ring at the N atom on the benzimidazole nuclei, displayed a strong antiproliferative activity against several cancer cell lines (IC
1.1-4.4 μM). The strongest antitumoral effect was observed towards acute myeloid leukemia (HL-60).
Newly designed pentacyclic benzimidazole derivatives featuring amino or amido side chains were synthesized to assess their in vitro antiproliferative activity. Additionally, we investigated their ...direct interaction with nucleic acids, aiming to uncover potential mechanisms of biological action. These compounds were prepared using conventional organic synthesis methodologies alongside photochemical and microwave-assisted reactions. Upon synthesis, the newly derived compounds underwent in vitro testing for their antiproliferative effects on various human cancer cell lines. Notably, derivatives
and
exhibited significant antiproliferative activity within the submicromolar concentration range. The biological activity was strongly influenced by the N atom's position on the quinoline moiety and the position and nature of the side chain on the pentacyclic skeleton. Findings from fluorescence, circular dichroism spectroscopy, and thermal melting assays pointed toward a mixed binding mode-comprising intercalation and the binding of aggregated compounds along the polynucleotide backbone-of these pentacyclic benzimidazoles with DNA and RNA.
In this paper, we report the synthesis of novel hybrids
2
–
14
based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with ...a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cysteine residue of a specific protein. Aromatic parts of the hybrids also come from the substances reported as anticancer or antiviral agents. The synthetic route employed to access the amido-ester hybrids
2
–
13
used monomethyl itaconate or monomethyl itaconyl chloride and corresponding amines as the starting materials. Dimers
14
and
15
with two aminoindole or mefloquine moieties were prepared from itaconic acid and corresponding amino derivative, using standard coupling conditions (HATU/DIEA). All hybrids exerted anticancer effects in vitro against almost all the tumour cell lines that were evaluated (MCF-7, HCT 116, H460, LN-229, Capan-1, DND-41, HL-60, K-562, Z-138). Solid tumour cells were, in general, more responsive than the haematological cancer cells. The MCF-7 breast adenocarcinoma cell line appeared the most sensitive. Amido-ester
12
with chloroquine core and mefloquine homodimer
15
showed the highest activity with GI
50
values between 0.7 and 8.6 µM. In addition, compound
15
also exerted antiviral activity against Zika virus and Coxsackievirus B4 in low micromolar concentrations.
Graphic abstract
Sixteen new 2-substituted quinazolines were synthesized using a straightforward methodology starting from 2-methoxybezoic acid or 3-methoxy-2-naphthoic acid. The anti-proliferative activity of the ...target compounds was evaluated against nine cancer cell lines. Additionally, all the compounds were screened for their potency and selectivity against a panel of 109 kinases and four bromodomains, using Differential Scanning Fluorimetry (DSF). Compound
bearing a 2-methoxyphenyl substitution along with a basic side chain displayed a remarkable profile against the majority of the tested cell lines.
A series of cyano- and amidino-substituted imidazo4,5-
pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation ...included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound
, which contained an unsubstituted amidino group, and compound
, which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC
0.4 and 0.7 μM, respectively). All tested compounds lacked antibacterial activity, with the exception of compound
, which showed moderate activity against
(MIC 32 μM). Bromo-substituted derivative
, which contained an unsubstituted phenyl ring (EC
21 μM), and
-cyano-substituted derivative
(EC
58 μM) showed selective but moderate activity against respiratory syncytial virus (RSV).
A convenient strategy for molecular editing of available
-kauranic natural scaffolds has been developed based on radical mediated C-C bond formation. Iodine atom transfer radical addition (ATRA) ...followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the
-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing
-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates.
Herein, we present the design, synthesis, and biological activity of novel iminocoumarin imidazo4,5-
b
pyridine derivatives. The prepared compounds were designed to study the type of substituent in ...position 6 of the coumarin nucleus as well as the type of the substituent at the N atom of imidazo4,5-
b
pyridine core for their effect on the biological activity. Therefore, all compounds were tested for their antiproliferative action on several human cancer cell lines
in vitro
, for their antioxidative activity, antibacterial activity on several bacterial strains, and for their antiviral activity on several viruses. The results of the evaluation of biological activity revealed that the tested derivatives did not display significant biological activities. The majority of the tested compounds were not active at all, while some derivatives showed low activity in these assays. Therefore, we could conclude that the biological potential of 6-substituted iminocoumarin derivatives is very low – the substitution in position 6 of the coumarin nucleus, in comparison to 7-substituted iminocoumarins, strongly decreases biological activity.
We used classical linear and microwave-assisted synthesis methods to prepare novel
-substituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in ...vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin's β-subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues.
The superimposition of the X-ray complexes of cyclohexanediones (i.e., TUB015), described by our research group, and nocodazole, within the colchicine binding site of tubulin provided an almost ...perfect overlap of both ligands. This structural information led us to propose hybrids of TUB015 and nocodazole using a salicylanilide core structure. Interestingly, salicylanilides, such as niclosamide, are well-established signal transducers and activators of transcription (STAT3) inhibitors with anticancer properties. Thus, different compounds with this new scaffold have been synthesized with the aim to identify compounds inhibiting tubulin polymerization and/or STAT3 signaling. As a result, we have identified new salicylanilides (6 and 16) that showed significant antiproliferative activity against a panel of cancer cells. Both compounds were able to reduce the levels of p-STAT3Tyr705 without affecting the total expression of STAT3. While compound 6 inhibited tubulin polymerization and arrested the cell cycle of DU145 cells at G2/M, similar to TUB015, compound 16 showed a more potent effect on inhibiting STAT3 phosphorylation and arrested the cell cycle at G1/G0, similar to niclosamide. In both cases, no toxicity towards PBMC cells was detected. Thus, the salicylanilides described here represent a new class of antiproliferative agents affecting tubulin polymerization and/or STAT3 phosphorylation.
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