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1.
Bioorg Chem ; 127: 106032, 2022 10.
Article in English | MEDLINE | ID: mdl-35872398

ABSTRACT

Imidazo[4,5-b]pyridine derived acrylonitriles were synthesized and explored for their in vitro antiproliferative effect on a diverse human cancer cell line panel. Three compounds, 20, 21 and 33, showed strong activity in the submicromolar range (IC50 0.2-0.6 µM), and were chosen for further biological experiments. Immunofluorescence staining and tubulin polymerization assays confirmed tubulin as the main target, but excluded its colchicine-binding site as a potential interacting unit. This was supported by the computational analysis, which revealed that the most potent ligands act on the extended colchicine site on the surface between interacting tubulin subunits, where they interfere with their polymerization and reveal pronounced antitumor properties. In addition, lead molecule 21 potently inhibited cancer cell migration, while it did not affect the viability of normal cells even at the highest concentration tested (100 µM).


Subject(s)
Antineoplastic Agents , Neoplasms , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation , Colchicine/pharmacology , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Polymerization , Pyridines/chemistry , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators
2.
Eur J Med Chem ; 217: 113342, 2021 May 05.
Article in English | MEDLINE | ID: mdl-33751978

ABSTRACT

A novel series of tetracyclic imidazo[4,5-b]pyridine derivatives was designed and synthesized as potential antiproliferative agents. Their antiproliferative activity against human cancer cells was influenced by the introduction of chosen amino side chains on the different positions on the tetracyclic skeleton and particularly, by the position of N atom in the pyridine nuclei. Thus, the majority of compounds showed improved activity in comparison to standard drug etoposide. Several compounds showed pronounced cytostatic effect in the submicromolar range, especially on HCT116 and MCF-7 cancer cells. The obtained results have confirmed the significant impact of the position of N nitrogen in the pyridine ring on the enhancement of antiproliferative activity, especially for derivatives bearing amino side chains on position 2. Thus, regioisomers 6, 7 and 9 showed noticeable enhancement of activity in comparison to their counterparts 10, 11 and 13 with IC50 values in a nanomolar range of concentration (0.3-0.9 µM). Interactions with DNA (including G-quadruplex structure) and RNA were influenced by the position of amino side chains on the tetracyclic core of imidazo[4,5-b]pyridine derivatives and the ligand charge. Moderate to high binding affinities (logKs = 5-7) obtained for selected imidazo[4,5-b]pyridine derivatives suggest that DNA/RNA are potential cell targets.


Subject(s)
Antineoplastic Agents/pharmacology , DNA, Neoplasm/drug effects , Drug Design , Imidazoles/pharmacology , Pyridines/pharmacology , RNA, Neoplasm/drug effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites/drug effects , Cell Proliferation/drug effects , Cells, Cultured , DNA, Neoplasm/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , RNA, Neoplasm/chemistry , Structure-Activity Relationship
3.
Antioxidants (Basel) ; 8(10)2019 Oct 12.
Article in English | MEDLINE | ID: mdl-31614731

ABSTRACT

We present the synthesis of a range of benzimidazole/benzothiazole-2-carboxamides with a variable number of methoxy and hydroxy groups, substituted with nitro, amino, or amino protonated moieties, which were evaluated for their antiproliferative activity in vitro and the antioxidant capacity. Antiproliferative features were tested on three human cancer cells, while the antioxidative activity was measured using 1,1-diphenyl-picrylhydrazyl (DPPH) free radical scavenging and ferric reducing antioxidant power (FRAP) assays. Trimethoxy substituted benzimidazole-2-carboxamide 8 showed the most promising antiproliferative activity (IC50 = 0.6-2.0 µM), while trihydroxy substituted benzothiazole-2-carboxamide 29 was identified as the most promising antioxidant, being significantly more potent than the reference butylated hydroxytoluene BHT in both assays. Moreover, the latter also displays antioxidative activity in tumor cells. The measured antioxidative capacities were rationalized through density functional theory (DFT) calculations, showing that 29 owes its activity to the formation of two [O•∙∙∙H-O] hydrogen bonds in the formed radical. Systems 8 and 29 were both chosen as lead compounds for further optimization of the benzazole-2-carboxamide scaffold in order to develop more efficient antioxidants and/or systems with the antiproliferative activity.

4.
Chem Res Toxicol ; 32(9): 1880-1892, 2019 09 16.
Article in English | MEDLINE | ID: mdl-31381319

ABSTRACT

This paper discusses antioxidative and biological activities of 25 novel amidino substituted benzamides with a variety of heteroaromatic nuclei attached to the benzamide moiety and with a variable number of methoxy or hydroxy substituents. Targeted compounds, bearing either amidino or 2-imidazolinyl substituent, were obtained in the Pinner reaction from cyano precursors. 3D-QSAR models were generated to predict antioxidative activity of the 25 novel aromatic and heteroaromatic benzamide derivatives. The compounds were tested for antioxidative activity using in vitro spectrophotometric assays. Direct validation of 3D-QSAR approach for predicting activities of novel benzamide derivatives was carried out by comparing experimental and computationally predicted antioxidative activity. Experimentally determined activities for all novel compounds were found to be within a standard deviation of error of the models. Following this, structure-activity relationships among the synthesized compounds are discussed. Furthermore, antiproliferative activity in vitro against HeLa cells as well as antibacterial and antifungal activity was tested to confirm the other biological activities of the prepared compounds.


Subject(s)
Anti-Infective Agents/pharmacology , Antineoplastic Agents/pharmacology , Antioxidants/pharmacology , Benzamides/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Aspergillus/drug effects , Bacteria/drug effects , Benzamides/chemical synthesis , Benzamides/chemistry , Candida albicans/drug effects , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Microbial Sensitivity Tests , Molecular Structure , Principal Component Analysis , Quantitative Structure-Activity Relationship , Saccharomyces cerevisiae/drug effects
5.
Chem Res Toxicol ; 31(9): 974-984, 2018 09 17.
Article in English | MEDLINE | ID: mdl-30109922

ABSTRACT

We prepared a range of N-arylbenzamides with a variable number of methoxy and hydroxy groups, bearing either amino or amino-protonated moieties, and used DPPH and FRAP assays to evaluate their antioxidant capacity. Most of the systems exhibit improved antioxidative properties relative to the reference BHT molecule in both assays. Combining results from both sets of experiments, the most promising antioxidative potential was displayed by the trihydroxy derivative 26, which we propose as a lead compound for a further optimization of the benzamide scaffold. Computational analysis helped in interpreting the observed trends and demonstrated that protonated systems are better antioxidants than their neutral counterparts, while underlying the positive influence of the electron-donating methoxy group on the antioxidant properties, thus confirming the experiments. It also revealed that the introduction of the hydroxy groups shifts the reactivity from both amide and amine groups toward this moiety and additionally enhances antioxidative features. This is particularly evident in 26H•+, which owes its pronounced reactivity to the stabilizing [O•···H-O] hydrogen bonding between the created phenoxyl radical and the two neighboring hydroxy groups. We demonstrated that its antioxidative activities are more favorable than those for analogous trihydroxy derivatives without the N-phenyl group or without the amide moiety, which strongly justifies the employed strategy in utilizing bisphenylamides in designing potent antioxidants.


Subject(s)
Amines/chemistry , Antioxidants/pharmacology , Benzamides/pharmacology , Computer Simulation , Antioxidants/chemistry , Benzamides/chemistry , Free Radicals/chemistry , Hydrogen Bonding , Structure-Activity Relationship
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