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•Twenty novel 2-substituted quinoline-4-carboxylic acids were synthesized.•Several compounds exhibited good hDHODH inhibitory activity.•Very low cytotoxicity against healthy HaCaT ...cell was observed.•Optimal lipophilicity was determined at physiological pH.•Molecular docking distinguished highly active from low active hDHODH inhibitors.
Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound’s pharmacology and provide guidelines for further lead optimization.
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Two 2-amino-1,3,4-thiadiazoles containing phenolic hydroxyl groups were combined with different carboxylic acid chlorides giving sixteen amide derivatives with good antioxidant and ...antiproliferative potential. The compound 3′c with an adamantane ring displayed excellent DPPH radical scavenging activity and good cytotoxic activity against human acute promyelocytic leukemia HL-60 cells, while 1,3,4-thiadiazole 3′h with 4-chlorophenyl moiety was found to be the most effective in inhibition of survival of lung carcinoma A549 cells. All examined thiadiazoles except 3a and 3′a exerted higher cytotoxic activities on A549 and HL-60 cancer cells when compared with normal fibroblasts MRC-5, pointing to selectivity in their antiproliferative action. Some of the most active novel compounds 3c, 3′c, 3′g and 3′h induced significant increase in the percentage of HL-60 cells in the subG1 cell cycle phase in comparison with the control cells. The induction of cell death in HL-60 cells by these compounds was at least partially dependent on activation of caspase-3 and caspase-8. The compounds 3c and 3′c exerted strong antiangiogenic activity. Furthermore, compounds 3c, 3′c, 3′g and 3′h showed the ability to down-regulate the MMP2 and VEGFA expression levels in the treated HL-60 cells when compared with the control cell samples.
A new class of imine derivatives of hybrid chalcone analogues containing anthraquinone scaffold was synthesized and evaluated for their in vitro cytotoxic activity against HeLa, LS174, and A549 ...cancer cells. The compound 5n with furan ring linked to imino group showed potent activity against all target cells with IC50 values ranging from 1.76 to 6.11μM. A mode of action study suggested that compounds induced changes typical for apoptosis in HeLa cells. The most active compounds inhibited tubulogenesis and 5h was found to exhibit a strong anti-angiogenic effect.
Hybrid compounds that combine the 1,3,4-thiadiazole-containing catechol moiety with a chalcone motif were synthesized and examined for their antioxidant activity, cytotoxicity, and DNA-binding ...activity. A series of thirteen compounds showed strong antioxidant and cytotoxic effects on human acute promyelocytic leukemia HL-60 cells. Several compounds exerted good cytotoxic activities on cervical adenocarcinoma HeLa cells. The treatment of HeLa cells with IC
and double IC
concentrations of the compounds
,
,
, and
induced a statistically significant increase in the percentage of cells within a subG1 cell cycle phase. The examined compounds caused G2/M cell cycle arrest in HeLa cells. Each of these compounds triggered apoptosis in HeLa cells through activation of caspase-3, the main effector caspase, caspase-8, which is involved in the extrinsic apoptotic pathway, and caspase-9, which is involved in the intrinsic apoptotic pathway. All of the examined compounds decreased the expression levels of MMP2 in HeLa cells and levels of protumorigenic miR-133b. Compounds
and
lowered the expression level of oncogenic miR-21 in HeLa cells. In addition, compounds
,
, and
decreased the expression levels of oncogenic miR-155 while the treatment of HeLa cells with compounds
,
, and
increased expression of tumor-suppressive miR-206. Observed effects of these compounds on expression levels of four examined miRNAs suggest their prominent cancer-suppressive activity. An investigation by absorption and fluorescence spectroscopy showed more efficient calf thymus DNA binding activity of the compound
in comparison to other tested compounds. Results of a pUC19 plasmid cleavage study and comet assay showed DNA damaging activities of compounds
and
.
Fourteen novel quinoline‐4‐carboxylic acid‐chalcone hybrids were obtained via Claisen–Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ...ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 μM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N‐terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.
Fourteen novel quinoline‐4‐carboxylic acid‐chalcone hybrids were synthesized and screened as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. Six compounds showed better hDHODH inhibitory activity than the reference drug, leflunomide. Compound 4d demonstrated the highest cytotoxic activity against A375 cells. Bioactive conformations within hDHODH were resolved by molecular docking.
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•A new class of 2-substituted quinoline-4-carboxylic acids was synthesized.•Several compounds exhibited excellent hDHODH inhibition and good lipophilicity.•High cytotoxicity against ...MCF-7 and A375 cancer cell lines was observed.•Only one hydrophobic substituent led to high selectivity.•Molecular docking distinguished highly active from low active hDHODH inhibitors.
A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD7.4 values obtained by the experimental method were found to be in the range from −1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.
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•Twenty-three anthraquinone-chalcone hybrids were synthesized and characterized.•The compounds exerted strong cytotoxicity against three human leukemia cell lines.•Four tested ...compounds decreased expression levels of MMP2, MMP9 and VEGFA.•MiR-155 expression strongly depends on the nature and position of substituents.•The 3-D QSAR models for 6f and 6e confirm pro-apoptotic activity against caspase-3.
A series of 23 novel anthraquinone-chalcone hybrids containing amide function was synthesized and structurally characterized. Sixteen compounds exerted strong cytotoxic activities against K562, Jurkat and HL-60 leukemia cell lines and significantly lower cytotoxic effects against normal MRC-5 cells, indicating very high selectivity in their anticancer action. The compounds 6g, 6u and 6v activate apoptosis in K562 cells through the extrinsic and intrinsic apoptotic pathway. The compound 6e triggered apoptosis in K562 cells only through the extrinsic apoptotic pathway. Treatment of K562 cells with each of these four compounds caused decrease in the expression levels of MMP2, MMP9, and VEGF, suggesting their anti-invasive, antimetastatic and antiangiogenic properties. The compounds 6g and 6v downregulated expression levels of miR-155 in K562 cells, while compounds 6e and 6u upregulated miR-155 levels in treated cells, in comparison with control cells. The structure-based 3-D QSAR models for 6f, 6e, 6i and 6l describe pro-apoptotic activity against caspase-3.
An efficient pTSA-mediated cyclization cascade reaction of Pfitzinger's ester and benzoyl hydrazines has been developed providing a simple procedure for synthesis of pyrrolo 3,4-cquinoline-1,3-dione ...derivatives. Unlike traditional synthetic protocol, this method avoids an additional step of conversion of quinoline-3,4-dicarboxylic acids to an anhydride, allowing direct reaction of ester derivative with hydrazine nucleophiles.
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•Pyrrolo3,4-cquinoline-1,3-diones were prepared by cyclization cascade reactions.•New class of potent hDHODH inhibitory demonstrated better activity than leflunomide.•Very low ...cytotoxicity against healthy HaCaT cells was observed.•The optimal lipophilicity was determined at physiological pH value.•The toxicological profile of the most active compounds was evaluated.
Twenty N-substituted pyrrolo3,4-cquinoline-1,3-diones 3a-t were synthesized by a cyclization reaction of Pfitzinger's quinoline ester precursor with the selected aromatic, heteroaromatic and aliphatic amines. The structures of all derivatives were confirmed by IR, 1H NMR, 13C NMR and HRMS spectra, while their purity was determined using HPLC techniques. Almost all compounds were identified as a new class ofpotent inhibitors against hDHODH among which 3a and 3t were the most active ones with the same IC50 values of 0.11 μM, about seven times better than reference drug leflunomide. These two derivatives also exhibited very low cytotoxic effects toward healthy HaCaT cells and the optimal lipophilic properties with logP value of 1.12 and 2.07 respectively, obtained experimentally at physiological pH. We further evaluated the comparative differences in toxicological impact of the three most active compounds 3a, 3n and 3t and reference drug leflunomide. The rats were divided into five groups and were treated intraperitoneally, control group (group I) with a single dose of leflunomide (20 mg/kg) group II and the other three groups, III, IV and V were treated with 3a, 3n and 3t (20 mg/kg bw) separately. The investigation was performed in liver, kidney and blood by examining serum biochemical parameters and parameters of oxidative stress.
Nine imines and the corresponding amines were synthesized and screened for their in vitro antimicrobial activity against 11 bacteria and three fungal/yeast strains. One of amines (R
=
tert-butyl) ...showed the higher activity in comparison with widely used tetracycline.
A series of new imines and amines have been synthesized by condensation of 1
H-3-ferrocenyl-1-phenylpyrazole-4-carboxaldehyde with the corresponding amines, followed by reduction with sodium borohydride. The synthesized compounds have been screened for their in vitro antimicrobial activity against 11 bacteria and three fungal/yeast strains, using disc diffusion and broth microdilution susceptibility assays. They have shown a wide range of activities, from completely inactive to the highly active compounds.
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