Facile synthesis and antiproliferative activity of new 3-cyanopyridines (original) (raw)
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Chemistry of Heterocyclic Compounds, 2009
The reaction of 2-chloro-4,6-dimethylpyridine-3-carbonitrile with hydrazine hydrate, hydroxylamine, and anthranilic acid afforded the corresponding pyrazolo, isoxazolo, and pyridoquinazoline derivatives. Alkylation of 2-mercapto-4,6-dimethylpyridine-3-carbonitrile with ethyl chloroacetate or phenacyl bromide followed by cyclization in NaOH gave thienopyridine derivatives. Diazotization of ethyl 3-amino-4,6-dimethylthiеno[2,3-b]pyridine-2-carboxylate followed by the reaction with thiourea, guanidine carbonate, and hydroxylamine hydrochloride gave the corresponding thienopyridine derivatives. The biological activity of some new compounds has been discussed.
Design and Synthesis of New Substituted Pyrazolopyridines with Potent Antiproliferative Activity
Medicinal Chemistry, 2020
Background:Purine isosteres are often endowed with interesting pharmacological properties, due to their involvement in cellular processes replacing the natural purines. Among these compounds, pyrazolopyridines are under active investigation for potential anticancer properties.Objectives:Based on previously discovered substituted pyrazolopyridines with promising antiproliferative activity, we designed and synthesized new, suitably substituted analogues aiming to investigate their potential activity and contribute to SAR studies of this class of bioactive compounds.Methods:The new compounds were synthesized using suitably substituted 2-amino-4-picolines, which upon ring-closure provided substituted pyrazolo[3,4-c] pyridine-5-carbonitriles that served as key intermediates for the preparation of the target 3,5,7 trisubstituted derivatives. The antiproliferative activity of 31 new target derivatives was evaluated against three cancer cell lines (MIA PaCa-2, PC-3 and SCOV3), whereas cell-cycle perturbations of exponentially growing PC-3 cells, using three selected derivatives were also performed.Results:Eight compounds displayed IC50 values in the low μM range, allowing the extraction of interesting SAR’s. Two of the most potent compounds against all cell lines share a common pattern, by accumulating cells at the G0/G1 phase. From this project, a new carboxamidine-substituted hit has emerged.Conclusion:Among the new compounds, those possessing the 3-phenylpyrazolo[3,4-c]pyridine scaffold, proved to be worth investigating and the majority of them showed strong cytotoxic activity against all cell lines, with IC50 values ranging from 0.87–4.3 μM. A carboxamidine analogue that resulted from the synthetic procedure, proved to be highly active against the cancer cells and could be considered as a useful lead for further optimization.
CHEMICAL & PHARMACEUTICAL BULLETIN, 2015
The multi-component reaction of either acetoacetanilide derivative 1a or b with any of the aldehyde derivatives 2a-d and malononitrile 3 in the presence of triethylamine as a catalyst gave the 4H-pyran derivatives 4a-g, respectively. Carrying the same reaction but using a catalytic amount of ammonium acetate gave the 1,4-dihydropyridine derivatives 5a-f, respectively. The use of ethyl cyanoacetate instead of malononitrile in the presence of a catalytic amount of triethylamine gave the 4H-pyran derivatives 7a-d, respectively. Compound 4e was used to synthesize 1,4-dihydropyridine 9a-c and arylhydraone 11a-e derivatives were synthesized from 4a and e. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that compounds 4a, b, f, 5d, f, 9 and 11a-d had optimal cytotoxic effect against cancer cell lines with IC 50 <550 nM. The toxicity of the most active compounds was further measured against shrimp larvae.
The discovery of new cytotoxic pyrazolopyridine derivatives
Bioorganic & Medicinal Chemistry Letters, 2016
A number of new 3,7-disubstituted pyrazolo[3,4-c]pyridines have been designed and synthesized from suitable 2-aminopyridines. The antiproliferative activity of the derivatives was determined against the pancreatic MIA PaCa-2 and ovarian SCOV3 cancer cell-lines. IC 50 values of the most promising analogue 46 lie in the submicromolar or low micromolar range. Furthermore, compound 46 shows similar inhibitory activities against DU145, A2058 and PC-3 cancer cells, blocks the cell cycle at the G 0 /G 1 phase and induce apoptosis, as determined by the appearance of apoptotic nuclei.
Tropical Journal of Pharmaceutical Research, 2021
Purpose: To synthesize novel pyridine derivatives and evaluate their efficiency as potent inhibitors of cyclin dependent kinase 2 (CDK2) enzyme for cancer therapy.Methods: Pyridine scaffold were synthesized using one-pot multicomponent condensation reaction of arylidine with different primary amines. The cytotoxic potential of the new compounds was assessed using various cell lines. Furthermore, molecular docking studies based on the crystal structure of CDK2 was carried out to determine the possible binding modes that influence the anticancer activities.Results: The results indicate that one-pot multicomponent reaction generated a series of functionalized pyridines with good yield. In vitro cytotoxicity study revealed superior cytotoxicity of the designed compounds against prostate and cervical cancer cell lines compared to 5-fluorouracil (standard anticancer compound) with half-maximal inhibitory concentration (IC50) values of 0.1 – 0.85 and 1.2 –74.1 μM, respectively. Finally, mo...
Molecules, 2011
The title compounds were prepared by reaction of 6-acetyltetralin (1) with different aromatic aldehydes 2a-c, namely 2,6-dichlorobenzaldehyde, 2,6-diflourobenzaldehyde, and 3-ethoxy-4-hydroxybenzaldehyde, to yield the corresponding α,β-unsaturated ketones 3a-c. Compound 3b was reacted with hydrazine hydrate to yield the corresponding 2-pyrazoline 4, while compounds 3a,b reacted with thiourea to afford the 2-thioxopyrimidine derivatives 5a,b, respectively. The reaction of 1, and the aromatic aldehydes 2a-c with ethyl cyanoacetate, 2-cyano-thioacetamide or malononitrile in the presence of ammonium acetate yielded the corresponding 2-oxopyridines 6a,b, 2-thioxopyridines 7a-c or 2-iminopyridines 8a,b, respectively. The newly prepared compounds were evaluated for anticancer activity against two human tumor cell lines. Compound 3a showed the highest potency with IC 50 = 3.5 and 4.5 μg/mL against a cervix carcinoma cell line (Hela) and breast carcinoma cell line (MCF7), respectively.
Journal of Molecular Structure, 2023
Novel pyridine-3-carbonitrile derivatives, denoted as (4a-j), were synthesized using a convergent synthetic approach that involved a one-pot four-component reaction. This was achieved by utilizing a combination of various aromatic aldehydes, acetophenone derivatives, malononitrile, and four different sodium alkoxide solutions. The synthesized compounds were characterized using various spectroscopic techniques such as IR, 1 H-NMR, 13 C-NMR, and elemental analysis. Molecular docking simulations were employed to investigate the binding affinity of compounds (4a-j) towards two proteins, DHFR and HT-hTS. The results revealed that 4-(4-chlorophenyl)-2-ethoxy-6-phenyl-pyridine-3-carbonitrile (4a) compound exhibited the highest binding affinity score (G =-8.06 Kcal/mol) upon docking into the active site of DHFR, while 2-(4-nitrophenyl)-6-(4-chlorophenyl)-4-ethoxy-pyridine-3-carbonitrile (4d) compound displayed the strongest binding affinity score (G =-4.17 Kcal/mol) when docked to the active site of HT-hTS. These results were supported by the cytotoxic activity of selected compounds (4a, 4b, 4e, and 4h) against human cancer cell lines (MCF7, HT29, and A2780) as well as normal human fetal lung fibroblast (MRC5) using MTT assay. The cytotoxicity analyses revealed that compound (4a) displayed cytotoxic activity against all cancer cell lines, particularly human colorectal carcinoma (HT29) with an IC 50 value of 2.243±0.217 μM, which is lower than that of the reference drug (Doxorubicin) with an IC 50 value of 3.964±0.360 μM. Furthermore, 3 compound (4a) exhibited a lower cytotoxic effect on normal human fetal lung fibroblast (MRC5) with an IC 50 value of 2.222±0.137 μM, as compared to the IC 50 value of the reference drug (Doxorubicin) which was 2.476±0.033 μM. The antimicrobial activity of selected compounds such as (4a, 4c, and 4f) was also evaluated against a panel of microorganisms, including two gram-positive strains (Staphylococcus aureus and Enterococcus faecalis) and two gram-negative strains (Escherichia coli and Pseudomonas aeruginosa). The zone of inhibition and minimum inhibition concentration (MIC) demonstrated the potency of these compounds. Specifically, compounds 4-(4-chlorophenyl)-2-ethoxy-6-phenyl-pyridine-3-carbonitrile (4a) and 4-(4-methoxyphenyl)-2-methoxy-6-(4-nitrophenyl)-pyridine-3-carbonitrile (4f) exhibited MIC of 0.013 µM against Escherichia coli strains, which is comparable to that of the reference drug amoxicillin (MIC=0.01 µM). Finally, Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TDDFT) studies were performed on compounds (4a-j) to obtain a more comprehensive understanding of the structure-activity relationship and solvatochromic behavior of these molecules. Overall, the results suggest that compound (4a) could potentially serve as a promising cytotoxic and antibacterial agent with a better safety profile and reduced side effects on normal cells.
Molecules (Basel, Switzerland), 2015
1-(2,4-Dichlorophenyl)-3-(4-fluorophenyl)propen-1-one (1) was prepared and reacted with an active methylene compound (ethyl cyanoacetate) in the presence of ammonium acetate to give the corresponding cyanopyridone 2. Compound 2 reacted with hydrazine hydrate, malononitrile, ethyl bromoacetate and phosphorous oxychloride to afford compounds 4 and 7-11, respectively. The 2-chloropyridine derivative 11 reacted with different primary amines, namely benzyl amine, piperonyl amine, 1-phenylethyl amine, and/or the secondary amines 2-methyl-pipridine and morpholine to give the corresponding derivatives 12-15. Hydrazinolysis of chloropyridine derivative 11 with hydrazine hydrate afforded the corresponding hydrazino derivative 17. Condensation of compound 17 with ethyl acetoacetate, acetylacetone, isatin and different aldehydes gave the corresponding derivatives 18-21. Some of newly synthesized compounds were screened for cytotoxic activity against three tumor cell lines. The results indicated...
Synthesis and in vitro antitumoral activity of new hydrazinopyrimidine-5-carbonitrile derivatives
Bioorganic & Medicinal Chemistry, 2006
A new series of 2-amino-4-aryl-6-dialkylamino-3,5-dicyanopyridines, 20-47, were synthesized in satisfactory overall yield, through a simple synthetic strategy using 3-amino-3-(dialkylamino)-propenenitriles 1 and 2 as key intermediates. 3,5-Dicyanopyridine derivatives 20-47 were evaluated for their in vitro anticancer activity toward cell lines of nine different types of human cancers. Some of the newly prepared compounds demonstrated inhibitory effects on the growth of a wide range of cancer cell lines generally at 10 À6 M level and in some cases at 10 À8 M concentration.
Pharmaceuticals
In the current work, we designed and synthesized three families of non-fused and fused compounds based on cyanopyridone: derivatives of 6-amino-1,2-dihydropyridine-3,5-dicarbonitrile (5a-f) and 3,4,7,8-tetrahydro pyrimidine-6-carbonitrile (6a-b and 7a-e). The newly synthesized compounds’ structure were determined using a variety of techniques, including 1H NMR, 13C NMR, mass spectrum, infrared spectroscopy, and elemental analysis. The developed compounds were tested for the ability to inhibit the growth of breast adenocarcinoma (MCF-7) and hepatic adenocarcinoma (HepG2) cell lines using MTT assay. Some of the synthesized compounds were more effective towards the cancer cell lines than the standard treatment taxol. The best antiproliferative activities were demonstrated by non-fused cyanopyridones 5a and 5e against the MCF-7 cell line (IC50 = 1.77 and 1.39 μM, respectively) and by compounds 6b and 5a against the HepG2 cell line (IC50 = 2.68 and 2.71 μM, respectively). We further expl...