Synthesis and bioactivity of novel amino-pyrazolopyridines (original) (raw)
Related papers
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.
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.
Facile synthesis and antiproliferative activity of new 3-cyanopyridines
BMC Chemistry
Background Pyridines have been reported to possess various pharmacological activities. Results Sodium 3-oxo-3-(2-oxo-2H-chromen-3-yl)prop-1-en-1-olate (2) and sodium 3-oxo-3-(3-oxo-3H-benzo[f]chromen-2-yl)prop-1-en-1-olate (7) were prepared and reacted with 2-cyano-N’-(1-aryl(heteryl)ethylidene)acetohydrazides 3a–d to produce 2-oxo-1,2-dihydropyridine-3-carbonitrile derivatives 5a–d and 9a–d, respectively, in good yields. Also, 3a–d reacted with sodium (2-oxocyclopentylidene)methanolate (11a) or sodium (2-oxocyclohexylidene) methanolate (11b) to yield 2-oxo-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitriles 13a–d and 2-oxo-hexahydroquinoline-3-carbonitriles 13e–h, respectively. The mechanisms that account for the formation of the products are discussed. Additionally, the structures of all the newly synthesized products are confirmed, based on elemental analysis and spectral data. Several of the newly synthesized compounds are evaluated for their antitumor activity against HEPG2 and...
Design, Synthesis and Cancer Cell Line Activities of Pyrazolo[3,4-b]pyridine Derivatives
Open Journal of Medicinal Chemistry, 2012
Starting from 4,6-dimethyl-2-oxo-(1H)-3-pyridinecarbonitrile 1 and 3-aminopyrazolopyridine 4, a series of cyanopyridine derivatives 3a-i, Schiff bases 5a-f, urea and thiourea derivatives 6a-b, amide derivatives 7a-h, pyridopyrazolopyrimidine 8a-b and pyridopyrazolotriazine 10a-b were synthesized. Activities of eleven representative compounds were evaluated against A-549 (lung), HEPG2 (liver) and HCT-116 (colon) cancer cell lines. The findings revealed that some of the synthesized compounds showed remarkable anticancer activities, especially 8b which displayed the highest activity among the tested compounds with IC 50 equal to 2.9, 2.6 and 2.3 µmol. In addition to synthesis and biological activities, we present discussion about the rationale of the design and activity of the potent compound 8b using structure-based modeling tools.
Bioorganic & Medicinal Chemistry Letters, 2007
4-Arylpyrano-[3,2-c]-pyridones have been prepared by a one-step cyclocondensation of 4hydroxy-1,6-dimethylpyridin-2(1H)-one with various substituted benzaldehydes and malononitrile. These heterocycles exhibit micromolar and submicromolar antiproliferative activity in HeLa and induce apoptosis in Jurkat cell lines. Structure-activity studies performed on a small library of these compounds show a pronounced cytotoxicity enhancing effect of the bromo substituent at the meta position of the C4 aromatic moiety.
Anticancer activities of some newly synthesized pyrazole and pyrimidine derivatives
Archives of Pharmacal Research, 2013
A series of pyrazolopyridine and pyridopyrimidine derivatives 2-6 were newly synthesized using 3,5-bisarylmethylene-1-methylpiperidone as the starting material. The anticancer activities of the synthesized compounds were evaluated using 59 different human tumor cell lines, representing cancers of CNS, ovary, renal, breast, colon, lung, leukemia, and melanoma, prostate as well as kidney. Some of the tested compounds, especially those with a fluorine substituent at the para-position in the phenyl ring and those with a pyridopyrimidine-2-thione with a free -NH or -SH, exhibited greater in vitro antitumor activities at low concentrations (log 10 [GI 50 ] = -4.6) against the human tumor cell lines. Additionally, some of the compounds had moderate inhibitory effects on the growth of the cancer cell lines. The detailed synthesis, spectroscopic data and antitumor properties of the synthesized compounds are reported.
Synthesis and Biological Evaluation of Some Pyrazolinylpyridines and Pyrazolylpyridines
Archiv Der Pharmazie, 2006
Various new 2-(1′-acetyl-5′-substituted-aryl-2′-pyrazolin-3′-yl)aminopyridines (3a–3e) and 2-(1′-phenyl 5′-substituted aryl-2′-pyrazol-3′-yl)aminopyridines (4a–4e) have been derived from 2-(substituted benzylidenylacetyl)aminopyridines (2a–2e). The structure of these compounds have been elucidated by elemental and spectral (IR, 1H-NMR, mass) analysis. Furthermore, above said compounds were evaluated for their insecticidal, antifungal, and antibacterial activities. Compound 4b 2-[1′-phenyl-5′-(o-chlorophenyl)-2′-pyrazol-3′-yl]aminopyridine, when compared for insecticidal and antifungal activities with parathion and fluconazole, respectively, was found to be the most potent one in this series. It also possessed remarkable antibacterial properties.
Bioorganic & Medicinal Chemistry Letters, 2010
The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3b and tumor growth in a BT474 tumor xenograft model in mice.
Bioorganic Chemistry, 2019
New series of fused pyrazolopyridines were prepared and assessed for antimicrobial, antiquorum-sensing and antitumor activities. Antimicrobial screening toward selected Gram-positive bacteria, Gram-negative bacteria and fungi indicated that 5-phenylpyrazolopyridotriazinone 4a has good and broad-spectrum antimicrobial activity. In addition, 5-(4-chlorophenyl)pyrazolopyridotriazinone 4b and 5-(4-(dimethylamino)phenyl)pyrazolopyridotriazinone 4c exhibited good activity against the tested Gram-positive bacteria and A. fumigatus, whereas 5-amino-4phenylpyrazolopyridopyrimidine 6a demonstrated good activity against B. cereus and P. aeruginosa. Furthermore, 6-amino-5-imino-4-phenylpyrazolopyridopyrimidine 7a and 6amino-4-(4-chlorophenyl)-5-imino-4-phenylpyrazolopyridopyrimidine 7b demonstrated promising activity against the tested Gram-negative bacteria and fungi, and moderate activity against Gram-positive bacteria. Antiquorum-sensing screening over C. violaceum illustrated that compounds 4a, 6a and 7a-c have strong activity. In vitro antiproliferative screening of the new members against HepG2, HCT-116 and MCF-7 cancer cells revealed that 6-amino-5-imino-4-phenylpyrazolopyridopyrimidine 7a is the most active analog against all tested cell lines. Likewise, 3,7-dimethyl-4-phenylpyrazolopyridopyrimidinone 2a and 6-amino-4-(4-chlorophenyl)-5-imino-4-phenylpyrazolopyridopyrimidine 7b manifested strong activity against all examined cell lines. In vivo antitumor testing of 3,7-dimethyl-4phenylpyrazolopyridopyrimidinone 2a, 6-amino-5-imino-4phenylpyrazolopyridopyrimidine 7a and 6-amino-4-(4-chlorophenyl)-5-iminopyrazolopyridopyrimidine 7b against EAC cells in mice indicated that 7a has the highest activity. Cytotoxicity against WI38 and WISH normal cells was also assessed and results assured that all investigated analogs have lower cytotoxicity than doxorubicin. DNAbinding affinity and topoisomerase II inhibitory activity were evaluated, and results revealed that 5b, 7a and 7b have strong DNA-binding affinity; in addition, 2a, 4a, 7a and 7b manifested higher topoisomerase II inhibitory activity than that of doxorubicin. Analogs 5b, 7a and 7b were docked into topoisomerase II and results indicated that 7a and 7b have-2-the highest binding affinity toward topoisomerase II. In silico simulation studies referred that most of the new analogs comply with the optimum needs for good oral absorption. Also, computational carcinogenicity evaluation was predicted.