Pfitzinger Reaction in the Synthesis of Bioactive Compounds - A Review

Sangshetti, Jaiprakash N.; Zambare, Abhay S.; Gonjari, Indrajeet D.; Shinde, Devanand B.

doi:10.2174/1570193x113106660020

Cited by 23 publications

(11 citation statements)

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“…Starting from the commercially available 5‐methyl‐4‐nitro‐3‐(trifluoromethyl)‐1 H ‐pyrazole 62 benzylation with Cs 2 CO 3 yielded regioselectively nitropyrazole 64 that was subsequently reduced using zinc under acidic conditions . With this aminopyrazole in hand the quinoline part of BAY‐876 ( 19 ) was derived from inexpensive 6‐fluoroisatine 66 that was converted into the 7‐fluoroquinoline‐2,4‐dicarboxylic acid 67 with pyruvic acid under basic Pfitzinger conditions . After transforming 67 into the diester 68 , reaction with ammonia in methanol gave the 2‐quinolinecarboxamide 69 regioselectively .…”

Section: Resultsmentioning

confidence: 99%

“…[36] With this aminopyrazolei nh and the quinoline part of BAY-876 (19)w as derived from inexpensive6 -fluoroisatine 66 that was converted into the 7-fluoroquinoline-2,4-dicarboxylic acid 67 with pyruvic acid under basic Pfitzinger conditions. [37] After transforming 67 into the diester 68,r eaction with ammonia in methanol gave [38] Af inal amide bond formation between 65 and 69 using HATU [39] as coupling reagent yielded the desired compound BAY-876 (19).…”

Section: Resultsmentioning

confidence: 99%

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Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

et al. 2016

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Despite the long‐known fact that the facilitative glucose transporter GLUT1 is one of the key players safeguarding the increase in glucose consumption of many tumor entities even under conditions of normal oxygen supply (known as the Warburg effect), only few endeavors have been undertaken to find a GLUT1‐selective small‐molecule inhibitor. Because other transporters of the GLUT1 family are involved in crucial processes, these transporters should not be addressed by such an inhibitor. A high‐throughput screen against a library of ∼3 million compounds was performed to find a small molecule with this challenging potency and selectivity profile. The N‐(1H‐pyrazol‐4‐yl)quinoline‐4‐carboxamides were identified as an excellent starting point for further compound optimization. After extensive structure–activity relationship explorations, single‐digit nanomolar inhibitors with a selectivity factor of >100 against GLUT2, GLUT3, and GLUT4 were obtained. The most promising compound, BAY‐876 [N 4‐[1‐(4‐cyanobenzyl)‐5‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐4‐yl]‐7‐fluoroquinoline‐2,4‐dicarboxamide], showed good metabolic stability in vitro and high oral bioavailability in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

et al. 2016

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“…[ 17 ] These are promising scaffolds of biologically active compounds, isolated from natural products. [ 18 ] Researchers mainly focused on the synthesis of 1,2,4‐oxadiazole derivatives in medicinal chemistry [ 19 ] due to their remarkable biological activities, such as anticancer, [ 20 ] antibiotic, [ 21 ] antifungal, [ 22 ] antioxidant, [ 23 ] anti‐inflammatory, [ 24 ] and anticonvulsant activities. [ 25 ] Recently, several 1,2,4‐oxadiazole derivatives were reported having anticancer activities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, cytotoxicity, and molecular docking of substituted 3‐(2‐methylbenzofuran‐3‐yl)‐5‐(phenoxymethyl)‐1,2,4‐oxadiazoles

Mokenapelli

Thalari

Vadiyaala

et al. 2020

Archiv der Pharmazie

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A series of new benzofuran/oxadiazole hybrids (8a-n) was synthesized from 2H-chromene-3-carbonitriles (3a-c) through the multistep synthetic methodology, and these hybrids are known to exhibit anticancer activities. All the compounds were evaluated for their in vitro cytotoxicity against the HCT116 and MIA PaCa2 cell lines. Compounds 6a (IC 50 : 9.71 ± 1.9 μM), 6b (IC 50 : 7.48 ± 0.6 μM), and 6c (IC 50 : 3.27 ± 1.1 μM) displayed a significant cytotoxic activity, whereas compounds 8d and 8e exhibited good activity against both cell lines. The depletion of glycogen synthase kinase-3β (GSK3β) induces apoptosis through the inhibition of basal NF-κB activity in HCT116 colon cancer cells and MIA PaCa2 pancreatic cancer cells. Molecular docking of compounds 6a, 6b, 6c, 8d, and 8e with GSK3β demonstrated the best binding affinity, correlating with the biological activity assay. Furthermore, the structure-activity relationship of these novel compounds reveals promising features for their use in anticancer therapy. K E Y W O R D S 1,2,4-oxadiazole, benzofuran, cytotoxicity, docking studies, glycogen synthase kinase-3β 2 of 12 | MOKENAPELLI ET AL.

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“…On the other side, the reaction of isatin (1) with 2a and/or 3a under action of aqueous potassium hydroxide 33% (Pfitzinger condition [24]) resulted in opening of the 2-oxopyrolidine ring of isatin and then re-cyclized to give 4-quinoline carboxylic acids 15a and 15b, correspondingly. The analytical and spectral data of the entire target compounds were compatible with their structures; see experimental part.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects

et al. 2020

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The present work aims to design and synthesize novel series of spiro pyrazole-3,3'-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial agents, as well as antiproliferative potency against selected human cancerous cell lines (i.e., breast, MCF-7; colon, HCT-116 and liver, HepG-2) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti-and proapoptotic protein markers. The analytical and spectral data of the all synthesized target congeners were compatible with their structures. Synthesized compounds showed diverse moderate to powerful antimicrobial and antioxidant activities. Results of MTT assay revealed that seven synthesized compounds (i.e., 11a, 11b, 12a, 12b, 13b, 13c and 13h) particularly exhibited significant cytotoxicity against the three cancerous cell lines under investigation. Ranges of IC 50 values obtained were 5.7-21.3 and 5.8-37.4 µg/mL against HCT-116 and MCF-7, respectively; which is 3.8 and 6.5-fold (based on the least IC 50 values) more significant relative to the reference chemotherapeutic drug doxorubicin. In HepG-2 cells, the analogue 13h exhibited the highest cytotoxicity with IC 50 value of 19.2µg/mL relative to doxorubicin (IC 50 = 21.6µg/mL). The observed cytotoxicity was specific to cancerous cells, as evidenced by the minimal toxicity in the noncancerous control skin-fibroblast cells. ELISA results indicated that the observed antiproliferative effect against examined cancer cell lines is mediated via engaging the activation of apoptosis as illustrated by the significant increase in proapoptotic protein markers (p53, bax and caspase-3) and reduction in the antiapoptotic marker bcl-2. Taken together, results of the present study emphasize the potential of spiro pyrazole-oxindole analogues as valuable candidate anticancer agents against human cancer cells.

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Pfitzinger Reaction in the Synthesis of Bioactive Compounds - A Review

Cited by 23 publications

References 0 publications

Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

Identification and Optimization of the First Highly Selective GLUT1 Inhibitor BAY‐876

Synthesis, cytotoxicity, and molecular docking of substituted 3‐(2‐methylbenzofuran‐3‐yl)‐5‐(phenoxymethyl)‐1,2,4‐oxadiazoles

Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects

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