1735-96-2

Usage

Uses

Used in Pharmaceutical Research and Drug Development:
2-CYANO-N-(2-FLUORO-PHENYL)-ACETAMIDE is used as a chemical intermediate for the synthesis of various pharmaceutical compounds. Its unique structure and potential biological activities make it a valuable candidate for the development of new drugs.
Used in Medicinal Chemistry:
In the field of medicinal chemistry, 2-CYANO-N-(2-FLUORO-PHENYL)-ACETAMIDE is utilized as a building block for designing and optimizing drug molecules. Its presence in a molecule can influence the pharmacokinetic and pharmacodynamic properties, which are crucial for drug efficacy and safety.
Used in Biological Research:
2-CYANO-N-(2-FLUORO-PHENYL)-ACETAMIDE is also used in biological research to study the interactions between small molecules and biological targets, such as enzymes, receptors, and other proteins. This can provide insights into the molecular mechanisms of diseases and help in the discovery of novel therapeutic agents.
Used in Chemical Synthesis:
2-CYANO-N-(2-FLUORO-PHENYL)-ACETAMIDE serves as a versatile reagent in chemical synthesis, allowing for the preparation of a wide range of organic compounds. Its reactivity and functional groups make it suitable for various synthetic transformations, contributing to the development of new chemical entities.
Used in Material Science:
Although not explicitly mentioned in the provided materials, 2-CYANO-N-(2-FLUORO-PHENYL)-ACETAMIDE, due to its structural features, could potentially be used in material science for the development of new materials with specific properties, such as in polymers or as part of a molecular assembly.

Upstream product

• 348-54-9 2-Fluoroaniline 
• 36140-83-7 1-cyanoacetyl-3,5-dimethylpyrazole 
• 105-56-6 ethyl 2-cyanoacetate 
• 372-09-8 cyanoacetic acid 

Downstream Products

• 1417720-41-2 (E)-2-cyano-N-(2-fluorophenyl)-3-(7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)acrylamide 
• 1574664-99-5 N-(2-fluorophenyl)-2-amino-6-tert-butyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 
• 1574664-34-8 N-(2-fluorophenyl)-2-[(3-carboxy-1-oxopropyl)amino]-6-tertbutyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide 
• 924871-21-6 3-amino-3-(hydroxyimino)-N-[2-(fluoro)phenyl]propanamide 
• 1263303-89-4 3-(2-fluorophenyl)amino-2-hydroxyimino-3-oxopropionitrile 

Relevant academic research and scientific papers

Development of Novel AKR1C3 Inhibitors as New Potential Treatment for Castration-Resistant Prostate Cancer

Aldo-keto reductase (AKR) 1C3 catalyzes the synthesis of active androgens that promote the progression of prostate cancer. AKR1C3 also contributes to androgen-independent cell proliferation and survival through the metabolism of prostaglandins and reactive aldehydes. Because of its elevation in castration-resistant prostate cancer (CRPC) tissues, AKR1C3 is a promising therapeutic target for CRPC. In this study, we found a novel potent AKR1C3 inhibitor, N-(4-fluorophenyl)-8-hydroxy-2-imino-2H-chromene-3-carboxamide (2d), and synthesized its derivatives with IC50 values of 25-56 nM and >220-fold selectivity over other AKRs (1C1, 1C2, and 1C4). The structural factors for the inhibitory potency were elucidated by crystallographic study of AKR1C3 complexes with 2j and 2l. The inhibitors suppressed proliferation of prostate cancer 22Rv1 and PC3 cells through both androgen-dependent and androgen-independent mechanisms. Additionally, 2j and 2l prevented prostate tumor growth in a xenograft mouse model. Furthermore, the inhibitors significantly augmented apoptotic cell death induced by anti-CRPC drugs (abiraterone or enzalutamide).

Synthesis, cytotoxic characterization, and SAR study of imidazo[1,2-b]pyrazole-7-carboxamides

The synthesis and in vitro cytotoxic characteristics of new imidazo[1,2-b]pyrazole-7-carboxamides were investigated. Following a hit-to-lead optimization exploiting 2D and 3D cultures of MCF-7 human breast, 4T1 mammary gland, and HL-60 human promyelocytic leukemia cancer cell lines, a 67-membered library was constructed and the structure–activity relationship (SAR) was determined. Seven synthesized analogues exhibited sub-micromolar activities, from which compound 63 exerted the most significant potency with a remarkable HL-60 sensitivity (IC50 = 0.183 μM).

Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A)

Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure-activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of ～30 nM, ～3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1

Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.

Synthesis of 8-hydroxy-2-iminochromene derivatives as selective and potent inhibitors of human carbonyl reductase 1

Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase superfamily, reduces anthracycline anticancer drugs to their less potent anticancer C-13 hydroxy metabolites, which are linked with pathogenesis of cardiotoxicity, a side effect of the drugs. CBR1 inhibitors are thought to be promising agents for adjuvant therapy with a twofold beneficial effect in prolonging the anticancer efficacy of the anthracyclines while decreasing cardiotoxicity. In order to search for new potential inhibitors of CBR1, we synthesized a series of des-methoxyphenyl derivatives of (Z)-2-(4-methoxyphenylimino)-7-hydroxy-N-(pyridin-2-yl)-2H-chromene-3-carboxamide (1) that was developed previously as a potent inhibitor of aldo-keto reductase (AKR) 1B10 and AKR1B1. Among the newly synthesized inhibitors, 8-hydroxy-2-imino-2H-chromene-3-carboxylic acid (2-chlorophenyl)amide (13h) was the most potent competitive inhibitor of CBR1, showing a Ki value of 15 nM. 13h also showed high selectivity to CBR1 over its isozyme CBR3 and other enzymes with CBR activity (AKR1B1, AKR1B10, AKR1C1, AKR1C2, AKR1C4, DXCR and DHRS4). Furthermore, 13h inhibited the cellular metabolism by CBR1 at its concentration of 4 μM. The structure-activity relationship of the derivatives, site-directed mutagenesis of putative binding residues (Met141 and Trp229) and molecular docking of 13h in CBR1 revealed that the interactions of 13h with the substrate-binding residues (Ser139, Met141, Tyr193 and Trp229) are important for the tight binding.

Designing, synthesis, and characterization of some novel coumarin derivatives as probable anticancer drugs

Coumarin is a naturally occurring oxygen heterocyclic having multifarious medicinal properties, hence used as a lead compound for designing new potent analogs. Based on the X-ray crystal structure of complexes of inhibitors containing coumarin nucleus with human NAD(P)H:quinone oxidoreductase-1 and human phosphodiesterase 4B enzymes, some novel coumarin derivatives have been designed as probable inhibitors specifically for pancreatic cancer. These two enzymes are overexpressed in various tumors, the former specifically in pancreatic cancer. The computational analysis by e-pharmacophore and docking studies suggested that specific groups at position 8 of 4-methyl-7- hydroxycoumarin have anticancer activity against skin cancer in mice and can enhance the anti-tumor activity. The chemical syntheses of 4-methyl-7- hydroxycoumarin and its 8-formyl derivative were carried out using Pechmann's condensation followed by Duffs reaction. Treatment of the 8-formyl derivative with nine different N,N-di substituted cyanoacetamides in the presence of piperidine afforded the corresponding nine new 8-substituted-4-methyl-7- hydroxycoumarin derivatives. These compounds were characterized by IR, 1H, 13C NMR, mass spectra and elemental analysis. Intriguingly, molecular docking suggested a remarkable binding pose for all the nine coumarin derivatives vis-a-vis coumarin itself, opening further options for designing inhibitors for tumor suppression. From the docking simulation study, it was concluded that the derived coumarin derivatives are active against more than one proteins and most importantly addition of substituents at the 8th position of 4-methyl-7-hydroxycoumarin support the possibility of new coumarin derivatives having comparatively higher binding affinity and therefore more potent inhibitors.

Low molecular weight amidoximes that act as potent inhibitors of lysine-specific demethylase 1

The recently discovered enzyme lysine-specific demethylase 1 (LSD1) plays an important role in the epigenetic control of gene expression, and aberrant gene silencing secondary to LSD1 dysregulation is thought to contribute to the development of cancer. We reported that (bis)guanidines, (bis)biguanides, and their urea- and thiourea isosteres are potent inhibitors of LSD1 and induce the re-expression of aberrantly silenced tumor suppressor genes in tumor cells in vitro. We now report a series of small molecule amidoximes that are moderate inhibitors of recombinant LSD1 but that produce dramatic changes in methylation at the histone 3 lysine 4 (H3K4) chromatin mark, a specific target of LSD1, in Calu-6 lung carcinoma cells. In addition, these analogues increase cellular levels of secreted frizzle-related protein (SFRP) 2, H-cadherin (HCAD), and the transcription factor GATA4. These compounds represent leads for an important new series of drug-like epigenetic modulators with the potential for use as antitumor agents.

Structural influence on the intermolecular/intramolecular hydrogen bonding in solid state of substituted leflunomides: Evidence by X-ray crystal structure

We report the results of an X-ray crystal structure study of nine substituted leflunomide metabolite analogs (LFM). Comparison of the hydrogen bonding characteristics exhibited by these structurally distinct LFM analogs was especially informative about the inter- and intra-molecular hydrogen bonding patterns that exist in the crystal structure of individual compounds. All compounds had the strong intramolecular hydrogen bonds. In addition, with the exception of the 2,5-difluorophenyl substituted LFM analog, all other compounds formed inter- or intra-molecular hydrogen bonds with the halogen atom and the NH group. However, we found that the presence of a fluorine atom at the 2-position on the phenyl ring of the 2,5-difluoro and 2-fluoro derivatives resulted in only one intramolecular hydrogen bond in the structural framework. Conversely, the 3,5-difluoro substituted LFM analog had an intramolecular hydrogen bond common to the other halide substituted derivatives. The anomaly exhibited by the 2,5-difluoro and the 2-fluoro substituted compounds may be owing to the smaller size of fluorine atom in comparison with the chlorine and bromine atoms in the structures of the other analogs. The presence of a fluorine at the 2-position of the phenyl ring may disrupt the intermolecular hydrogen bonding that was observed for the other derivatives due to differences in the crystal packing for these molecules.