- Design, synthesis, biological evaluation and molecular docking study of novel thieno[3,2-d]pyrimidine derivatives as potent FAK inhibitors
-
A series of 2,7-disubstituted-thieno[3,2-d]pyrimidine derivatives were designed, synthesized and evaluated as novel focal adhesion kinase (FAK) inhibitors. The novel 2,7-disubstituted-thieno[3,2-d]pyrimidine scaffold has been designed as a new kinase inhibitor platform that mimics the bioactive conformation of the well-known diaminopyrimidine motif. Most of the compounds potently suppressed the enzymatic activities of FAK and potently inhibited the proliferation of U-87MG, A-549 and MDA-MB-231 cancer cell lines. Among these derivatives, the optimized compound 26f potently inhibited the enzyme (IC50 = 28.2 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.16, 0.27, and 0.19 μM, respectively. Compound 26f also exhibited relatively less cytotoxicity (IC50 = 3.32 μM) toward a normal human cell line, HK2. According to the flow cytometry results, compound 26f induced the apoptosis of MDA-MB-231 cells in a dose-dependent manner and effectively arrested MDA-MB-231 cells in G0/G1 phase. Further investigations revealed that compound 26f potently suppressed the migration of MDA-MB-231 cells. Collectively, these data support the further development of compound 26f as a lead compound for FAK-targeted anticancer drug discovery.
- Chen, Yixuan,Cheng, Maosheng,Hao, Chenzhou,Wang, Ruifeng,Wu, Tianxiao,Yang, Bowen,Yu, Sijia,Zhao, Dongmei,Zhao, Xiangxin
-
-
- Discovery of 7H-pyrrolo[2,3-d]pyridine derivatives as potent FAK inhibitors: Design, synthesis, biological evaluation and molecular docking study
-
Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase responsible for development of various tumor types. Aiming to explore new potent inhibitors, two series of 2,4-disubstituted-7H-pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized on the base of structure-based design strategy. Biological evaluation indicated that most of these new compounds could potently inhibit FAK kinase, leading to the promising inhibitors against the proliferation of U-87MG, A-549, and MDA-MB-231 cancer cell lines. Among them, the optimized compound 18h potently inhibited the enzyme (IC50 = 19.1 nM) and displayed stronger potency than TAE-226 in U-87MG, A-549 and MDA-MB-231 cells, with IC50 values of 0.35, 0.24, and 0.34 μM, respectively. Compound 18h is a multi-target kinase inhibitor. Furthermore, compound 18h also exhibited relatively less cytotoxicity (IC50 = 3.72 μM) toward a normal human cell line, HK2. According to the flow cytometry and wound healing assay results, compound 18h effectively induced apoptosis and G0/G1 phase arrest of MDA-MB-231 cells and suppressed the migration of U-87MG, A-549 and MDA-MB-231 cells. The docking study of compound 18h was performed to elucidate its possible binding modes and to provide a structural basis for the further structural guidance design of FAK inhibitors. Collectively, these data support the further development of compound 18h as a lead compound for FAK-targeted anticancer drug discovery.
- Wang, Ruifeng,Zhao, Xiangxin,Yu, Sijia,Chen, Yixuan,Cui, Hengxian,Wu, Tianxiao,Hao, Chenzhou,Zhao, Dongmei,Cheng, Maosheng
-
-
- ANTIMALARIAL COMPOUNDS
-
Antimalarial compounds of the formula: in which n is 1 or 2; X is C or N; R1 is a moiety comprising a secondary amine and a tertiary amine joined by a C2 to C4 alkyl chain; and R2 is CF3, F, or H, or an analog, combination, derivative, prodrug, stereoisomer, or pharmaceutically acceptable salt thereof. Pharmaceutical compounds including the antimalarial compounds. Methods of treating or preventing malaria comprising administering an effective amount of the antimalarial compounds.
- -
-
-
- Synthesis, Structure-Activity Relationship, and Antimalarial Efficacy of 6-Chloro-2-arylvinylquinolines
-
There is an urgent need to develop new efficacious antimalarials to address the emerging drug-resistant clinical cases. Our previous phenotypic screening identified styrylquinoline UCF501 as a promising antimalarial compound. To optimize UCF501, we herein report a detailed structure-activity relationship study of 2-arylvinylquinolines, leading to the discovery of potent, low nanomolar antiplasmodial compounds against a Plasmodium falciparum CQ-resistant Dd2 strain, with excellent selectivity profiles (resistance index 200). Several metabolically stable 2-arylvinylquinolines are identified as fast-acting agents that kill asexual blood-stage parasites at the trophozoite phase, and the most promising compound 24 also demonstrates transmission blocking potential. Additionally, the monophosphate salt of 24 exhibits excellent in vivo antimalarial efficacy in the murine model without noticeable toxicity. Thus, the 2-arylvinylquinolines represent a promising class of antimalarial drug leads.
- Huang, Guang,Murillo Solano, Claribel,Melendez, Joel,Shaw, Justin,Collins, Jennifer,Banks, Robert,Arshadi, Arash Keshavarzi,Boonhok, Rachasak,Min, Hui,Miao, Jun,Chakrabarti, Debopam,Yuan, Yu
-
p. 11756 - 11785
(2020/11/26)
-
- Second-generation aryl isonitrile compounds targeting multidrug-resistant Staphylococcus aureus
-
Antibiotic resistance remains a major global public health threat that requires sustained discovery of novel antibacterial agents with unexploited scaffolds. Structure-activity relationship of the first-generation aryl isonitrile compounds we synthesized led to an initial lead molecule that informed the synthesis of a second-generation of aryl isonitriles. From this new series of 20 compounds, three analogues inhibited growth of methicillin-resistant Staphylococcus aureus (MRSA) (from 1 to 4 μM) and were safe to human keratinocytes. Compound 19, with an additional isonitrile group exhibited improved activity against MRSA compared to the first-generation lead compound. This compound emerged as a candidate worthy of further investigation and further reinforced the importance of the isonitrile functionality in the compounds’ anti-MRSA activity. In a murine skin wound model, 19 significantly reduced the burden of MRSA, similar to the antibiotic fusidic acid. In summary, 19 was identified as a new lead aryl isonitrile compound effective against MRSA.
- Kyei-Baffour, Kwaku,Mohammad, Haroon,Seleem, Mohamed N.,Dai, Mingji
-
p. 1845 - 1854
(2019/03/28)
-
- Design and synthesis of phosphoryl-substituted diphenylpyrimidines (Pho-DPPYs) as potent Bruton's tyrosine kinase (BTK) inhibitors: Targeted treatment of B lymphoblastic leukemia cell lines
-
A family of phosphoryl-substituted diphenylpyrimidine derivatives (Pho-DPPYs) were synthesized and biologically evaluated as potent BTK inhibitors in this study. Compound 7b was found to markedly inhibit BTK activity at concentrations of 0.82?nmol/L, as well as to suppress the proliferations of B-cell leukemia cell lines (Ramos and Raji) expressing high levels of BTK at concentrations of 3.17?μM and 6.69?μM. Moreover, flow cytometry analysis results further indicated that 7b promoted cell apoptosis to a substantial degree. In a word, compound 7b is a promising BTK inhibitor for the treatment of B-cell lymphoblastic leukemia.
- Ge, Yang,Yang, Haijun,Wang, Changyuan,Meng, Qiang,Li, Lei,Sun, Huijun,Zhen, Yuhong,Liu, Kexin,Li, Yanxia,Ma, Xiaodong
-
p. 765 - 772
(2016/12/27)
-
- Phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) as potent focal adhesion kinase (FAK) inhibitors with enhanced activity against pancreatic cancer cell lines
-
A family of phosphamide-containing diphenylpyrimidine analogues (PA-DPPYs) were synthesized as potent focal adhesion kinase (FAK) inhibitors. The PA-DPPY derivatives could significantly inhibit the FAK enzymatic activity at concentrations lower than 10.69 nM. Among them, compounds 7a and 7e were two of the most active FAK inhibitors, possessing IC50 values of 4.25 nM and 4.65 nM, respectively. In particular, compound 7e also displayed strong activity against AsPC cell line, with an IC50 of 1.66 μM, but show low activity against the normal HPDE6-C7 cells (IC50 > 20 μM), indicating its low cell cytotoxicity. Additionally, flow cytometry analysis showed that after treatment with 7e (8 μM, 72 h), both AsPC and Panc cells growth were almost totally inhibited, with a cell viability rate of 16.8% and 18.1%, respectively. Overall, compound 7e may be served as a valuable FAK inhibitor for the treatment of pancreatic cancer.
- Liu, He,Wu, Bin,Ge, Yang,Huang, Jiaxin,Song, Shijie,Wang, Changyuan,Yao, Jihong,Liu, Kexin,Li, Yanxia,Li, Yongming,Ma, Xiaodong
-
p. 6313 - 6321
(2017/11/16)
-
- Arylmethyl phosphonate preparation method
-
The invention provides an arylmethyl phosphonate preparation method. The method includes the following steps that arylmethyl ester, triethyl phosphate and a catalyst are sequentially added into a reactor and reacted for 5-8 h at the temperature of 100-200 DEG C after full stirring, and after excessive triethyl phosphate is distilled off through decompression, the mixture continues to be reacted for 3-7 h at the temperature of 100-200 DEG C; then, the mixture is cooled to the room temperature, a product is extracted through a mixed solvent, and arylmethyl phosphonate is obtained after the mixed solvent is removed. The catalyst is one or more of tetramethyl ammonium bromide, tetraethylammonium bromide, tetrabutyl ammonium bromide, benzyltrimethyl ammonium bromide, cetyl trimethyl ammonium bromide, cetyltrimethyl ammonium chloride, ammonium chloride, sodium iodide and potassium iodide. Arylmethyl phosphonate is synthesized through a one-step method, other solvents are not added, operation is easy, and the product yield is high and can be 85.3% at maximum.
- -
-
Paragraph 0036; 0037
(2017/01/02)
-
- Synthetic Strategy and Performances of a UV-Curable Poly Acryloyl Phosphinate Flame Retardant by Carbene Polymerization
-
A route to synthesize poly ethyl (4-acrylamidebenzyl) phosphinate (PPAC) was discussed and the optimal route was determined. Diethyl benzylphosphonate was synthesized by Arbuzov reaction, then, a nitryl was introduced onto the aromatic ring by the nitration reaction of ethyl benzylphosphonate. Subsequently the carbene polymerization of the product was carried out. Finally, the nitryls were reduced and amidated to introduce the acryloyl group into the prepolymer to obtain the target product (PPAC). PPAC can rapidly photopolymerize under UV light irradiation. The addition of PPAC decreased the smoke production rate (SPR), CO2 production (CO2P), and CO production (COP) of the UV-cured resin.
- Yu, Jia,Li, Minglei,Yu, Yong,Gao, Yanjing,Liu, Jiancheng,Sun, Fang
-
p. 1958 - 1970
(2015/12/12)
-
- Discovery and characterization of aryl isonitriles as a new class of compounds versus methicillin- and vancomycin-resistant Staphylococcus aureus
-
Methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA and VRSA) have emerged as a global health concern. A new class of compounds featuring an aryl isonitrile moiety has been discovered that exhibits potent inhibitory activity against several clinically-relevant MRSA and VRSA isolates. Structure-activity relationship studies have been conducted to identify the aryl isonitrile group as the key functional group responsible for the observed antibacterial activity. The most potent antibacterial aryl isonitrile analogs (MIC 2 μM) did not show any toxicity against mammalian cells up to a concentration of 64 μM.
- Davis, Dexter C.,Mohammad, Haroon,Kyei-Baffour, Kwaku,Younis, Waleed,Creemer, Cassidy Noel,Seleem, Mohamed N.,Dai, Mingji
-
p. 384 - 390
(2015/07/20)
-
- Synthesis and evaluation of phosphorus containing, specific CDK9/CycT1 inhibitors
-
Although there is a significant effort in the design of a selective CDK9/CycT1 inhibitor, no compound has been proven to be a specific inhibitor of this kinase so far. The aim of this research was to develop novel and selective phosphorus containing CDK9/CycT1 inhibitors. Molecules bearing phosphonamidate, phosphonate, and phosphinate moieties were synthesized. Prepared compounds were evaluated in an enzymatic CDK9/CycT1 assay. The most potent molecules were tested in cell-based toxicity and HIV proliferation assays. Selectivity of shortlisted compounds against CDKs and other kinases was tested. The best compound was shown to be a highly specific, ATP-competitive inhibitor of CDK9/CycT1 with antiviral activity.
- Németh, Gábor,Greff, Zoltán,Sipos, Anna,Varga, Zoltán,Székely, Rita,Sebestyén, Mónika,Jászay, Zsuzsa,Béni, Szabolcs,Nemes, Zoltán,Pirat, Jean-Luc,Volle, Jean-No?l,Virieux, David,Gyuris, ágnes,Kelemenics, Katalin,áy, éva,Minarovits, Janos,Szathmary, Susan,Kéri, Gy?rgy,Orfi, László
-
p. 3939 - 3965
(2014/06/09)
-
- Designing anti-inflammatory drugs from parasitic worms: A synthetic small molecule analogue of the acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis
-
In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.
- Al-Riyami, Lamyaa,Pineda, Miguel A.,Rzepecka, Justyna,Huggan, Judith K.,Khalaf, Abedawn I.,Suckling, Colin J.,Scott, Fraser J.,Rodgers, David T.,Harnett, Margaret M.,Harnett, William
-
p. 9982 - 10002
(2014/01/17)
-
- NOVEL COMPOUNDS, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME, METHODS OF USE FOR SAME, AND METHODS FOR PREPARING SAME
-
The present invention relates to a novel class of compounds comprising formula I, wherein n is 0 or 1. A is NR1, O, or S, wherein R1 is H, hydroxyl, C1-C10 alkyl, C1-C10 alkoxy, alkenyl, aryl, alkylaryl or arylalkyl. X is a carboxylate, a phosphonate, or a phosphate residue, or a C1-C10 alkyl residue optionally substituted with a carboxylate, phosphonate or phosphate residue. Y is a C1-C20 alkyl, alkenyl, halide, hydroxyl, C1-C20 alkoxy, aryl, alkylaryl, arylalkyl, cycloalkyl, cycloalkenyl, or a heterocyclic ring and is optionally substituted with one or more halides. Z is a H, a hydroxyl group, a halide, an aryl group, an alkylaryl group, an arylalkyl group, a cycloalkyl group, a cycloalkenyl group or a heterocyclic ring and is optionally substituted with one or more C1-C10 alkyl groups, C1-C10alkoxy groups, hydroxyl groups, cyano groups, carboxylate groups, halides, aryl groups, alkylaryl groups, arylalkyl groups, cycloalkyl groups, cycloalkenyl groups or heterocyclic rings.
- -
-
Page/Page column 31
(2010/04/03)
-
- COMPOUNDS AND METHODS FOR INHIBITING NHE-MEDIATED ANTIPORT IN THE TREATMENT OF DISORDERS ASSOCIATED WITH FLUID RETENTION OR SALT OVERLOAD AND GASTROINTESTINAL TRACT DISORDERS
-
The present disclosure is directed to corn- pounds and methods for the treatment of disorders associated with fluid retention or salt overload, such as heart failure (in particular, congestive heart failure), chronic kidney disease, end-stage renal disease, liver disease, and peroxisome proliferator-activated receptor (PPAR) gamma agonist-induced fluid retention. The present disclosure is also directed to compounds and methods for the treatment of hypertension. The present disclosure is also directed to compounds and methods for the treatment of gastrointestinal tract disorders, including the treatment or reduction of pain associated with gastrointestinal tract disorders. The methods generally comprise administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that is designed to be substantially active in the gastrointestinal (GI) tract to inhibit NHE-mediated antiport of sodium ions and hydrogen ions therein. More particularly, the method comprises administering to a mammal in need thereof a pharmaceutically effective amount of a compound, or a pharmaceutical composition comprising such a compound, that inhibits NHE-3, -2 and/ or -8 mediated antiport of sodium and/or hydrogen ions in the GI tract and is designed to be substantially impermeable to the layer of epithelial cells, or more specifically the epithelium of the GI tract. As a result of the compound being substantially impermeable, it is not absorbed and is thus essentially systemically non-bioavailable, so as to limit the exposure of other internal organs (e.g., liver, heart, brain, etc.) thereto. The present disclosure is still further directed to a method wherein a mammal is administered such a compound with a fluid-absorbing polymer, such that the combination acts as described above and further provides the ability to sequester fluid and/or salt present in the GI tract
- -
-
Page/Page column 152
(2010/08/04)
-
- Design and synthesis of small molecule glycerol 3-phosphate acyltransferase inhibitors
-
The incidence of obesity and other diseases associated with an increased triacylglycerol mass is growing rapidly, particularly in the United States. Glycerol 3-phosphate acyltransferase (GPAT) catalyzes the ratelimiting step of glycerolipid biosynthesis, the acylation of glycerol 3-phosphate with saturated long-chain acyl-CoAs. In an effort to produce small molecule inhibitors of this enzyme, a series of benzoic and phosphonic acids was designed and synthesized. In vitro testing of this series has led to the identification of several compounds, in particular 2-(nonylsulfonamido)benzoic acid (15g), possessing moderate GPAT inhibitory activity in an intact mitochondrial assay.
- Wydysh, Edward A.,Medghalchi, Susan M.,Vadlamudi, Aravinda,Townsendd, Craig A.
-
experimental part
p. 3317 - 3327
(2010/03/26)
-
- Phosphonated Fluoroquinolones, Antibacterial Analogs Thereof, and Methods for the Prevention and Treatment of Bone and Joint Infections
-
The present invention relates to phosphonated fluoroquinolones, antibacterial analogs thereof, and methods of using such compounds. These compounds are useful as antibiotics for prevention and/or the treatment of bone and joint infections, especially for the prevention and/or treatment of osteomyelitis.
- -
-
-
