- Ferric Chloride-catalyzed Synthesis of 2-Oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate Derivatives and Their Biological Evaluation
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A new methodology has been developed for the synthesis of novel 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylates from 2-aminonicotinaldehyde, Meldrum’s acid, and the corresponding alcohols in the presence of anhydrous iron(III) chloride as a cheap and readily available catalyst. The structure of the synthesized compounds was established by IR, 1H NMR, and mass spectral data and elemental analyses. All the synthesized compounds were evaluated for their in vitro antibacterial and antifungal activity, and the activity of some derivatives was comparable with the activity of Ciprofloxacin and Nystatin used as reference drugs.
- Sakram,Madhu,Sonyanaik,Rambabu,Ravi,Kurumanna
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- Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile
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We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.
- Bacci, Andrea,Chiarugi, Sara,Gado, Francesca,Garau, Gianpiero,Gul, Sheraz,Huguet, Samuel,Manera, Clementina,Margheritis, Eleonora,Rapposelli, Simona,Rezai, Keyvan,Riveiro, Maria E.,Runfola, Massimiliano,Sestito, Simona,Vazquez, Ramiro
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supporting information
(2021/10/08)
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- Development of [18f]lu14 for pet imaging of cannabinoid receptor type 2 in the brain
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Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.
- Teodoro, Rodrigo,Gündel, Daniel,Deuther-Conrad, Winnie,Ueberham, Lea,Toussaint, Magali,Bormans, Guy,Brust, Peter,Moldovan, Rare?-Petru
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- Structure-activity relationship of spop inhibitors against kidney cancer
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Speckle-type POZ protein (SPOP) is overexpressed in the nucleus and misallocated in the cytoplasm in almost all the clear-cell renal cell carcinomas (ccRCCs), which leads to kidney tumorigenesis. Previously, we elucidated that the oncogenic SPOP-signaling pathway in ccRCC could be suppressed by 6b that inhibits SPOP-mediated protein interactions. Herein, we have established a structure-activity relationship for 6b analogues as SPOP inhibitors. Compound 6lc suppresses the viability and inhibits the colony formation of ccRCC cell lines driven by cytoplasmic SPOP, superior to 6b. Compound 6lc binds to the SPOP protein in vitro and disrupts SPOP binding to phosphatase-and-tensin homologue (PTEN) in HEK293T cells, which causes the observable phenomena: a decline in the ubiquitination of PTEN, elevated levels of both PTEN and dual-specificity phosphatase 7, and decreased levels of phosphorylated AKT and ERK when ccRCC cell lines are exposed to 6lc in a dose-response manner. Taken together, compound 6lc is a potent candidate against kidney tumorigenesis.
- Dong, Ze,Wang, Zhen,Guo, Zhong-Qiang,Gong, Shouzhe,Zhang, Tao,Liu, Jiang,Luo, Cheng,Jiang, Hualiang,Yang, Cai-Guang
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p. 4849 - 4866
(2020/06/08)
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- 5-MEMBERED AND BICYCLIC HETEROCYCLIC AMIDES AS INHIBITORS OF ROCK
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The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically-acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.
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Page/Page column 101
(2019/02/02)
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- Anti-proliferative properties and proapoptotic function of new CB2 selective cannabinoid receptor agonist in jurkat leukemia cells
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Several studies demonstrated that cannabinoids reduce tumor growth, inhibit angiogenesis, and decrease cancer cell migration. As these molecules are well tolerated, it would be interesting to investigate the potential benefit of newly synthesized compounds, binding cannabinoid receptors (CBRs). In this study, we describe the synthesis and biological effect of 2-oxo-1,8-naphthyridine-3-carboxamide derivative LV50, a new compound with high CB2 receptor (CB2R) affinity. We demonstrated that it decreases viability of Jurkat leukemia cells, evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), but mainly induces a proapoptotic effect. We observed an increase of a hypodiploid peak by propidium iodide staining and changes in nuclear morphology by Hoechst 33258. These data were confirmed by a significant increase of Annexin V staining, cleavage of the nuclear enzyme poly(ADP-ribose)-polymerase (PARP), and caspases activation. In addition, in order to exclude that LV50 non-specifically triggers death of all normal leukocytes, we tested the new compound on normal peripheral blood lymphocytes, excluding the idea of general cytotoxicity. To characterize the involvement of CB2R in the anti-proliferative and proapoptotic effect of LV50, cells were pretreated with a specific CB2R antagonist and the obtained data showed reverse results. Thus, we suggest a link between inhibition of cell survival and proapoptotic activity of the new compound that elicits this effect as selective CB2R agonist.
- Capozzi, Antonella,Mattei, Vincenzo,Martellucci, Stefano,Manganelli, Valeria,Saccomanni, Giuseppe,Garofalo, Tina,Sorice, Maurizio,Manera, Clementina,Misasi, Roberta
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- The Discovery and Hit-to-Lead Optimization of Tricyclic Sulfonamides as Potent and Efficacious Potentiators of Glycine Receptors
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Current pain therapeutics suffer from undesirable psychotropic and sedative side effects, as well as abuse potential. Glycine receptors (GlyRs) are inhibitory ligand-gated ion channels expressed in nerves of the spinal dorsal horn, where their activation is believed to reduce transmission of painful stimuli. Herein, we describe the identification and hit-to-lead optimization of a novel class of tricyclic sulfonamides as allosteric GlyR potentiators. Initial optimization of high-throughput screening (HTS) hit 1 led to the identification of 3, which demonstrated ex vivo potentiation of glycine-activated current in mouse dorsal horn neurons from spinal cord slices. Further improvement of potency and pharmacokinetics produced in vivo proof-of-concept tool molecule 20 (AM-1488), which reversed tactile allodynia in a mouse spared-nerve injury (SNI) model. Additional structural optimization provided highly potent potentiator 32 (AM-3607), which was cocrystallized with human GlyRα3cryst to afford the first described potentiator-bound X-ray cocrystal structure within this class of ligand-gated ion channels (LGICs).
- Bregman, Howard,Simard, Jeffrey R.,Andrews, Kristin L.,Ayube, Shawn,Chen, Hao,Gunaydin, Hakan,Guzman-Perez, Angel,Hu, Jiali,Huang, Liyue,Huang, Xin,Krolikowski, Paul H.,Lehto, Sonya G.,Lewis, Richard T.,Michelsen, Klaus,Pegman, Pamela,Plant, Matthew H.,Shaffer, Paul L.,Teffera, Yohannes,Yi, Shuyan,Zhang, Maosheng,Gingras, Jacinthe,DiMauro, Erin F.
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p. 1105 - 1125
(2017/02/19)
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- Indium(Iii) Chloride as an efficient catalyst for friedlander synthesis 1,8-Naphthyridines under solventfree conditions
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InCl3 catalyzed Friedlander condensation of 2-aminonicotinaldehyde 1 with carbonyl compounds containing methylene group 2 has been achieved in solvent-free grinding conditions to give 1,8-naphthyridines 3 in high yields. The method is simple an
- Mogilaiah,Manasa,Babu, H. Ramesh
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p. 209 - 212
(2019/01/18)
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- PYRROLO PYRIMIDINE DERIVATIVE
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The compound represented by general formula (I) has strong Axl inhibition activity by means of a pyridone ring structure being introduced into a pyrrolo pyrimidine skeleton, and so the result can serve as a treatment agent for Axl-related diseases, for example cancers such as acute myeloid leukemia, melanoma, breast cancer, pancreatic cancer, and glial tumors, renal disease, immune system disorders, and cardiovascular disease.
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Paragraph 0237
(2016/09/26)
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- ZrOClinf2/inf.8Hinf2/infO catalyzed solvent-free Friedlander synthesis of 1,8-naphthyridines
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ZrOClinf2/inf.8Hinf2/infO catalyzed Friedlander condensation of 2-Aminonicotinaldehyde 1 with carbonyl compounds containing-methylene group 2 has been achieved in solvent-free grinding conditions to give 1,8-naphthyridines 3. The yields are very good and
- Mogilaiah,Nageswara Rao,Koteswara Rao
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p. 1280 - 1282
(2015/11/25)
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- Cecl3.7H2O catalyzed Friedlander synthesis of 1,8-naphthyridines under solvent-free grinding conditions
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CeCl3.7H2O catalyses the Friedlander condensation of 2-aminonicotinaldehyde 1 with varius carbonyl compounds containing α-methylene group 2 in solvent-free grinding conditions to afford the corresponding 1,8-naphthyridines 3. The rea
- Mogilaiah,Kumara Swamy,Jyothi,Kavitha
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p. 305 - 308
(2019/01/21)
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- Green approach for the efficient synthesis of 1,8-naphthyridines promoted by citric acid
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Citric acid catalyzed Friedlander condensation of 2-aminonicotinaldehyde 1 with various carbonyl compounds containing α-methylene group 2 has been achieved under neat conditions at 100° to give the corresponding 1,8-naphthyridines 3. The products are obta
- Mogilaiah,Srivani,Vinay Chandra
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- Piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides: Novel 5-HT3 receptor antagonists with antidepressant-like activity
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Series of piperazine analogs of naphthyridine-3-carboxamides and indole-2-carboxamides were designed using a ligand-based approach with consideration of the pharmacophoric requirements for 5-HT3 receptor antagonists. The title carboxamides were synthesized using appropriate synthetic routes. Initially, the 5-HT3 receptor antagonistic activity of all the compounds was determined on isolated guinea pig ileum tissue against the 5-HT3 agonist, 2-methyl-5-hydroxytryptamine, which was denoted in the form of pA2 values. The structure-activity relationship regarding the influence of the aromatic part and basic moiety as features in the 5-HT3 pharmacophore was derived. Among all the compounds screened, the piperazine derivatives of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h exhibited prominent 5-HT3 receptor antagonism with pA2 values of 7.5 and 7.3, respectively. Subsequent investigation of the antidepressant activities of selected compounds in the mouse forced swim test (FST) led to the identification of the piperazine analogs of indole-2-carboxamide 13i and naphthyridine-3-carboxamide 8h as the most promising compounds. Both 13i and 8h demonstrated significant reduction in the duration of immobility as compared to the control. Importantly, none of the tested compounds affected the baseline locomotion of mice at the tested dose levels.
- Dhar, Arghya K.,Mahesh, Radhakrishnan,Jindal, Ankur,Bhatt, Shvetank
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- Design, Synthesis, and Pharmacological Evaluation of Novel 2-(4-substituted piperazin-1-yl)1, 8 Naphthyridine 3-Carboxylic Acids as 5-HT3 Receptor Antagonists for the Management of Depression
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1, 8-naphthyridine-3-carboxylic acid analogs were synthesized and found to possess potential 5-HT3 receptor antagonism as well as antidepressant-like activity. Initially, 5-HT3 receptor antagonism of all the compounds was determined in the form of pA2 value against agonist 2-methyl 5-HT in longitudinal muscle-myenteric plexus preparation from Guinea-pig ileum. Among all the compounds tested, compound 7a demonstrated most promising pA2 value of 7.6. Subsequently, all the compounds were evaluated for antidepressant activity using forced swim test and tail suspension test in mice. Compounds 7a, 7d, 7f, 7h, and 7i exhibited significant (p 0.05) antidepressant-like activity as compound to vehicle-treated group. Importantly, none of the tested compound affected locomotor activity of mice at tested dose levels.
- Dhar, Arghya K.,Mahesh, Radhakrishnan,Jindal, Ankur,Devadoss, Thangaraj,Bhatt, Shvetank
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p. 721 - 731
(2015/08/25)
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- NAPHTHYRIDINONE DERIVATIVES AS INHIBITORS OF CYTOMEGALOVIRUS DNA POLYMERASE
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Compounds of Formula (I) wherein n, m, R1, R2, R3, R4, R5 and R6 are defined herein, are useful for the treatment of cytomegalovirus disease and/or infection.
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Page/Page column 39-40
(2013/10/22)
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- NOVEL BRONCHODILATING DIAZAHETEROARYLS
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The invention relates to novel compounds having the general formula (I), and which compounds are useful to treat a disorder or disease characterized by bronchoconstriction, e.g. COPD and asthma.
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Page/Page column 56
(2012/03/08)
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- RING-FUSED 2-PYRIDONE DERIVATIVES AND HERBICIDES
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Provided are 2-pyridone derivatives which have excellent herbicidal activity and exhibit high safety to useful crops and so on; salts thereof; and herbicides containing same. In more detail, 2-pyridone derivatives represented by general formula [I] or agrochemically acceptable salts thereof, and herbicides containing these compounds are provided. In general formula [I], X1 is an oxygen atom or a sulfur atom; X2, X3, and X4 are to each CH or N(O)m; m is an integer of 0 or 1; R1 is a hydrogen atom, a C1-12 alkyl group, or the like; R2 is a halogen atom, a cyano group, or the like; n is an integer of 0 to 4; R3 is a hydroxyl group, a halogen atom, or the like; A1 is C(R11R12); A2 is C(R13R14) or C═O; A3 is C(R15R16); and R11, R12, R13, R14, R15, and R16 are each independently a hydrogen atom or a C1-6 alkyl group.
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- Potassium triiodide catalyzed Friedlander synthesis of 1,8-naphthyridines in aqueous media
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Potassium triiodide catalyses the Friedlander condensation of 2-aminonicotinaldehyde 1 with carbonyl compounds containing α-methylene group 2 in aqueous media to afford 1,-naphthyridines 3 in high yields.
- Mogilaiah,Kumar, K. Shiva,Reddy, N. Vasudeva
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experimental part
p. 253 - 255
(2010/11/04)
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- NOVEL BRONCHODILATING DIAZAHETEROARYLS
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The invention relates to novel compounds having the general formula (I), and which compounds are useful to treat a disorder or disease characterized by bronchoconstriction, e.g. COPD and asthma.
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Page/Page column 121
(2010/09/17)
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- Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists
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The CB2 receptor activation can be exploited for the treatment of diseases such as chronic pain and tumors of immune origin, devoid of psychotropic activity. On the basis of our already reported 1,8-naphthyridin- 4(1H)-on-3-carboxamide derivati
- Manera, Clementina,Saccomanni, Giuseppe,Adinolfi, Barbara,Benetti, Veronica,Ligresti, Alessia,Cascio, Maria Grazia,Tuccinardi, Tiziano,Lucchesi, Valentina,Martinelli, Adriano,Nieri, Paola,Masini, Emanuela,Di Marzo, Vincenzo,Ferrarini, Pier Luigi
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experimental part
p. 3644 - 3651
(2010/03/25)
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- NOVEL ANTIMALARIA AGENT CONTAINING HETEROCYCLIC COMPOUND
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Disclosed is an antimalarial agent containing a compound represented by the formula: [wherein A1 represents a 3-pyridyl group that may have a substituent, a 6-quinolyl group that may have a substituent, or the like; X1 represents a group represented by the formula -C(=O)-NH- or the like; E represents a furyl group, a thienyl group or a phenyl group; with the proviso that A1 may have one to three substituents, and E has one of two substituents] or a salt thereof or hydrates thereof.
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Page/Page column 59-60
(2008/06/13)
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- Microwave-assisted solvent-free Friedlander synthesis of 1,8-naphthyridines using ammonium acetate as catalyst
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The microwave enhanced synthesis of 1,8-naphthyridines 3 is achieved rapidly and in good yield via the Friedlander condensation of 2-aminonicotinaldehyde 1 with carbonyl compounds containing α-methylene group 2 in the presence of ammonium acetate.
- Mogilaiah,Rani, J. Uma
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p. 1051 - 1053
(2007/10/03)
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- NOVEL ANTIFUNGAL AGENT COMPRISING HETEROCYCLIC COMPOUND
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The present invention provides an antifungal agent represented by the formula: [wherein A1 represents a 3-pyridyl group which may have a substituent, a quinolyl group which may have a substituent, or the like; X1 represents a group represented by the formula -NH-C(=O)-, a group represented by the formula -C(=O)-NH-, or the like; E represents a furyl group, a thienyl group, a pyrrolyl group, a phenyl group, a pyridyl group, a tetrazolyl group, a thiazolyl group or a pyrazolyl group; with the proviso that A1 may have 1 to 3 substituents, and E has one or two substituents].
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Page/Page column 67-68
(2010/11/08)
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- Microwave induced Friedlander condensation - A facile synthesis of 1,8-naphthyridines
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A simple and efficient method has been developed for the rapid synthesis of 1,8-naphthyridines 3 from 2-aminonicotinaldehyde 1 and active methylene compounds 2 in methanol in the presence of a catalytic amount of piperidine in unmodified domestic microwav
- Mogilaiah,Reddy, N. Vasudeva
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p. 215 - 217
(2007/10/03)
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- Tyrosine kinase inhibitors
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The present invention relates to compounds which inhibit, regulate and/or modulate tyrosine kinase signal transduction, compositions which contain these compounds, and methods of using them to treat tyrosine kinase-dependent diseases and conditions, such
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- Synthesis of 1,8-naphthyridines under solvent free conditions
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Various active methylene compounds 2 reacts efficiently with 2-aminonicotinaldehyde 1 in the presence of piperidine at room temperature within a few minutes and furnish the corresponding 1,8-naphthyridines 3 in high yield under solvent free conditions.
- Mogilaiah,Rao
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p. 713 - 714
(2007/10/03)
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