- Exploring the cycloheptathiophene-3-carboxamide scaffold to disrupt the interactions of the influenza polymerase subunits and obtain potent anti-influenza activity
-
With the aim to identify small molecules able to disrupt PA-PB1 subunits interaction of influenza virus (flu) RNA-dependent RNA polymerase, and based on previous structural and computational information, in this paper we have designed and synthesized a new series of cycloheptathiophene-3-carboxamide (cHTC) derivatives. Their biological evaluation led to highlight important structural insights along with new interesting compounds, such as the 2-hydroxybenzamido derivatives 29, 31, and 32, and the 4-aminophenyl derivative 54, which inhibited viral growth in the low micromolar range (EC50 = 0.18–1.2 μM) at no toxic concentrations (CC50 > 250 μM). This study permitted to obtain among the most potent anti-flu compounds within the PA-PB1 interaction inhibitors, confirming the cHTC scaffold as particularly suitable to achieve innovative anti-flu agents.
- Desantis, Jenny,Nannetti, Giulio,Massari, Serena,Barreca, Maria Letizia,Manfroni, Giuseppe,Cecchetti, Violetta,Palù, Giorgio,Goracci, Laura,Loregian, Arianna,Tabarrini, Oriana
-
-
Read Online
- Synthesis and Docking Study of Novel Pyranocoumarin Derivatives
-
Abstract: A new series of fused tricyclic coumarin derivatives were designed, synthesized by a simple and convenient method, starting from 4-hydroxycoumarin and virtually screened by molecular docking on the target protein 3FRZ (PDB ID: 3FRZ), a HCV RNA-dependent RNA polymerase, for potency against hepatitis C virus (HCV). Efficient binding to the target protein was found for most of the synthesized compounds.
- Karteek, S. Durga,Reddy, A. Gopi,Tej, M. Bhuvan,Rao, M. V. Basaveswara
-
p. 272 - 282
(2021/04/02)
-
- Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones
-
The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.
- Wen, Li-Rong,Wang, Ning-Ning,Du, Wu-Bo,Ma, Qiang,Zhang, Lin-Bao,Li, Ming
-
supporting information
p. 2895 - 2900
(2021/04/14)
-
- Structure-activity relationship of spop inhibitors against kidney cancer
-
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
-
p. 4849 - 4866
(2020/06/08)
-
- Synthesis and biological evaluation of flavone-8-acrylamide derivatives as potential multi-target-directed anti Alzheimer agents and investigation of binding mechanism with acetylcholinesterase
-
In a search for novel multifunctional anti-Alzheimer agents, a congeneric set of seventeen flavone-8-acrylamide derivatives (8a─q)were synthesized and evaluated for their cholinesterase inhibitory, antioxidant, neuroprotective and modulation of Aβ aggregation activities. The target compounds showed effective and selective inhibitory activity against the AChE over BuChE. In addition, the target compounds also showed moderate anti-oxidant activity and strong neuroprotective capacities, and accelerated dosage-dependently the Aβ aggregation. Also, we presented here a complete study on the interaction of 8a, 8d, 8e, 8h and 8i with AChE. Through fluorescence emission studies, the binding sites number found to be 1, binding constants were calculated as 2.04 × 104, 2.22 × 104, 1.18 × 104, 9.8 × 103 and 3.2 × 104 M?1 and free energy change as ?5.83, ?5.91, ?5.51, ?5.41 and ?6.12 kcal M?1 at 25 °C which were well agreed with the computational calculations indicating a strong binding affinity of flavones and AChE. Furthermore, the CD studies revealed that the secondary structure of AChE became partly unfolded upon binding with 8a, 8d, 8e, 8h and 8i.
- Shaik, Jeelan Basha,Yeggoni, Daniel Pushparaju,Kandrakonda, Yelamanda Rao,Penumala, Mohan,Zinka, Raveendra Babu,Kotapati, Kasi Viswanath,Darla, Mark Manidhar,Ampasala, Dinakara Rao,Subramanyam, Rajagopal,Amooru, Damu Gangaiah
-
-
- New Flavone-Cyanoacetamide Hybrids with a Combination of Cholinergic, Antioxidant, Modulation of β-Amyloid Aggregation, and Neuroprotection Properties as Innovative Multifunctional Therapeutic Candidates for Alzheimer's Disease and Unraveling Their Mechanism of Action with Acetylcholinesterase
-
In line with the modern multi-target-directed ligand paradigm of Alzheimer's disease (AD), a series of 19 compounds composed of flavone and cyanoacetamide groups have been synthesized and evaluated as multifunctional agents against AD. Biological evaluation demonstrated that compounds 7j, 7n, 7o, 7r, and 7s exhibited excellent inhibitory potency (AChE, IC50 of 0.271 ± 0.012 to 1.006 ± 0.075 μM) and good selectivity toward acetylcholinesterase, significant antioxidant activity, good modulation effects on self-induced Aβ aggregation, low cytotoxicity, and neuroprotection in human neuroblastoma SK-N-SH cells. Further, an inclusive study on the interaction of 7j, 7n, 7o, 7r, and 7s with AChE at physiological pH 7.2 using fluorescence, circular dichroism, and molecular docking methods suggested that these derivatives bind strongly to the peripheral anionic site of AChE mostly through hydrophobic interactions. Overall, the multifunctional profiles and strong AChE binding affinity highlight these compounds as promising prototypes for further pursuit of innovative multifunctional drugs for AD.
- Basha, Shaik Jeelan,Mohan, Penumala,Yeggoni, Daniel Pushparaju,Babu, Zinka Raveendra,Kumar, Palaka Bhagath,Rao, Ampasala Dinakara,Subramanyam, Rajagopal,Damu, Amooru Gangaiah
-
p. 2206 - 2223
(2018/05/23)
-
- A Concise [3?+?3] Heteroaromatization Synthetic Strategy Afford Dicarboxamide Functionalized Novel Pyrazolo[1,5-a]Pyrimidines
-
A concise and effective approach to dicarboxamide functionalized novel pyrazolo[1,5-a]pyrimidine has been developed. The method involves [3?+?3] hetroaromatization of oxoketene dithioacetals (16a–x) with 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-c
- Patel, Anilkumar S.,Kapuriya, Naval P.,Naliapara, Yogesh T.
-
supporting information
p. 2635 - 2643
(2017/09/26)
-
- Design, Multicomponent Synthesis and Characterization of Diversely Substituted Pyrazolo[1,5-a] Pyrimidine Derivatives
-
The synthesis of various heterocyclic compounds using acetoacetanilide[AAA], we have demonstrated that acetoactanilide are versatile intermediate for the synthesis of pyrazolopyrimidine derivatives. Thus, to explore further, we sought that the reaction of various acetoactanilide, an appropriate aldehyde and 5-amino-N-cyclohexyl-3-(methylthio)-1H-pyrazole-4-carboxamide in the presence of base in isopropyl alcohol could be an effective strategy to furnish the novel pyrazolopyrimidine derivatives. Here we describe the novel synthetic methodology for the fused pyrazolopyrimidines.
- Ghelani, Satish M.,Naliapara, Yogesh T.
-
p. 1843 - 1851
(2016/11/23)
-
- Synthesis, pharmacological assessment, molecular modeling and in silico studies of fused tricyclic coumarin derivatives as a new family of multifunctional anti-Alzheimer agents
-
A series of fused tricyclic coumarin derivatives bearing iminopyran ring connected to various amido moieties were developed as potential multifunctional anti-Alzheimer agents for their cholinesterase inhibitory and radical scavenging activities. In vitro studies revealed that most of these compounds exhibited high inhibitory activity on acetylcholinesterase (AChE), with IC50 values ranging from 0.003 to 0.357 μM which is 2-220 folds more potent than the positive control, galantamine. Their inhibition selectivity against AChE over butyrylcholinesterase (BuChE) has increased about 194 fold compared with galantamine. The developed compounds also showed potent ABTS radical scavenging activity (IC50 7.98-15.99 μM). Specifically, the most potent AChE inhibitor 6n (IC50 0.003 ± 0.0007 μM) has an excellent antioxidant profile as determined by the ABTS method (IC50 7.98 ± 0.77 μM). Moreover, cell viability studies in SK N SH cells showed that the compounds 6m-q have significant neuroprotective effects against H2O2-induced cell death, and are not neurotoxic at all concentrations except 6n and 6q. The kinetic analysis of compound 6n proved that it is a mixed-type inhibitor for EeAChE (Ki1 0.0103 μM and Ki2 0.0193 μM). Accordingly, the molecular modeling study demonstrated that 6m-q with substituted benzyl amido moiety possessed an optimal docking pose with interactions at catalytic active site (CAS) and peripheral anionic site (PAS) of AChE simultaneously and thereby they might prevent aggregation of Aβ induced by AChE. Furthermore, in silico ADMET prediction studies indicated that these compounds satisfied all the characteristics of CNS acting drugs. Most active inhibitor 6n is permeable to BBB as determined in the in vivo brain AChE activity. To sum up, the multipotent therapuetic profile of these novel tricyclic coumarins makes them promising leads for developing anti-Alzheimer agents.
- Shaik, Jeelan Basha,Palaka, Bhagath Kumar,Penumala, Mohan,Kotapati, Kasi Viswanath,Devineni, Subba Rao,Eadlapalli, Siddhartha,Darla, M. Manidhar,Ampasala, Dinakara Rao,Vadde, Ramakrishna,Amooru, G. Damu
-
p. 219 - 232
(2015/11/24)
-
- Synthesis, Biological Evaluation, and Molecular Docking of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene Analogs: New Dual AChE Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease
-
Alzheimer's disease onset and progression are associated with the dysregulation of multiple and complex physiological processes, and a successful therapeutic approach should therefore address more than one target. In line with this modern paradigm, a series of 8-imino-2-oxo-2H,8H-pyrano[2,3-f]chromene analogs (4a–q) were synthesized and evaluated for their multitarget-directed activity on acetylcholinesterase, butyrylcholinesterase (BuChE), 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical, and amyloid-β peptide (Aβ) specific targets for Alzheimer's disease therapy. Most of the synthesized compounds showed remarkable acetylcholinesterase inhibitory activities in low nm concentrations and good ABTS radical scavenging activity, however, no evidence of BuChE inhibitory activity. Among them, 3-bromobenzylamide derivative 4m exhibited the best acetylcholinesterase inhibitory activity with IC50 value of 13 ± 1.4 nm which is 51-fold superior to galantamine, a reference drug. Kinetic and molecular docking studies indicated 4m as mixed-type inhibitor, binding simultaneously to catalytic active and peripheral anionic sites of acetylcholinesterase. Five compounds 4e, 4f, 4g, 4j, and 4k have shown 1.4- to 2.5-fold of higher antioxidant activities than trolox. Interestingly, the most active compound 4m demonstrated dosage-dependent acceleration of Aβ1?42 aggregation, which may reduce toxicity of oligomers. Overall, these results lead to discovery of fused tricyclic coumarins as promising dual binding site inhibitors of acetylcholinesterase and afford multifunctional compounds with potential impact for further pharmacological development in Alzheimer's therapy.
- Shaik, Jeelan Basha,Palaka, Bhagath Kumar,Penumala, Mohan,Eadlapalli, Siddhartha,Darla Mark, Manidhar,Ampasala, Dinakara Rao,Vadde, Ramakrishna,Amooru Gangaiah, Damu
-
-
- Synthesis of resveratrol acrylamides derivatives and biological evaluation of their anti-proliferative effect on cancer cell lines
-
A new series of resveratrol acrylamides amine derivatives was designed, synthesized, and evaluated for their anti-proliferative activity against three cancer cell lines including human chronic myelocytic leukemia cell K562, human hepatoma HuH-7 and human lung carcinoma A549. Most of the compounds showed superior activity against three cell lines when compared to parent resveratrol. C13 had the best anti-tumor activity against the HuH-7 cell line and its IC 50 was 4.5 μmol/L; C16 had the best anti-tumor activity against the K562 cell line and its IC50 was 2.9 μmol/L; C18 had the best anti-tumor activity against the A549 cell line and its IC50 was 3.8 μmol/L. It could be seen that the activity of the aromatic amine derivatives was better than the fatty amine derivatives by analyzing the experimental data.
- Ruan, Ban-Feng,Wang, Si-Qi,Ge, Xiao-Lin,Yao, Ri-Sheng
-
-
- A simple and general approach for the synthesis of highly functionalized 6-oxo-1,6-dihydropyridines
-
A variety of 5-cyano-4-methylthio-6-oxo-1,6-dihydropyridine-3-carboxylates have been efficiently synthesized in a one-pot reaction from N-alkyl and N-aryl derivatives of 2-cyano-3,3-bis(methylthio)acrylamides and selected β-keto esters. The reaction proceeds via potassium hydrogen carbonate mediated conjugate addition of a β-keto ester to 2-cyano-3,3-bis(methylthio) acrylamide followed by loss of methyl mercaptan and subsequent intramolecular condensation of amide group with the acyl carbonyl group. The mechanism of the reaction has been established by isolation of the 2-acetyl-4-cyano-5-amino-3- (methylthio)-5-oxopent-3-enoate intermediate and its independent cyclization to the desired 6-oxo-1,6-dihydropyridine.
- Kumar, Sukeerthi,Thakur, Rajni R.,Margal, Sanjay R.,Thomas, Abraham
-
supporting information
p. 5112 - 5118
(2013/06/27)
-
- Cyanoacetamides (IV): Versatile one-pot route to 2-quinoline-3-carboxamides
-
Cyanoacetic acid derivatives are the starting materials for a plethora of multicomponent reaction (MCR) scaffolds. Herein, we describe scope of a valuable general protocol for the synthesis of arrays of 2-aminoquinoline-3-carboxamides from cyanoacetamides and 2-aminobenzaldehydes or heterocyclic derivatives via a Friedlaender reaction variation. In many cases, the reactions involve a very convenient work up by simple precipitation and filtration. More than 40 new products are described. We foresee our protocol and the resulting derivatives becoming very valuable to greatly expanding the scaffold space of cyanoacetamide derivatives.
- Wang, Kan,Herdtweck, Eberhardt,Doemling, Alexander
-
scheme or table
p. 316 - 322
(2012/06/18)
-
- Efficient synthesis of new butenolides by subsequent reactions: Application for the synthesis of original iminolactones, bis-iminolactones and bis-lactones
-
We have developed the synthesis of twenty four new iminolactones, bis-iminolactones and bis-lactones by subsequent esterification-condensation or addition-condensation reactions according to two strategies from α-hydroxyketones. The X-ray diffraction data of a bis-iminolactone is described and present an interesting helical column packing.
- Cheikh, Nawel,Bar, Nathalie,Choukchou-Braham, Nourredine,Mostefa-Kara, Bachir,Lohier, Jean-Franois,Sopkova, Jana,Villemin, Didier
-
experimental part
p. 1540 - 1551
(2011/04/15)
-
- Green chemistry: A facile synthesis of polyfunctionally substituted thieno[3,4-c]pyridinones and thieno[3,4-d]pyridazinones under neat reaction conditions
-
A facile, solvent free, ecofriendly approach for the synthesis of pyridine-2,6-diones 4a-d, pyridazinone derivatives 8a-c and thienoazines 6 and 9 is herein described employing neat reaction conditions under both microwave and ultrasound irradiations. This solventless methodology is environmentally benign as it completely eliminates the use of solvent from the reaction procedure.
- Al-Zaydi, Khadijah M.,Borik, Rita M.,Mekheimer, Ramadan A.,Elnagdi, Mohamed H.
-
body text
p. 909 - 915
(2011/10/08)
-
- Ring-expansion reaction of cyclopropane: A novel process for synthesis of bicyclic dicarboximides from cyclopropanedicarboximides and carbon nucleophile
-
The ring-expansion reaction of cyclopropane with carbon nucleophile was studied. The novel process for synthesis of bicyclic dicarboximides from cyclopropanedicarboximides with malononitrile or ethyl cyanoacetate was described. Copyright Taylor & Francis
- Ren, Zhongjiao,Cao, Weiguo,Lu, Yeying,Wang, Yun,Wang, Sihui
-
p. 2215 - 2226
(2008/09/21)
-
- PYRAZOLE DERIVATIVES AS 11-BETA-HSD1 INHIBITORS
-
A compound of formula (I): and pharmaceutically -acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11βHSD1, processes for making them and pharmaceutical compositions comprising them are also described.
- -
-
Page/Page column 88
(2008/12/08)
-
- Synthesis of N-substituted γ-methylene γ-lactams
-
N-Substituted cyanoacetamides 1 were condensed with 1,2-diketones 2 under base catalysis to form ?-hydroxy ?-lactams 3. Treatment of 3 with acids gave novel fungicidal ?-methylene ?-lactams 4. The exocyclic double bond of 4b reacted reversibly with 4-toluene sulfinate. CSIRO 2005.
- Adhikari, Raju,Jones, Dionne A.,Liepa, Andris J.,Nearn, Roland H.
-
p. 882 - 890
(2007/10/03)
-
- Tyrphostins. 2. Heterocyclic and α-Substituted Benzylidenemalonitrile Tyrphostins as Potent Inhibitors of EGF Receptor and ErbB2/neu Tyrosine Kinases
-
We have previously described a novel series of low molecular weight protein tyrosine kinase inhibitors which we named tyrphostins.The characteristic active pharmacophore of these compounds was the hydroxy-cis-benzylidenemalonitrile moiety.In this article we describe three novel groups of tyrphostins: (i) one group has the phenolic moiety of the cis-benzylidenemalononitrile replaced either with other substituted benzenes or with heteroaromatic rings, (ii) another is a series of conformationally constrained derivatives of hydroxy-cis-benzylidenemalononitriles in which the malononitrile moiety is fixed relative to the aromatic ring, and (iii) two groups of compounds in which the position trans to the benzenemalononitrile has been substituted by ketones and amides.Among the novel tyrphostins examined we found inhibitors which discriminate between the highly homologous EGF receptor kinase (HER1) and ErbB2/neu kinase (HER2).These findings may lead to selective tyrosine kinase blockers for the treatment of diseases in which ErbB2/neu is involved.
- Gazit, Aviv,Osherov, Nir,Posner, Israel,Yaish, Pnina,Poradosu, Enrique,et al.
-
p. 1896 - 1907
(2007/10/02)
-
- Rapid, Low-Temperature Amidation of Ethyl Cyanoacetate with Lithium Amides Derived from Primary and Secondary Amines
-
A facile, rapid method for amidating ethyl cyanoacetate with lithium amides derived from various primary and secondary amines, including sterically demanding amines is described.
- Bhawal, Baburao M.,Khanapure, Subhash P.,Biehl, Edward R.
-
p. 3235 - 3243
(2007/10/02)
-