- Synthesis, Characterization, and Antifungal Activity of Some New Thieno[2,3-b]pyridines Incorporating Quinazoline or Benzimidazole Moiety
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Abstract: Reaction of 4,6-dimethyl-3-cyanopyridine-2(1H)-thione (IIIa) or 4,5,6-trisubstituted-3-cyanopyridine-2(1H)-thiones (IIIb–d) with 2-chloromethylquinazoline-4(3H)-one (IVa) furnished the corresponding 3-amino-2-(4-oxo-3,4-dihydroquinazolin-2-yl)thieno[2,3-b]pyridines (VIa–d). Reaction of aminothieno-pyridines (VIa, b, d) were reacted with triethyl orthoformate, acetic anhydride or nitrous acid to furnish pyridothienopyrimidoquinazolines (VIIIa, b, d), (IXa, b, d) or pyridothienotriazinoquinazolines (Xa, b, d). The new compound, 3-cyano-5-acetyl-6-methyl-4-styrylpyridine-2(1H)-thione (IIIe) was synthesized and reacted with 2-chloromethyl-1H-benzimadazole to give 5-acetyl-3-amino-2-(1H-benzimidazol-2-yl)-6-methyl-4-styryl-thieno[2,3-b]pyridine (XII) which was used as a key intermediate for synthesizing pyridothienopyrimidobenzimidazoles (XIII, XIV). All newly synthesized compounds were characterized on the basis of their elemental and spectral analyses. Also, most of the synthesized compounds were screened in vitro for their antifungal activity.
- Abdu-Allah, H. H. M.,Al-Taifi, E. A.,Bakhite, E. A.,El-Ossaily, Y. A.,Ibrahim, O. F.,Kandel, M.,Metwally, S. A. M.
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p. 918 - 928
(2021/08/25)
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- Synthesis, in-vitro antibacterial and anticancer screening of novel nicotinonitrile-coumarin hybrids utilizing piperazine citrate
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An efficient, low-cost, high yield% and eco-friendly synthetic procedure is designed for the synthesis of novel series of nicotinonitrile-coumarin hybrid molecules bearing several aryl and/or heteroaryl moieties. Our strategy includes the synthesis of a novel series of 2-hydroxybenzaldehydes, bearing nicotinonitrile moiety, followed by its Knoevenagel reaction with ethyl acetoacetate in the presence of an organo-base. The above reaction is studied in different reaction conditions. The optimized conditions are performing the reaction in ethanol at 80 °C in the presence of 10 mol% of piperazine citrate (1:1). The in-vitro antibacterial activities of the nicotinonitrile-coumarins were evaluated against different Gram-positive and negative bacterial strains. Moreover, the in-vitro cytotoxicity of nicotinonitrile-coumarins were estimated against different eukaryotic cell lines. Compounds 5a and 5b exhibited the most promising antibacterial agents among the novel series. The structures of novel series of the target nicotinonitrile-coumarin hybrid molecules were confirmed by considering their elemental analyses and spectral data.
- Mekky, Ahmed E. M.,Sanad, Sherif M. H.
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- Discovery and optimization of thienopyridine derivatives as novel urea transporter inhibitors
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Urea transporters (UTs) play an important role in the urine concentrating mechanism and are recognized as novel targets for developing small molecule inhibitors with salt-sparing diuretic activity. Thienoquinoline derivatives, a class of novel UT-B inhibitors identified by our group, play a significant diuresis in animal model. However, the poor solubility and low bioavailability limited its further development. To overcome these shortcomings, the structure modification of thienoquinoline was carried out in this study, which led to the discovery of novel thienopyridine derivatives as specific urea transporter inhibitors. Further optimization obtained the promising preclinical candidate 8n with not only excellent inhibition effect on urea transporters and diuretic activity on rat model, but also suitable water solubility and Log P value.
- Zhao, Yan,Li, Min,Li, Bowen,Zhang, Shun,Su, Aoze,Xing, Yongning,Ge, Zemei,Li, Runtao,Yang, Baoxue
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p. 131 - 142
(2019/04/08)
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- Experimental and theoretical study on the regioselective bis- and polyalkylation of 2-mercaptonicotinonitrile and 2-mercaptopyrimidine-5-carbonitrile derivatives
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The synthetic utility of 2-mercaptonicotinonitriles 3 and 4, as well as 2-mercapto-4-oxo-6-phenyl-1,4-dihydropyrimidine-5-carbonitrile 20 as building blocks for novel bis- and poly(pyridines), along with poly(pyrimidines) via alkylation with the corresponding bis- and poy(halo) compounds was investigated. Spectroscopic and theoretical studies confirmed the S-alkylation rather than the N-alkylation.
- Abd El-Fatah, Nesma A.,Darweesh, Ahmed F.,Mohamed, Adel A.,Abdelhamid, Ismail A.,Elwahy, Ahmed H.M.
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p. 1436 - 1450
(2017/02/18)
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- 3-Amino-thieno[2,3-b]pyridines as microtubule-destabilising agents: Molecular modelling and biological evaluation in the sea urchin embryo and human cancer cells
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A series of 3-amino-thieno[2,3-b]pyridines was prepared and tested in a phenotypic sea urchin embryo assay to identify potent and specific molecules that affect tubulin dynamics. The most active compounds featured a tricyclic core ring system with a fused cycloheptyl or cyclohexyl substituent and unsubstituted or alkyl-substituted phenyl moiety tethered via a carboxamide. Low nano-molar potency was observed in the sea urchin embryos for the most active compounds (1–5) suggestive of a microtubule-destabilising effect. The molecular modelling studies indicated that the tubulin colchicine site is inhibited, which often leads to microtubule-destabilisation in line with the sea urchin embryo results. Finally, the identified hits displayed a robust growth inhibition (GI50of 50–250?nM) of multidrug-resistant melanoma MDA-MB-435 and breast MDA-MB-468 human cancer cell lines. This work demonstrates that for the thieno[2,3-b]pyridines the most effective mechanism of action is microtubule-destabilisation initiated by binding to the colchicine pocket.
- Eurtivong, Chatchakorn,Semenov, Victor,Semenova, Marina,Konyushkin, Leonid,Atamanenko, Olga,Reynisson, Jóhannes,Kiselyov, Alex
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p. 658 - 664
(2016/12/27)
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- Synthesis of 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile by condensation of cyanothioacetamide with acetaldehyde and 1-(Prop-1-en-2-yl)piperidine
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Three-component condensation of cyanothioacetamide with acetaldehyde and 1-(prop-1-en-2-yl)-piperidine afforded 4,6-dimethyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile which was alkylated with alkyl halides to obtain substituted 2-alkylsulfanyl-4,6-dimethylpyridine-3-carbonitriles, (3-amino-4,6-dimethylthieno-[2,3-b]pyridin-2-yl)(4-cyclohexylphenyl)methanone, and 2,2′-[ethane-1,2-diylbis(sulfanediyl)]bis(4,6-dimethylpyridine-3-carbonitrile).
- Dyachenko,Dyachenko
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- Novel method of 4,6-dimethyl-2-thioxo-1,2-dihydronicotinonitrile synthesis
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Condensation of acetaldehyde with cyanothioacetamide and 1-(prop-1-en-2-yl)pyrrolidine has afforded 4,6-dimethyl-2-thioxo-1,2-dihydronicotinonitrile. Alkylation of the latter with α-haloketones yields substituted 2-alkylsulfanyl-4,6-dimethylnicotinonitriles and thieno[2,3-b]pyridines.
- Dyachenko
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p. 1834 - 1837
(2015/10/12)
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- Structure-activity relationships of privileged structures lead to the discovery of novel biased ligands at the dopamine D2 receptor
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Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.
- Szabo, Monika,Klein Herenbrink, Carmen,Christopoulos, Arthur,Lane, J. Robert,Capuano, Ben
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p. 4924 - 4939
(2014/07/07)
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- Probing structural requirements of positive allosteric modulators of the M4 muscarinic receptor
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The M4 mAChR is implicated in several CNS disorders and possesses an allosteric binding site for which ligands modulating the affinity and/or efficacy of ACh may be exploited for selective receptor targeting. We report the synthesis of a focused library of putative M4 PAMs derived from VU0152100 and VU10005. These compounds investigate the pharmacological effects of previously identified methoxy and fluoro substituents, providing useful estimates of affinity (KB), cooperativity (αβ), and direct agonist properties (τB).
- Huynh, Tracey,Valant, Celine,Crosby, Ian T.,Sexton, Patrick M.,Christopoulos, Arthur,Capuano, Ben
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supporting information
p. 8196 - 8200
(2013/11/06)
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- Synthesis and formulation of some new azines and evaluation of their fungicidal efficiency
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TWENTY FIVE new 3-cyanopyridine-2(lH)-thione derivatives were synthesized by different routes. Structural elucidation of the prepared compounds was carried out by their correct elemental analyses as well as spectroscopic data (IR, Ms, 1Η-NMR). Fungicidal activity of the new compounds, on two soil borne fungi, was assayed by food poison technique where, some of the new compounds showed good fungicidal activity. Formulation of the most potent one, in the form of 20% EC, was carried out and its fungicidal activity was evaluated which was found to be more active than the standard fungicide Flutolanil (Moncut 25%WP).
- Youssef,Ibrahim,Attia, Hanaa A.E.,Hamouda
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scheme or table
p. 163 - 175
(2011/06/19)
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- Pyridine and pyrimidine ring syntheses from 4-(4-morpholino)-3-pentenone and from ethyl 3-(4-morpholino)-2-butenoate
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3-Substituted 2(1H)-pyridones are produced from reaction of 4-(4- morpholino)-3-pentenone 1 with each of the following carbon acids: cyanoacetamide, malononitrile, cyanothioacetamide, acetylacetamide, benzoyl- acetonitrile. Reaction of ethyl 3-(4-morpholino)-2-butenoate 2 with cyanoacetamide gives the corresponding hydroxypyridone. Pyrimidines are formed by reaction of 1 and of 2 with benzamidine and with S-benzylthiourea; in the last case, the eliminated morpholine displaces the benzylthio group to give the final product.
- Ratemi,Namdev,Gibson
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p. 1513 - 1516
(2007/10/02)
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