- Regioselective convergent synthesis of 2-arylidene thiazolo[3,2-: A] pyrimidines as potential anti-chikungunya agents
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Convergent and convenient regioselective synthesis of novel thiazolo[2,3-a]pyrimidine derivatives was accomplished using the one-pot reaction of 6-ethylthiouracil, bromoacetic acid, anhydrous sodium acetate, acetic anhydride, acetic acid and suitable aldehyde. X-ray crystallographic study reveals the presence of the Z configuration of only one regioisomer confirmed by computational studies as being the most likely isomer present.
- Alsherbiny, Muhammad A.,Clark, Timothy,Fares, Mohamed,Jochmans, Dirk,Keller, Paul A.,McCosker, Patrick M.,Neyts, Johan,Willis, Anthony C.
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- Synthesis, X-ray crystallographic analysis, DFT studies and biological evaluation of triazolopyrimidines and 2-anilinopyrimidines
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Inspired by the reported antiviral activity of pyrimidines and triazolopyrimidines, two series of 2-anilinopyrimidines (5a-e) and 1-aryl-[1,2,4]triazolo[4,3-a]pyrimidines (14a-k) were designed and synthesized as potential antiviral agents. X-ray crystallographic study of compounds (14d) and (14k) confirmed the structure of the desired isomer and revealed the coplanarity of the fused [1,2,4]triazolo[4,3-a]pyrimidine rings with the aryl side group. DFT studies revealed insights into the mechanism of the micro-reversible cyclisation step using DFT [B3LYP-D3(BJ)/6–31++G(d,p)]. The pharmacokinetic properties and calculation of drug likeness scores (DLS) of (5a-e) and (14a-k) suggested good traditional drug-like properties and led to the synthesis of derivatives (14a-k) which were evaluated for their anti-viral activity with the most potent derivatives subjected to cytotoxicity screening. Compounds (14a), (14c), (14e), (14f) and (14k) showed moderate to strong antiviral activity with EC50 values 38 - 186 μM. Compound (14e) (DLS = 0.29) showed the best anti-CHIKV activity (EC50 = 38 μM) and lowest cytotoxicity (CC50 > 300 μg/ml) against breast cancer cell lines, MCF-7 and MD-AMB-231 and normal cell line EA.hy926. Simplification of [1,2,4]triazolo[4,3-a]pyrimidine ring, led to series (5a-e) (DLS = 0.03 - 0.77). Derivatives (5a-d) showed fair anti-CHIKV activity (EC50 > 200 μM), while (5e) emerged as the most active antiviral agent, however the most cytotoxic.
- Alsherbiny, Muhammad A.,Canfield, Peter,Fares, Mohamed,Gale, Philip A.,Guang Li, Chun,Jochmans, Dirk,Keller, Paul A.,Lewis, William,Neyts, Johan,Willis, Anthony C.
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- PYRAZOLYL PYRIMIDINONE COMPOUNDS AND THE USES THEREOF
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The present invention relates to a method of treatment for chronic pain, opioid dependence, alcohol use disorder or autism using a class of pyrimidinone compounds, an adenylyl cyclase 1 (AC1) inhibitor. The invention described herein also pertains to phar
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Paragraph 0120-0122
(2021/04/10)
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- Design, synthesis, and acaricidal activity of phenyl methoxyacrylates containing 2-alkenylthiopyrimidine
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A series of novel phenyl methoxyacrylate derivatives containing a 2-alkenylthiopyrimidine substructure were designed, synthesized, and evaluated in terms of acaricidal activity. The structures of the title compounds were identified by 1H NMR, 13C NMR and high-resolution mass spectra (HRMS). Compound (E)-methyl 2-(2-((2-(3,3-dichloroallylthio)-6-(trifluoromethyl)pyrimidin-4-yloxy) methyl)phenyl)-3-methoxyacr-ylate (4j) exhibited significant acaricidal activity against Tetranychus cinnabarinus (T. cinnabarinus) in greenhouse tests possessing nearly twice the larvicidal and ovicidal activity compared to fluacrypyrim. Furthermore, the results of the field trials demonstrated that compound 4j could effectively control Panonychuscitri with long-lasting persistence and rapid action. The toxicology data in terms of LD50 value confirmed that compound 4j has a relatively low acute toxicity to mammals, birds, and honeybees.
- Hao, Shulin,Cai, Zengfei,Cao, Yangyang,Du, Xiaohua
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- Laccase-catalyzed green synthesis and cytotoxic activity of novel pyrimidobenzothiazoles and catechol thioethers
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The laccase-catalyzed reaction between unsubstituted catechol and 2-thioxopyrimidin-4(1H)-ones using aerial O2 as the oxidant delivers novel pyrimidobenzothiazoles with high yields in an aqueous solvent system under mild reaction conditions. With 4-substituted catechols, catechol thioethers are formed exclusively. The synthetic protocols developed provide a sustainable approach for these compound classes. In addition, the cytotoxicity of the products against HepG2 cell line is reported. Most compounds exhibit antiproliferative activities with IC50 values at the micromolar level. A structure-activity relationship study will facilitate the further development of these compounds as cytotoxic agents.
- Abdel-Mohsen,Conrad,Harms,Nohr,Beifuss
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p. 17427 - 17441
(2017/03/31)
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- Synthesis and evaluation of 5,6-disubstituted thiopyrimidine aryl aminothiazoles as inhibitors of the calcium-activated chloride channel TMEM16A/Ano1
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Transmembrane protein 16A (TMEM16A), also called Ano1, is a Ca2+ activated Cl? channel expressed widely in mammalian epithelia, as well as in vascular smooth muscle and some tumors and electrically excitable cells. TMEM16A inhibitors have potential utility for treatment of disorders of epithelial fluid and mucus secretion, hypertension, some cancers and other diseases. 4-Aryl-2-amino thiazole T16Ainh-01 was previously identified by high-throughput screening. Here, a library of 47 compounds were prepared that explored the 5,6-disubstituted pyrimidine scaffold found in T16Ainh-01. TMEM16A inhibition activity was measured using fluorescence plate reader and short-circuit current assays. We found that very little structural variation of T16Ainh-01 was tolerated, with most compounds showing no activity at 10 μM. The most potent compound in the series, 9bo, which substitutes 4-methoxyphenyl in T16Ainh-01 with 2-thiophene, had IC50 ~1 μM for inhibition of TMEM16A chloride conductance.
- Piechowicz, Katarzyna A.,Truong, Eric C.,Javed, Kashif M.,Chaney, Rachelle R.,Wu, Johnny Y.,Phuan, Puay W.,Verkman, Alan S.,Anderson, Marc O.
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p. 1362 - 1368
(2016/10/09)
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- Microwave-assisted synthesis of substituted: 2-(benzylthio)imidazo[1,2a] pyrimidin-5-ones
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A microwave-assisted solid-phase synthesis of 2-(benzylthio)imidazo[1,2a] pyrimidin-5-ones has been developed. Using microwave irradiation, the reaction time was significantly reduced from a few days to 80 min. A representative set of 10 2-(benzylthio)-6,7-substituted-imidazo[1,2a]pyrimidin-5-ones was prepared. These compounds were subsequently N-alkylated and formylated in good yields.
- Soh, Chai Hoon,Lam, Yulin
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experimental part
p. 286 - 291
(2010/08/20)
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- Synthesis of an AZT-HEPT hybrid and homologous AzddU derivatives
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3′-Azido-2′,3′-dideoxyuridines 6 and their corresponding α anomers 5 were syrthesizes by condensation of silylated 6-alkyl and 5,6-dialkyl substituted uracils 2 with methyl 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-α,β-D-erythro- pentofuranoside (4). Compounds 5 and 6 were treated with tetrabutylammonium fluoride to obtain the deprotected nucleosides 7 and 8, respectively. Acta Chemica Scandinavica 1996.
- Larsen, Erik,Danel, Krzysztof,Vaaben, Gitte B.,El-Emam, Ali A.,Pedersen, Erik B.,Nielsen, Claus
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p. 417 - 421
(2007/10/03)
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