- Design, synthesis and in vitro evaluation of novel SARS-CoV-2 3CLpro covalent inhibitors
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Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro (main coronaviruses cysteine-protease) has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in the design and synthesis of submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.
- Stille, Julia K.,Tjutrins, Jevgenijs,Wang, Guanyu,Venegas, Felipe A.,Hennecker, Christopher,Rueda, Andrés M.,Sharon, Itai,Blaine, Nicole,Miron, Caitlin E.,Pinus, Sharon,Labarre, Anne,Plescia, Jessica,Burai Patrascu, Mihai,Zhang, Xiaocong,Wahba, Alexander S.,Vlaho, Danielle,Huot, Mitchell J.,Schmeing, T. Martin,Mittermaier, Anthony K.,Moitessier, Nicolas
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- Structure-Based Design and Discovery of New M2 Receptor Agonists
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Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes.
- Fish, Inbar,St??el, Anne,Eitel, Katrin,Valant, Celine,Albold, Sabine,Huebner, Harald,M?ller, Dorothee,Clark, Mary J.,Sunahara, Roger K.,Christopoulos, Arthur,Shoichet, Brian K.,Gmeiner, Peter
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supporting information
p. 9239 - 9250
(2017/11/30)
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- Xylochemistry - Making Natural Products Entirely from Wood
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The first total synthesis of the dimeric berberine alkaloid ilicifoline (ilicifoline B) is reported. Its carbon skeleton is constructed from ferulic acid, veratrole, and methanol. The synthesis reported herein employs starting materials solely derived from wood. The natural product is thus constructed entirely from renewable resources. The same strategy is applied to a formal total synthesis of morphinan alkaloids. The use of wood-derived building blocks (xylochemicals) instead of the conventional petrochemicals represents a sustainable alternative to classical synthetic approaches.
- Stubba, Daniel,Lahm, Günther,Geffe, Mario,Runyon, Jason W.,Arduengo, Anthony J.,Opatz, Till
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supporting information
p. 14187 - 14189
(2016/01/25)
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- Praziquantel derivatives with antischistosomal activity: Aromatic ring modification
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A series of aromatic ring-modified praziquantel derivatives were prepared and evaluated against juvenile and adult stage of Schistosoma japonicumin. Several analogs comparable in activity to the drug praziquantel have been identified based on in vitro and in vivo japonuicum schistosomes worm viability assay. Structure and activity relationship of these praziquantel aromatic ring-modified compounds was revealed. Specifically, a compound in which a bromine has been introduced in the aromatic ring of praziquantel demonstrated close antischistosomal activity to praziquantel in vivo.
- Wang, Zhi-Xia,Chen, Jing-Lei,Qiao, Chunhua
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p. 216 - 225
(2013/08/23)
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- A synthesis of dihydroimidazo[5,1-a]isoquinolines using a sequential Ugi-Bischler-Napieralski reaction sequence
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A flexible route to analogues of dihydroimidazo[5,1-a]isoquinolines is described. The synthesis hinges on a sequential Ugi coupling, followed by a Bischler-Napieralski reaction to form the imidazole isoquinoline core. This route facilitates the introduction of a range of substitutions throughout the carbon framework.
- Seganish, W. Michael,Bercovici, Ana,Ho, Ginny D.,Loozen, Hubert J.J.,Timmers, Cornelis M.,Tulshian, Deen
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scheme or table
p. 903 - 905
(2012/03/10)
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- Benzoxazines for use in the treatment of parkinson's disease
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Benzoxazines of Formula (I) wherein R1 is C1-C6 alkyl, C2-C6 alkenyl, or (CH2)n phenyl, R2 is C3-C6 alkyl, R3 is hydrogen, halo, hydro
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Page/Page column 3-5
(2008/06/13)
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- Synthesis and pharmacology of benzoxazines as highly selective antagonists at M4 muscarinic receptors
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Previously, we reported on PD 102807 (41) as being the most selective synthetic M4 muscarinic antagonist identified to date. Synthesized analogues of 41 showed no improvement in affinity and selectivity at that time. However, several newly synthesized compounds exhibit a 7-fold higher affinity at M4 receptors and demonstrate a selectivity of at least 100-fold over all other muscarinic receptor subtypes. For example, compound 28 showed an affinity of pKi = 9.00 at M4 receptors and a selectivity of M1/M4 13 183-fold, M2/M4 = 339-fold, M3/M4 = 151-fold, and M5/M4 = 11 220-fold. This high selectivity along with high affinity has not been reported for any synthetic muscarinic antagonist, nor for natural occurring M4 antagonists such as the M4 selective Eastern Green Mamba venom MT3 (M4 pKb = 8.7, M1/M4 = 40-fold, M2/M4 ≥ 500-fold, M3/M4 500-fold, and M5/M4 ≥ 500-fold). Derivative 24, a compound with a high selectivity pattern as well, has been tested for in vivo efficacy. It was able to block the L-3,4-dihydroxyphenylalanine accumulation produced by CI-1017, an M1/M4 selective muscarinic agonist, in the mesolimbic region and striatum, which suggests that 24 is capable of crossing the blood-brain barrier and confirms the pharmacokinetic data obtained on this compound. This is evidence that suggests that agonist-induced increase in catecholamine synthesis observed in these regions is mediated by M4 receptors.
- B?hme, Thomas M.,Augelli-Szafran, Corinne E.,Hallak, Hussein,Pugsley, Thomas,Serpa, Kevin,Schwarz, Roy D.
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p. 3094 - 3102
(2007/10/03)
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- Identification and characterization of m4 selective muscarinic antagonists
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Our interest in the area of m4 muscarinic antagonists has led us to study a series of benzoxazine isoquinolines. One of the most potent and selective compounds of this series is example 1 with an IC50 value of 90.7nM at m4 receptors, and 72-fold (m1), 38-fold (m2), 10-fold (m3), and 82- fold (m5) more selective compared to the other receptors. The synthesis and receptor binding affinity of analogs of 1 are reported.
- Augelli-Szafran, Corinne E.,Jaen, Juan C.,Moreland, David W.,Nelson, Carrie B.,Penvose-Yi, Jan R.,Schwarz, Roy D.
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p. 1991 - 1996
(2007/10/03)
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- Process for the preparation of (8As,12AS,13AS)-decahydroisoquino ((2,1-G) (1,6)-naphthyridin-8-one derivatives
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The invention provides a process for preparing single enantiomers of compounds represented by the formula: STR1 and chiral acid addition salts thereof; wherein: X and Y are independently hydrogen; lower alkyl; lower alkoxy; or halo; or X and Y taken together is methylenedioxy or ethylene-1,2-dioxy; which includes reduction of a compound represented by the formula: STR2 to give a mixture of stereoisomers represented by the formula: STR3 wherein each wavy line independently represents a bond in either the α or β position; followed by dissolving the mixture of stereoisomers and a chiral resolving acid in a suitable solvent and allowing the solution to crystallize, giving a salt of the desired enantiomer.
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