- Novel imidazopyrimidines-based molecules induce tetramerization of tumor pyruvate kinase M2 and exhibit potent antiproliferative profile
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Discovery of novel and potent lead molecules for the specific therapeutic targets by de novo drug design is still in infancy. Here, we disclose the unprecedented development of imidazopyri(mi)dine-based tumor pyruvate kinase M2 (PKM2) modulators by subseq
- Patel, Sagarkumar,Globisch, Christoph,Pulugu, Priyanka,Kumar, Prasoon,Jain, Alok,Shard, Amit
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- Looking toward the Rim of the Active Site Cavity of Druggable Human Carbonic Anhydrase Isoforms
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We report the synthesis and biochemical evaluation of a series of substituted 4-(4-aroylpiperazine-1-carbonyl)benzenesulfonamides (5a-s) developed as inhibitors of druggable carbonic anhydrase (CA) isoforms, as tools for the identification of new therapeu
- Mancuso, Francesca,Di Fiore, Anna,De Luca, Laura,Angeli, Andrea,Monti, Simona M.,De Simone, Giuseppina,Supuran, Claudiu T.,Gitto, Rosaria
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p. 1000 - 1005
(2020/03/23)
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- Structure-Based Optimization of Pyridoxal 5′-Phosphate-Dependent Transaminase Enzyme (BioA) Inhibitors that Target Biotin Biosynthesis in Mycobacterium tuberculosis
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The pyridoxal 5′-phosphate (PLP)-dependent transaminase BioA catalyzes the second step in the biosynthesis of biotin in Mycobacterium tuberculosis (Mtb) and is an essential enzyme for bacterial survival and persistence in vivo. A promising BioA inhibitor 6 containing an N-aryl, N′-benzoylpiperazine scaffold was previously identified by target-based whole-cell screening. Here, we explore the structure-activity relationships (SAR) through the design, synthesis, and biological evaluation of a systematic series of analogues of the original hit using a structure-based drug design strategy, which was enabled by cocrystallization of several analogues with BioA. To confirm target engagement and discern analogues with off-target activity, each compound was evaluated against wild-type (WT) Mtb in biotin-free and -containing medium as well as BioA under- and overexpressing Mtb strains. Conformationally constrained derivative 36 emerged as the most potent analogue with a KD of 76 nM against BioA and a minimum inhibitory concentration of 1.7 μM (0.6 μg/mL) against Mtb in biotin-free medium.
- Liu, Feng,Dawadi, Surendra,Maize, Kimberly M.,Dai, Ran,Park, Sae Woong,Schnappinger, Dirk,Finzel, Barry C.,Aldrich, Courtney C.
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p. 5507 - 5520
(2017/07/22)
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- CARBAMATE COMPOUNDS AND OF MAKING AND USING SAME
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Provided herein are carbamate compounds which may be useful in the treatment of, for example, pain, solid tumors and/or obesity.
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Paragraph 00493
(2013/10/08)
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- Aminolysis of S-4-nitrophenyl X-substituted thiobenzoates: Effect of nonleaving-group substituents on reactivity and mechanism
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A kinetic study is reported for aminolysis of S-4-nitrophenyl X-substituted thiobenzoates 3a-g in 80 mol % H2O/20 mol % DMSO at 25.0 ± 0.1 °C. Thiol esters 3a-g are 7.8-47.6 fold more reactive than the corresponding oxygen esters (i.e., 4-nitrophenyl X-substituted benzoates 1a-g). Such reactivity order appears to be in accordance with the expectation that 4-nitrothiophenoxide in 3a-g is a better nucleofuge than 4-nitrophenoxide in 1a-g since the former is 2.64 pKa units less basic than the latter. Hammett plot for the reactions of 3a-g exhibit poor correlation coefficients (R2 = 0.977-0.986) with negative deviation by substrates possessing an electrondonating group (EDG), while the Yukawa-Tsuno plots result in excellent linear correlation (R2 = 0.995-0.997) with ? = 0.93-1.23 and r = 0.57-0.67, indicating that the negative deviation shown by substrates possessing an EDG is caused by ground-state stabilization through resonance interactions but not due to a change in ratedetermining step upon changing the nonleaving-group substituent X. The p value increases as the incoming amine becomes more basic and more reactive, indicating that the RSP is not operative in the current reactions.
- Im, Li-Ra,Jeon, Sang-Eun,Um, Ik-Hwan
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experimental part
p. 1153 - 1157
(2011/11/12)
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- Study of synthesis and cardiovascular activity of some furoxan derivatives as potential NO-donors
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A series of hybrid molecules incorporating the furoxan and nicorandil moieties were designed as potential NO donors with cardiovascular and cerebrovascular activities. Thirty-six target molecules were successfully synthesized by conventional methods and characterized by infrared spectroscopy, 1H-NMR spectroscopy and high resolution mass spectra. The compounds were tested for their effects on KCl-induced contraction of rabbit thoracic aorta whose endothelium was denuded. Eight compounds were found to reduce KCl-induced contraction by more than 30% at 10 μM. All except one of these compounds are characterized by the presence of electron withdrawing groups in the phenyl ring attached via an amide or ester linkage to the furoxan moiety. The nature of the terminal carbonyl linkage (ester or amide) and the length or type of the alkyl chain bridging the two carbonyl functions have little effect on the activity. One of the active compounds, N-(4- methoxy-benzoyl)-N'-[3-methylfuroxanyl-4-carbonyl)piperazine (17i) was tested for hypotensive effects on anaesthetized rats at 1.5 mg/kg, and found to demonstrate a gradual and sustained hypotensive effect. The results suggest that the furoxannicorandil derivatives are a useful lead in the design of NO- donor compounds for hypertension.
- Mu, Li,Feng, Si-Shen,Go, Mei Lin
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p. 808 - 816
(2007/10/03)
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- Effect of Acyl Substituents on the Reaction Mechanism for Aminolyses of 4-Nitrophenyl X-Substituted Benzoates
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Second-order rate constants (kN) have been measured spectrophotometrically for the reaction of 4-nitrophenyl X-substituted benzoates with a series of alicyclic secondary amines in H2O containing 20 mol % dimethyl sulfoxide at 25.0°C.
- Um, Ik-Hwan,Min, Ji-Sook,Ahn, Jung-Ae,Hahn, Hyun-Joo
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p. 5659 - 5663
(2007/10/03)
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