scholarly journals Green by Design: Convergent Synthesis, Computational Analyses, and Activity Evaluation of New FXa Inhibitors Bearing Peptide Triazole Linking Units

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 33
Author(s):  
Diego F. Rodríguez ◽  
Francisca Durán-Osorio ◽  
Yorley Duarte ◽  
Pedro Olivares ◽  
Yanina Moglie ◽  
...  
Keyword(s):  
Factor Xa ◽  
Waste Reduction ◽  
Pharmaceutically Active Compounds ◽  
Earth Abundant ◽  
Ic50 Values ◽  
Pharmacological Potential ◽  
Computational Analyses ◽  
Peptide Triazoles ◽  
Potent Factor ◽  
Important Drug

Green chemistry implementation has led to promising results in waste reduction in the pharmaceutical industry. However, the early sustainable development of pharmaceutically active compounds and ingredients remains a considerable challenge. Herein, we wish to report a green synthesis of new pharmaceutically active peptide triazoles as potent factor Xa inhibitors, an important drug target associated with the treatment of diverse cardiovascular diseases. The new inhibitors were synthesized in three steps, featuring cycloaddition reactions (high atom economy), microwave-assisted organic synthesis (energy efficiency), and copper nanoparticle catalysis, thus featuring Earth-abundant metals. The molecules obtained showed FXa inhibition, with IC50-values as low as 17.2 μM and no associated cytotoxicity in HEK293 and HeLa cells. These results showcase the environmental potential and chemical implications of the applied methodologies for the development of new molecules with pharmacological potential.

Inhibition of Thrombin Generation in Plasma by Inhibitors of Factor Xa

1997 ◽  
Vol 78 (04) ◽  
pp. 1215-1220 ◽  
Author(s):  
D Prasa ◽  
L Svendsen ◽  
J Stürzebecher
Keyword(s):  
Thrombin Generation ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Thrombin Generation Assay ◽  
Ic50 Values ◽  
Fxa Inhibitor ◽  
20 Nm ◽  
Tick Anticoagulant Peptide ◽  
Inhibition Of Thrombin

SummaryA series of inhibitors of factor Xa (FXa) were investigated using the thrombin generation assay to evaluate the potency and specificity needed to efficiently block thrombin generation in activated human plasma. By inhibiting FXa the generation of thrombin in plasma is delayed and decreased. Inhibitor concentrations which cause 50 percent inhibition of thrombin generation (IC50) correlate in principle with the Ki values for inhibition of free FXa. Recombinant tick anticoagulant peptide (r-TAP) is able to inhibit thrombin generation with considerably low IC50 values of 49 nM and 37 nM for extrinsic and intrinsic activation, respectively. However, the potent synthetic, low molecular weight inhibitors of FXa (Ki values of about 20 nM) are less effective in inhibiting the generation of thrombin with IC50 values at micromolar concentrations.The overall effect of inhibitors of FXa in the thrombin generation assay was compared to that of thrombin inhibitors. On the basis of similar Ki values for the inhibition of the respective enzyme, synthetic FXa inhibitors are less effective than thrombin inhibitors. In contrast, the highly potent FXa inhibitor r-TAP causes a stronger reduction of the thrombin activity in plasma than the most potent thrombin inhibitor hirudin.

scholarly journals Design, Synthesis and Discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as Highly Potent Factor Xa Inhibitors

2009 ◽  
Vol 57 (9) ◽  
pp. 1004-1007 ◽  
Author(s):  
Zhaozhong Jon Jia ◽  
Robert Murry Scarborough ◽  
Penglie Zhang ◽  
Sherin Halfon ◽  
Ann Elizabeth Arfsten ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Design Synthesis ◽  
Potent Factor

ChemInform Abstract: Design, Synthesis and Discovery of 1-(2-(6-Chloro-3-methylsulfonyl)-naphthyl)-1H-pyrazole-5-carboxylamides as Highly Potent Factor Xa Inhibitors.

ChemInform ◽  
2010 ◽  
Vol 41 (8) ◽  
Author(s):  
Zhaozhong Jon Jia ◽  
Robert Murry Scarborough ◽  
Penglie Zhang ◽  
Sherin Halfon ◽  
Ann Elizabeth Arfsten ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Design Synthesis ◽  
Potent Factor

Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part II: Exploration of 6–6 fused rings as alternative S1 moieties

2009 ◽  
Vol 17 (24) ◽  
pp. 8221-8233 ◽  
Author(s):  
Kenji Yoshikawa ◽  
Shozo Kobayashi ◽  
Yumi Nakamoto ◽  
Noriyasu Haginoya ◽  
Satoshi Komoriya ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Design Synthesis ◽  
Potent Factor

1-(2-Naphthyl)-1 H -pyrazole-5-carboxylamides as potent factor Xa inhibitors. Part 2: A survey of P4 motifs

2004 ◽  
Vol 14 (5) ◽  
pp. 1221-1227 ◽  
Author(s):  
Zhaozhong J. Jia ◽  
Yanhong Wu ◽  
Wenrong Huang ◽  
Penglie Zhang ◽  
Lane A. Clizbe ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Potent Factor

scholarly journals Discovery and Computational Analyses of Novel Small Molecule Zika Virus Inhibitors

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1465 ◽  
Author(s):  
Siyu Zhu ◽  
Chaozai Zhang ◽  
Lina S. Huang ◽  
Xing-Quan Zhang ◽  
Yan Xu ◽  
...  
Keyword(s):  
Zika Virus ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Zikv Infection ◽  
Docking Approach ◽  
Ic50 Values ◽  
Mechanistic Basis ◽  
Computational Analyses

Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain–Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC50 values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure–activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.

A morpholine-free process amenable convergent synthesis of apixaban: a potent factor Xa inhibitor

2017 ◽  
Vol 148 (8) ◽  
pp. 1477-1482 ◽  
Author(s):  
Narasimha Rao Nevuluri ◽  
Rajesh Kumar Rapolu ◽  
Javed Iqbal ◽  
Bhaskar Kandagatla ◽  
Saikat Sen ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitor ◽  
Convergent Synthesis ◽  
Free Process ◽  
Potent Factor

1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides as Potent Factor Xa Inhibitors. Part 2. A Survey of P4 Motifs.

ChemInform ◽  
2004 ◽  
Vol 35 (26) ◽  
Author(s):  
Zhaozhong J. Jia ◽  
Bing-Yan Zhu ◽  
et al. et al.
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Potent Factor

Evaluation of Acetylcholinesterase and Prolyl Oligopeptidase Inhibition of Novel Amino acid-functionalized Stigmasterol and Ursolic Acid Derivatives

2019 ◽  
Vol 23 (19) ◽  
pp. 2131-2140
Author(s):  
Nalin Seixas ◽  
Ionara I. Dalcol ◽  
Bruno Ravanello ◽  
Keiti Alessio ◽  
Fábio A. Duarte ◽  
...  
Keyword(s):  
Amino Acid ◽  
Ursolic Acid ◽  
Prolyl Oligopeptidase ◽  
Pharmacological Activities ◽  
Natural Sources ◽  
Structural Modifications ◽  
Ic50 Value ◽  
Ic50 Values ◽  
Pharmacological Potential ◽  
New Compounds

Triterpenes and phytosterols are classes of natural compounds widespread in plants possessing a great number of pharmacological activities. In our continued search for new compounds from natural sources with pharmacological potential, we prepared a series of novel stigmasterol and ursolic acid (UA) derivatives by coupling with L-proline, L-cysteine and L-glutamic acid. Unlike stigmasterol, the eight derivatives obtained showed good inhibitory capacity against acetylcholinesterase (AChE) or prolyl oligopeptidase (POP). Among these derivatives, we highlight 3 and 5 with IC50 values of 99.0 ± 8.8 and 97.5 ± 5.0 µM against AChE, respectively, and derivative 8 with a POP IC50 value of 75.7 ± 6.3 µM. The ursolic acid derivative 19 was the most promising compound of its class, with IC50 against AChE of 98.3 ± 7.7 µM. These results demonstrate that simple structural modifications on triterpenes and phytosterols can enhance their performance as enzymatic inhibitors.

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