scholarly journals Exploration of Active Site-Directed Plasmin Inhibitors: Beyond Tranexamic Acid

Processes ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 329
Author(s):  
Yuko Tsuda ◽  
Koushi Hidaka ◽  
Keiko Hojo ◽  
Yoshio Okada

Plasmin (Plm), a trypsin-like serine protease, is responsible for fibrinolysis pathway and pathologic events, such as angiogenesis, tumor invasion, and metastasis, and alters the expression of cytokines. A growing body of data indicates that a Plm inhibitor is a potential candidate as an anti-inflammatory and anti-cancer agent. A class of active site-directed plasmin inhibitors containing tranexamic acid residue has been designed. As evidenced by docking studies, the inhibitor binds to the active site not to the lysine binding site (LBS) in plasmin, thus preventing plasmin from digesting the substrate. Further optimization of the series, concerning both activity and selectivity, led to the second generation of inhibitors. This review focuses on the Plm inhibitory activity-structure relationship of Plm inhibitors with the goal of realizing their design and clinical application.

Author(s):  
Hüseyin K. Beker ◽  
Işıl Yıldırım

Background: Heterocyclic compounds play an important role in the pharmaceutical and biological processes. Among all heterocycles, quinolinone/quinoline has one of the most unique structures in the discovery of these compounds. These derivatives have been prepared by various on the structures, positions, and they have attracted a great deal of attention in the field of medicinal chemistry. The great interest to medicinal chemists is the basic scaffold of the fused quinolines derivative. The large road maps of gene and protein expression produced by these methods often can be used to classify cancers or predict responses to certain types of treatments targeting regulated at both the level of transcription and translation and at the level of enzyme activity. These specific regulations may open the door for the discovery of novel drug candidates including an anti-cancer target. Objective: This review will attempt to provide a comprehensive description of different quinolinone derivatives especially by concentrating on compounds containing benzimidazole ring. Quinolones moieties are experimentally proven anticancer pharmacophores. We think these pharmacophore and additional substitutions on these scaffolds would further enhance their activity as anticancer agents. This activity associate with the positioning of these different functional groups, such as fluoro, methoxy, methyl, amino, hydroxy, nitro, bromo, chloro, methylamino, ethoxy, carbonyl, iodo, and trifluoromethyl groups. Among the functional groups, most of the electronwithdrawing groups such as fluoro, chloro, nitro, amino, and carbonyl groups showed stronger activity than those with electron-donating groups such as methyl and methoxy groups. Presence of electron-withdrawing or electron-donating group by varying the quinolinone redox properties affect its capacity of DNA synthesis. Conclusion: The structural motifs attributed to noteworthy inhibitory results have been identified and highlighted in order to encourage further research and develop more efficient. This work to aim to present knowledge and it hoped that this review can be help researchers to explore an interesting quinoline class, and researchers will be able to develop a new vision in the search for rational designs of more powerful, active and less toxic quinoline-based anticancer drugs.


2013 ◽  
Vol 6 ◽  
pp. IJTR.S12094 ◽  
Author(s):  
Hollie E. Flick ◽  
Judith M. LaLonde ◽  
William P. Malachowski ◽  
Alexander J. Muller

β-lapachone is a naturally occurring 1,2-naphthoquinone-based compound that has been advanced into clinical trials based on its tumor-selective cytotoxic properties. Previously, we focused on the related 1,4-naphthoquinone pharmacophore as a basic core structure for developing a series of potent indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitors. In this study, we identified IDO1 inhibitory activity as a previously unrecognized attribute of the clinical candidate β-lapachone. Enzyme kinetics-based analysis of β-lapachone indicated an uncompetitive mode of inhibition, while computational modeling predicted binding within the IDO1 active site consistent with other naphthoquinone derivatives. Inhibition of IDO1 has previously been shown to breach the pathogenic tolerization that constrains the immune system from being able to mount an effective anti-tumor response. Thus, the finding that β-lapachone has IDO1 inhibitory activity adds a new dimension to its potential utility as an anti-cancer agent distinct from its cytotoxic properties, and suggests that a synergistic benefit can be achieved from its combined cytotoxic and immunologic effects.


2019 ◽  
Vol 11 (20) ◽  
pp. 2687-2699
Author(s):  
Wen Shuai ◽  
Wenlong Li ◽  
Ying Yin ◽  
Limei Yang ◽  
Feijie Xu ◽  
...  

Aim: A series of novel isothio- and isoselenochromanone derivatives bearing N-benzyl pyridinium moiety were designed, synthesized and evaluated as acetylcholinesterase (AChE) inhibitors. Results: Most of the target compounds exhibited potent anti-AChE activities with IC50 values in nanomolar ranges. Among them, compound 15a exhibited the most potent anti-AChE activity (IC50 = 2.7 nM), moderate antioxidant activity and low neurotoxicity. Moreover, the kinetic and docking studies revealed that compound 15a was a mixed-type inhibitor, which bounds to peripheral anionic site and catalytic active site of AChE. Conclusion: Those results suggested that compound 15a might be a potential candidate for AD treatment.


Author(s):  
Syed Saad Hussain ◽  
Kinza Rafi ◽  
Shaheen Faizi ◽  
Shabana Simjee

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