Synthesis and in vitro α-chymotrypsin inhibitory activity of 6-chlorobenzimidazole derivatives

Siddiqui, Hamid Latif; Farooq, Rabia; Marasini, Bishnu P.; Malik, Rehan; Syed, Naima; Moin, Syed Tarique; Atta-ur-Rahman, _; Choudhary, M. Iqbal

doi:10.1016/j.bmc.2016.05.018

Cited by 14 publications

(5 citation statements)

References 27 publications

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“…Chymotrypsin (EC 3.4.21.1), one of the most common serine proteases, is involved in many physiological processes, including digestion of dietary proteins, necrosis, and apoptosis. − In addition, it has been implied in the pathogenesis of various diseases, such as pancreatic fibrosis, maldigestion, diabetes mellitus, hypertension, inflammation, and many types of cancer, particularly pancreatic cancer. − Moreover, the chymotrypsin itself is a medicine for reducing redness, swelling, or damages that are associated with various situations like infection and surgery. , Therefore, the detection of chymotrypsin activity is highly important in drug discovery and clinical diagnostics.…”

mentioning

confidence: 99%

Nonpeptide-Based Small-Molecule Probe for Fluorogenic and Chromogenic Detection of Chymotrypsin

Yang

Xiong

et al. 2017

Anal. Chem.

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We report herein a nonpeptide-based small-molecule probe for fluorogenic and chromogenic detection of chymotrypsin, as well as the primary application for this probe. This probe was rationally designed by mimicking the peptide substrate and optimized by adjusting the recognition group. The refined probe 2 exhibits good specificity toward chymotrypsin, producing about 25-fold higher enhancement in both the fluorescence intensity and absorbance upon the catalysis by chymotrypsin. Compared with the most widely used peptide substrate (AMC-FPAA-Suc) of chymotrypsin, probe 2 shows about 5-fold higher binding affinity and comparable catalytical efficiency against chymotrypsin. Furthermore, it was successfully applied for the inhibitor characterization. To the best of our knowledge, probe 2 is the first nonpeptide-based small-molecule probe for chymotrypsin, with the advantages of simple structure and high sensitivity compared to the widely used peptide-based substrates. This small-molecule probe is expected to be a useful molecular tool for drug discovery and chymotrypsin-related disease diagnosis.

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mentioning

confidence: 99%

Nonpeptide-Based Small-Molecule Probe for Fluorogenic and Chromogenic Detection of Chymotrypsin

Yang

Xiong

et al. 2017

Anal. Chem.

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“…After validating the suitability of the FBFPD approach for small biologically important analytes, we investigated its applicability for biomacromolecule analytes. The selected example is chymotrypsin, which is an important proteolytic enzyme that can specifically cleave some peptides and proteins; in addition, chymotrypsin is associated with key physiological processes, such as necrosis and apoptosis, and tough diseases, such as pancreatic fibrosis, diabetes mellitus, maldigestion, inflammation, hypertension, and cancer. − Previously, we reported the first nonpeptide-based small-molecule probe for fluorogenic and chromogenic detection of chymotrypsin, and this probe exhibits several advantages, including a simple structure and high sensitivity compared to that of widely used peptide-based substrates . For the first time, 4-bromobutyryl was identified as the recognition group for chymotrypsin after structural optimization.…”

Section: Resultsmentioning

confidence: 99%

Rational Design of Esterase-Insensitive Fluorogenic Probes for In Vivo Imaging

Guo

Mei

et al. 2023

ACS Sens.

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Small-molecule fluorogenic probes are indispensable tools for performing research in biomedical fields and chemical biology. Although numerous cleavable fluorogenic probes have been developed to investigate various bioanalytes, few of them meet the baseline requirements for in vivo biosensing for disease diagnosis due to their insufficient specificity resulted from the remarkable esterase interferences. To address this critical issue, we developed a general approach called fragment-based fluorogenic probe discovery (FBFPD) to design esterase-insensitive probes for in vitro and in vivo applications. With the designed esterase-insensitive fluorogenic probe, we successfully achieved light-up in vivo imaging and quantitative analysis of cysteine. This strategy was further extended to design highly specific fluorogenic probes for other representative targets, sulfites, and chymotrypsin. The present study expands the bioanalytical toolboxes available and offers a promising platform to develop esterase-insensitive cleavable fluorogenic probes for in vivo biosensing and bioimaging for the early diagnosis of diseases.

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“…However, the complexes were not formed in the active site, where the catalytic triad take place. Some other works addressing the docking near the catalytic site do not reveal the complex binding energy for the association of a molecule to the protein [29,30]. Other larger molecules have been described to efficiently bind to α-chymotrypsin, however these molecules are used as inhibitors, and therefore cannot be compared to our work [30].…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 90%

α-Chymotrypsin catalyses the synthesis of methotrexate oligomers

Noro

Castro

Cavaco‐Paulo

et al. 2020

Process Biochemistry

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The enzymatic synthesis of methotrexate (MTX) catalysed by α -chymotrypsin was studied for the first time. The proteolytic enzyme displayed activity for the synthesis of MTX oligomers composed by 6 repeating units (DP avg = 1.5). For longer oligomers, molecular dynamics simulations confirmed that as the oligomeric chain grows its accommodation in the enzymes' active site is hindered, which is evidenced by a decrease of the binding energy associated. The full characterization of the oligomers produced was performed by nuclear magnetic resonance (NMR, 1 H and 13 C), matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF), electrospray ionization (ESI) and differential scanning calorimetry (DSC).

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Synthesis and in vitro α-chymotrypsin inhibitory activity of 6-chlorobenzimidazole derivatives

Cited by 14 publications

References 27 publications

Nonpeptide-Based Small-Molecule Probe for Fluorogenic and Chromogenic Detection of Chymotrypsin

Nonpeptide-Based Small-Molecule Probe for Fluorogenic and Chromogenic Detection of Chymotrypsin

Rational Design of Esterase-Insensitive Fluorogenic Probes for In Vivo Imaging

α-Chymotrypsin catalyses the synthesis of methotrexate oligomers

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