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Enzyme Inhibitors: Design, Synthesis and Biological Evaluation, 2nd Edition

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 4412

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Guest Editor
Pharmaceutical and Nutraceutical Section, University of Florence, Florence, Italy
Interests: enzyme inhibition; human neutrophil elastase; pannexine; panx1 blockers; GABAA receptor ligands; formyl peptide receptors (FPRs)
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Department of Chemistry, Northern Michigan University, Marquette, MI 49855, USA
Interests: medicinal plants; drug discovery from plants; enzymology; alkaloids; mass spectrometry; metabolomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Enzymes are specialized proteins that increase the speed of chemical reactions, thus acting as biocatalysts. In the human body, enzymes catalyze all kinds of chemical reactions, playing vital roles in digestion and metabolism, blood coagulation, neuronal signaling, DNA repair, and replication, as well as many other functions. Under physiological conditions, an enzyme works by first binding to its substrate, forming an enzyme-substrate complex, which is next converted into the final product. The final product then dissociates from the enzyme, and a new catalytic cycle begins. Although they are crucial for life, dysfunctional, improperly regulated, over-active, or over-expressed enzymes contribute to the pathology of many diseases. Both naturally derived and synthetic molecules can bind to enzymes and alter their catalytic activity, and, in most cases, reduce enzyme activity. Many of these enzyme inhibitors are approved drugs, and enzyme inhibition continues to play a pivotal role in medicinal chemistry. A primary understanding of the action of enzyme inhibitors is fundamental for the development of new therapeutic agents. This Special Issue focuses on all aspects of enzyme inhibitors, ranging from the design and synthesis of these compounds, to their pharmacological evaluation, to computational modeling and structural biology studies that seek to understand the interactions between inhibitors and enzymes. Papers that focus on innovative aspects or novel mechanisms of enzyme inhibition are also welcome. We hope that this Special Issue stimulates authors and readers and makes an important contribution to the field of medicinal chemistry.

Dr. Letizia Crocetti
Dr. Maris Cinelli
Guest Editors

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Published Papers (6 papers)

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Research

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24 pages, 4519 KiB  
Article
Anti-Inflammatory Activity of Pyrazolo[1,5-a]quinazolines
by Letizia Crocetti, Andrei I. Khlebnikov, Gabriella Guerrini, Igor A. Schepetkin, Fabrizio Melani, Maria Paola Giovannoni and Mark T. Quinn
Molecules 2024, 29(11), 2421; https://doi.org/10.3390/molecules29112421 - 21 May 2024
Viewed by 275
Abstract
Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-a]quinazoline compounds and related derivatives. Screening of these compounds [...] Read more.
Chronic inflammation contributes to a number of diseases. Therefore, control of the inflammatory response is an important therapeutic goal. To identify novel anti-inflammatory compounds, we synthesized and screened a library of 80 pyrazolo[1,5-a]quinazoline compounds and related derivatives. Screening of these compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP-1Blue monocytic cells identified 13 compounds with anti-inflammatory activity (IC50 < 50 µM) in a cell-based test system, with two of the most potent being compounds 13i (5-[(4-sulfamoylbenzyl)oxy]pyrazolo[1,5-a]quinazoline-3-carboxamide) and 16 (5-[(4-(methylsulfinyl)benzyloxy]pyrazolo[1,5-a]quinazoline-3-carboxamide). Pharmacophore mapping of potential targets predicted that 13i and 16 may be ligands for three mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase 2 (ERK2), p38α, and c-Jun N-terminal kinase 3 (JNK3). Indeed, molecular modeling supported that these compounds could effectively bind to ERK2, p38α, and JNK3, with the highest complementarity to JNK3. The key residues of JNK3 important for this binding were identified. Moreover, compounds 13i and 16 exhibited micromolar binding affinities for JNK1, JNK2, and JNK3. Thus, our results demonstrate the potential for developing lead anti-inflammatory drugs based on the pyrazolo[1,5-a]quinazoline and related scaffolds that are targeted toward MAPKs. Full article
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19 pages, 5109 KiB  
Article
Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer’s Disease
by Xiuyuan Wu, Xiaotong Ze, Shuai Qin, Beiyu Zhang, Xinnan Li, Qi Gong, Haiyan Zhang, Zheying Zhu and Jinyi Xu
Molecules 2024, 29(8), 1782; https://doi.org/10.3390/molecules29081782 - 14 Apr 2024
Viewed by 764
Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this [...] Read more.
Alzheimer’s disease (AD) is a complex neurodegenerative disease that can lead to the loss of cognitive function. The progression of AD is regulated by multiple signaling pathways and their associated targets. Therefore, multitarget strategies theoretically have greater potential for treating AD. In this work, a series of new hybrids were designed and synthesized by the hybridization of tacrine (4, AChE: IC50 = 0.223 μM) with pyrimidone compound 5 (GSK-3β: IC50 = 3 μM) using the cysteamine or cystamine group as the connector. The biological evaluation results demonstrated that most of the compounds exhibited moderate to good inhibitory activities against acetylcholinesterase (AChE) and glycogen synthase kinase 3β (GSK-3β). The optimal compound 18a possessed potent dual AChE/GSK-3β inhibition (AChE: IC50 = 0.047 ± 0.002 μM, GSK-3β: IC50 = 0.930 ± 0.080 μM). Further molecular docking and enzymatic kinetic studies revealed that this compound could occupy both the catalytic anionic site and the peripheral anionic site of AChE. The results also showed a lack of toxicity to SH-SY5Y neuroblastoma cells at concentrations of up to 25 μM. Collectively, this work explored the structure–activity relationships of novel tetrahydroacridin hybrids with sulfur-inserted linkers, providing a reference for the further research and development of new multitarget anti-AD drugs. Full article
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26 pages, 8840 KiB  
Article
New Charged Cholinesterase Inhibitors: Design, Synthesis, and Characterization
by Milena Mlakić, Danijela Barić, Ana Ratković, Ivana Šagud, Ivona Čipor, Ivo Piantanida, Ilijana Odak and Irena Škorić
Molecules 2024, 29(7), 1622; https://doi.org/10.3390/molecules29071622 - 4 Apr 2024
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Abstract
Triazoles and triazolium salts are very common subunits in the structures of various drugs. Medicaments with a characteristic 1,2,3-triazole core are also being developed to treat neurodegenerative disorders associated with cholinesterase enzyme activity. Several naphtho- and thienobenzo-triazoles from our previous research emerged as [...] Read more.
Triazoles and triazolium salts are very common subunits in the structures of various drugs. Medicaments with a characteristic 1,2,3-triazole core are also being developed to treat neurodegenerative disorders associated with cholinesterase enzyme activity. Several naphtho- and thienobenzo-triazoles from our previous research emerged as being particularly promising in that sense. For this reason, in this research, new naphtho- and thienobenzo-triazoles 2334, as well as 1,2,3-triazolium salts 4451, were synthesized and tested. Triazolium salts 4446 showed excellent activity while salts 47 and 49 showed very good inhibition toward both butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes. In contrast, neutral photoproducts were shown to be selective towards BChE but with very good inhibition potential as molecules 2427. The representative of newly prepared compounds, 45 and 50, were stable in aqueous solution and revealed intriguing fluorimetric properties, characterized by a strong Stokes shift of >160 nm. Despite their condensed polycyclic structure shaped similarly to well-known DNA-intercalator ethidium bromide, the studied compounds did not show any interaction with ds-DNA, likely due to the unfavorable steric hindrance of substituents. However, the studied dyes bind proteins, particularly showing very diverse inhibition properties toward AChE and BChE. In contrast, neutral photoproducts were shown to be selective towards a certain enzyme but with moderate inhibition potential. The molecular docking of the best-performing candidates to cholinesterases’ active sites identified cation–π interactions as the most responsible for the stability of the enzyme–ligand complexes. As genotoxicity studies are crucial when developing new active substances and finished drug forms, in silico studies for all the compounds synthesized have been performed. Full article
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11 pages, 4021 KiB  
Article
Design, Synthesis, and Antifungal Activity of N-(alkoxy)-Diphenyl Ether Carboxamide Derivates as Novel Succinate Dehydrogenase Inhibitors
by Bo He, Yanhao Hu, Wang Chen, Xu He, Enpei Zhang, Mengxu Hu, Pu Zhang, Wei Yan and Yonghao Ye
Molecules 2024, 29(1), 83; https://doi.org/10.3390/molecules29010083 - 22 Dec 2023
Viewed by 940
Abstract
Succinate dehydrogenase (SDH, EC 1.3.5.1) is one of the most promising targets for fungicide development and has attracted great attention worldwide. However, existing commercial fungicides targeting SDH have led to the increasingly prominent problem of pathogen resistance, so it is necessary to develop [...] Read more.
Succinate dehydrogenase (SDH, EC 1.3.5.1) is one of the most promising targets for fungicide development and has attracted great attention worldwide. However, existing commercial fungicides targeting SDH have led to the increasingly prominent problem of pathogen resistance, so it is necessary to develop new fungicides. Herein, we used a structure-based molecular design strategy to design and synthesize a series of novel SDHI fungicides containing an N-(alkoxy)diphenyl ether carboxamide skeleton. The mycelial growth inhibition experiment showed that compound M15 exhibited a very good control effect against four plant pathogens, with inhibition rates of more than 60% at a dose of 50 μg/mL. A structure–activity relationship study found that N-O-benzyl-substituted derivatives showed better antifungal activity than others, especially the introduction of a halogen on the benzyl. Furthermore, the molecular docking results suggested that π–π interactions with Trp35 and hydrogen bonds with Tyr33 and Trp173 were crucial interaction sites when inhibitors bound to SDH. Morphological observation of mycelium revealed that M15 could inhibit the growth of mycelia. Moreover, in vivo and in vitro tests showed that M15 not only inhibited the enzyme activity of SDH but also effectively protected rice from damage due to R. solani infection, with a result close to that of the control at a concentration of 200 μg/mL. Thus, the N-(alkoxy)diphenyl ether carboxamide skeleton is a new starting point for the discovery of new SDH inhibitors and is worthy of further investigation. Full article
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22 pages, 7050 KiB  
Article
Recent Development of Novel Aminoethyl-Substituted Chalcones as Potential Drug Candidates for the Treatment of Alzheimer’s Disease
by Pratibha Sharma, Manjinder Singh, Varinder Singh, Thakur Gurjeet Singh, Tanveer Singh and Sheikh F. Ahmad
Molecules 2023, 28(18), 6579; https://doi.org/10.3390/molecules28186579 - 12 Sep 2023
Cited by 1 | Viewed by 1071
Abstract
No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer’s disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer’s disease. A [...] Read more.
No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer’s disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer’s disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound PS-10 was found to have potent AChE inhibitory activity (IC50 = 15.3 nM), even more than the standard drug (IC50 = 15.68 nM). Further, the in vivo evaluation of PS-10 against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, PS-10 inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the PS-10 and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer’s molecules. Full article
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Review

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21 pages, 3830 KiB  
Review
State of the Art in the Development of Human Serum Carnosinase Inhibitors
by Luca Regazzoni
Molecules 2024, 29(11), 2488; https://doi.org/10.3390/molecules29112488 - 24 May 2024
Viewed by 208
Abstract
Human serum carnosinase is an enzyme that operates the preferential hydrolysis of dipeptides with a C-terminus histidine. Only higher primates excrete such an enzyme in serum and cerebrospinal fluid. In humans, the serum hydrolytic rate has high interindividual variability owing to gene polymorphism, [...] Read more.
Human serum carnosinase is an enzyme that operates the preferential hydrolysis of dipeptides with a C-terminus histidine. Only higher primates excrete such an enzyme in serum and cerebrospinal fluid. In humans, the serum hydrolytic rate has high interindividual variability owing to gene polymorphism, although age, gender, diet, and also diseases and surgical interventions can modify serum activity. Human genetic diseases with altered carnosinase activity have been identified and associated with neurological disorders and age-related cognitive decline. On the contrary, low peripheral carnosinase activity has been associated with kidney protection, especially in diabetic nephropathy. Therefore, serum carnosinase is a druggable target for the development of selective inhibitors. However, only one molecule (i.e., carnostatine) has been discovered with the purpose of developing serum carnosinase inhibitors. Bestatin is the only inhibitor reported other than carnostatine, although its activity is not selective towards serum carnosinase. Herein, we present a review of the most critical findings on human serum carnosinase, including enzyme expression, localization and substrate selectivity, along with factors affecting the hydrolytic activity, its implication in human diseases and the properties of known inhibitors of the enzyme. Full article
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