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Enzyme Inhibitors: Design, Synthesis and Biological Evaluation
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Enzyme Inhibitors: Design, Synthesis and Biological Evaluation

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 54500

Special Issue Editors

Dr. Letizia Crocetti

E-Mail Website
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
Dr. Maris Cinelli

E-Mail Website
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

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • enzyme inhibitors
  • drug design
  • organic synthesis
  • biological evaluation
  • molecular modeling studies
  • kinetic experiment

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Published Papers (24 papers)

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15 pages, 6969 KiB  
Article
Inhibition Mechanism of Chitooligosaccharide-Polyphenol Conjugates toward Polyphenoloxidase from Shrimp Cephalothorax
by Ajay Mittal, Avtar Singh, Bin Zhang, Qiancheng Zhao and Soottawat Benjakul
Molecules 2023, 28(14), 5560; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28145560 - 20 Jul 2023
Cited by 2 | Viewed by 1396
Abstract
Crustaceans are perishable with a short shelf-life. They are prone to deterioration after capture, particularly during handling, processing, and storage due to melanosis caused by polyphenoloxidase (PPO). Therefore, inhibitory effects of chitooligosaccharide (CHOS) in comparison with CHOS-catechin (CHOS-CAT), CHOS-epigallocatechin gallate (CHOS-EGCG), and CHOS-gallic [...] Read more.
Crustaceans are perishable with a short shelf-life. They are prone to deterioration after capture, particularly during handling, processing, and storage due to melanosis caused by polyphenoloxidase (PPO). Therefore, inhibitory effects of chitooligosaccharide (CHOS) in comparison with CHOS-catechin (CHOS-CAT), CHOS-epigallocatechin gallate (CHOS-EGCG), and CHOS-gallic acid (CHOS-GAL) conjugates on Pacific white shrimp cephalothorax PPO were studied. IC50 of CHOS-CAT (0.32 mg/mL) toward PPO was less than those of all conjugates tested (p < 0.05). CHOS-CAT exhibited the mixed-type inhibition. Kic (0.58 mg/mL) and Kiu (0.02 mg/mL) of CHOS-CAT were lower than those of other conjugates (p < 0.05). CHOS-CAT showed static fluorescence-quenching, suggesting a change in micro-environment around the active site of PPO. Moreover, CHOS-CAT was linked with various amino acid residues, including Tyr208 or Tyr209 of proPPO via van der Waals, hydrophobic interaction, and hydrogen bonding as elucidated by the molecular docking of proPPO. Although CHOS-CAT had the highest PPO inhibitory activity, it showed a lower binding energy (−8.5 kcal/mol) than other samples, except for CHOS-EGCG (−10.2 kcal/mol). Therefore, CHOS-CAT could act as an anti-melanosis agent in shrimp and other crustaceans to prevent undesirable discoloration associated with quality losses. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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16 pages, 4790 KiB  
Article
Novel 2-Sulfanylquinazolin-4(3H)-one Derivatives as Multi-Kinase Inhibitors and Apoptosis Inducers: A Synthesis, Biological Evaluation, and Molecular Docking Study
by Ali Altharawi, Mohammed M. Alanazi, Manal A. Alossaimi, Ashwag S. Alanazi, Safar M. Alqahtani, Mohammed H. Geesi and Yassine Riadi
Molecules 2023, 28(14), 5548; https://doi.org/10.3390/molecules28145548 - 20 Jul 2023
Cited by 2 | Viewed by 1221
Abstract
The discovery of multi-targeted kinase inhibitors emerged as a potential strategy in the therapy of multi-genic diseases, such as cancer, that cannot be effectively treated by modulating a single biological function or pathway. The current work presents an extension of our effort to [...] Read more.
The discovery of multi-targeted kinase inhibitors emerged as a potential strategy in the therapy of multi-genic diseases, such as cancer, that cannot be effectively treated by modulating a single biological function or pathway. The current work presents an extension of our effort to design and synthesize a series of new quinazolin-4-one derivatives based on their established anti-cancer activities as inhibitors of multiple protein kinases. The cytotoxicity of the new derivatives was evaluated against a normal human cell line (WI-38) and four cancer lines, including HepG2, MCF-7, MDA-231, and HeLa. The most active compound, 5d, showed broad-spectrum anti-cancer activities against all tested cell lines (IC50 = 1.94–7.1 µM) in comparison to doxorubicin (IC50 = 3.18–5.57 µM). Interestingly, compound 5d exhibited lower toxicity in the normal WI-38 cells (IC50 = 40.85 µM) than doxorubicin (IC50 = 6.72 µM), indicating a good safety profile. Additionally, the potential of compound 5d as a multi-targeted kinase inhibitor was examined against different protein kinases, including VEGFR2, EGFR, HER2, and CDK2. In comparison to the corresponding positive controls, compound 5d exhibited comparable activities in nanomolar ranges against HER2, EGFR, and VEGFR2. However, compound 5d was the least active against CDK2 (2.097 ± 0.126 µM) when compared to the positive control roscovitine (0.32 ± 0.019 µM). The apoptotic activity investigation in HepG2 cells demonstrated that compound 5d arrested the cell cycle at the S phase and induced early and late apoptosis. Furthermore, the results demonstrated that the apoptosis pathway was provoked due to an upregulation in the expression of the proapoptotic genes caspase-3, caspase-9, and Bax and the downregulation of the Bcl-2 anti-apoptotic gene. For the in silico docking studies, compound 5d showed relative binding interactions, including hydrogen, hydrophobic, and halogen bindings, with protein kinases that are similar to the reference inhibitors. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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22 pages, 8311 KiB  
Article
S-Ethyl-Isothiocitrullin-Based Dipeptides and 1,2,4-Oxadiazole Pseudo-Dipeptides: Solid Phase Synthesis and Evaluation as NO Synthase Inhibitors
by Elodie Mauchauffée, Jérémy Leroy, Jihanne Chamcham, Abdelaziz Ejjoummany, Manon Maurel, Lionel Nauton, Booma Ramassamy, Karima Mezghenna, Jean-Luc Boucher, Anne-Dominique Lajoix and Jean-François Hernandez
Molecules 2023, 28(13), 5085; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28135085 - 29 Jun 2023
Viewed by 1153
Abstract
We previously reported dipeptidomimetic compounds as inhibitors of neuronal and/or inducible NO synthases (n/iNOS) with significant selectivity against endothelial NOS (eNOS). They were composed of an S-ethylisothiocitrullin-like moiety linked to an extension through a peptide bond or a 1,2,4-oxadiazole link. Here, we [...] Read more.
We previously reported dipeptidomimetic compounds as inhibitors of neuronal and/or inducible NO synthases (n/iNOS) with significant selectivity against endothelial NOS (eNOS). They were composed of an S-ethylisothiocitrullin-like moiety linked to an extension through a peptide bond or a 1,2,4-oxadiazole link. Here, we developed two further series where the extension size was increased to establish more favorable interactions in the NOS substrate access channel. The extension was introduced on the solid phase by the reductive alkylation of an amino-piperidine moiety or an aminoethyl segment in the case of dipeptide-like and 1,2,4-oxadiazole compounds, respectively, with various benzaldehydes. Compared to the previous series, more potent inhibitors were identified with IC50 in the micromolar to the submicromolar range, with significant selectivity toward nNOS. As expected, most compounds did not inhibit eNOS, and molecular modeling was carried out to characterize the reasons for the selectivity toward nNOS over eNOS. Spectral studies showed that compounds were interacting at the heme active site. Finally, selected inhibitors were found to inhibit intra-cellular iNOS and nNOS expressed in RAW264.7 and INS-1 cells, respectively. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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21 pages, 4610 KiB  
Article
Discovery of N,4-Di(1H-pyrazol-4-yl)pyrimidin-2-amine-Derived CDK2 Inhibitors as Potential Anticancer Agents: Design, Synthesis, and Evaluation
by Biruk Sintayehu Fanta, Jimma Lenjisa, Theodosia Teo, Lianmeng Kou, Laychiluh Mekonnen, Yuchao Yang, Sunita K. C. Basnet, Ramin Hassankhani, Matthew J. Sykes, Mingfeng Yu and Shudong Wang
Molecules 2023, 28(7), 2951; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28072951 - 25 Mar 2023
Viewed by 2283
Abstract
Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and [...] Read more.
Cyclin-dependent kinase 2 (CDK2) has been garnering considerable interest as a target to develop new cancer treatments and to ameliorate resistance to CDK4/6 inhibitors. However, a selective CDK2 inhibitor has yet to be clinically approved. With the desire to discover novel, potent, and selective CDK2 inhibitors, the phenylsulfonamide moiety of our previous lead compound 1 was bioisosterically replaced with pyrazole derivatives, affording a novel series of N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amines that exhibited potent CDK2 inhibitory activity. Among them, 15 was the most potent CDK2 inhibitor (Ki = 0.005 µM) with a degree of selectivity over other CDKs tested. Meanwhile, this compound displayed sub-micromolar antiproliferative activity against a panel of 13 cancer cell lines (GI50 = 0.127–0.560 μM). Mechanistic studies in ovarian cancer cells revealed that 15 reduced the phosphorylation of retinoblastoma at Thr821, arrested cells at the S and G2/M phases, and induced apoptosis. These results accentuate the potential of the N,4-di(1H-pyrazol-4-yl)pyrimidin-2-amine scaffold to be developed into potent and selective CDK2 inhibitors for the treatment of cancer. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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22 pages, 6988 KiB  
Article
Solid-Phase Parallel Synthesis of Dual Histone Deacetylase-Cyclooxygenase Inhibitors
by Luisa M. Bachmann, Maria Hanl, Felix Feller, Laura Sinatra, Andrea Schöler, Jens Pietzsch, Markus Laube and Finn K. Hansen
Molecules 2023, 28(3), 1061; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28031061 - 20 Jan 2023
Viewed by 2226
Abstract
Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The [...] Read more.
Multi-target drugs (MTDs) are emerging alternatives to combination therapies. Since both histone deacetylases (HDACs) and cyclooxygenase-2 (COX-2) are known to be overexpressed in several cancer types, we herein report the design, synthesis, and biological evaluation of a library of dual HDAC-COX inhibitors. The designed compounds were synthesized via an efficient parallel synthesis approach using preloaded solid-phase resins. Biological in vitro assays demonstrated that several of the synthesized compounds possess pronounced inhibitory activities against HDAC and COX isoforms. The membrane permeability and inhibition of cellular HDAC activity of selected compounds were confirmed by whole-cell HDAC inhibition assays and immunoblot experiments. The most promising dual inhibitors, C3 and C4, evoked antiproliferative effects in the low micromolar concentration range and caused a significant increase in apoptotic cells. In contrast to previous reports, the simultaneous inhibition of HDAC and COX activity by dual HDAC-COX inhibitors or combination treatments with vorinostat and celecoxib did not result in additive or synergistic anticancer activities. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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12 pages, 1799 KiB  
Article
Design and Synthesis of New Modified Flexible Purine Bases as Potential Inhibitors of Human PNP
by Anastasia Khandazhinskaya, Ilja Fateev, Barbara Eletskaya, Anna Maslova, Irina Konstantinova, Katherine Seley-Radtke, Sergey Kochetkov and Elena Matyugina
Molecules 2023, 28(3), 928; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28030928 - 17 Jan 2023
Cited by 2 | Viewed by 1558
Abstract
The great interest in studying the structure of human purine nucleoside phosphorylase (hPNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, h [...] Read more.
The great interest in studying the structure of human purine nucleoside phosphorylase (hPNP) and the continued search for effective inhibitors is due to the importance of the enzyme as a target in the therapy of T-cell proliferative diseases. In addition, hPNP inhibitors are used in organ transplant surgeries to provide immunodeficiency during and after the procedure. Previously, we showed that members of the well-known fleximer class of nucleosides are substrates of E. coli PNP. Fleximers have great promise as they have exhibited significant biological activity against a number of viruses of pandemic concern. Herein, we describe the synthesis and inhibition studies of a series of new fleximer compounds against hPNP and discuss their possible binding mode with the enzyme. At a concentration of 2 mM for the flex-7-deazapurines 1–4, a decrease in enzymatic activity by more than 50% was observed. 4-Amino-5-(1H-pyrrol-3-yl)pyridine 2 was the best inhibitor, with a Ki = 0.70 mM. Docking experiments have shown that ligand 2 is localized in the selected binding pocket Glu201, Asn243 and Phe200. The ability of the pyridine and pyrrole fragments to undergo rotation around the C–C bond allows for multiple binding modes in the active site of hPNP, which could provide several plausible bioactive conformations. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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13 pages, 2382 KiB  
Communication
New Insights into Conformationally Restricted Carbonic Anhydrase Inhibitors
by Jacob Combs, Murat Bozdag, Lochlin D. Cravey, Anusha Kota, Robert McKenna, Andrea Angeli, Fabrizio Carta and Claudiu T. Supuran
Molecules 2023, 28(2), 890; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28020890 - 16 Jan 2023
Cited by 5 | Viewed by 1767
Abstract
This paper reports an investigation into the impact of pyridyl functional groups in conjunction with hydroxide-substituted benzenesulfonamides on the inhibition of human carbonic anhydrase (CA; EC 4.2.1.1) enzymes. These compounds were tested in vitro of CA II and CA IX, two physiologically important [...] Read more.
This paper reports an investigation into the impact of pyridyl functional groups in conjunction with hydroxide-substituted benzenesulfonamides on the inhibition of human carbonic anhydrase (CA; EC 4.2.1.1) enzymes. These compounds were tested in vitro of CA II and CA IX, two physiologically important CA isoforms. The most potent inhibitory molecules against CA IX, 3g, 3h, and 3k, were studied to understand their binding modes via X-ray crystallography in adduct with CA II and CA IX-mimic. This research further adds to the field of CA inhibitors to better understand ligand selectivity between isoforms found in humans. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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27 pages, 5151 KiB  
Article
Design and Synthesis of (Z)-2-(Benzylamino)-5-benzylidenethiazol-4(5H)-one Derivatives as Tyrosinase Inhibitors and Their Anti-Melanogenic and Antioxidant Effects
by Jieun Lee, Yu Jung Park, Hee Jin Jung, Sultan Ullah, Dahye Yoon, Yeongmu Jeong, Ga Young Kim, Min Kyung Kang, Dongwan Kang, Yujin Park, Pusoon Chun, Hae Young Chung and Hyung Ryong Moon
Molecules 2023, 28(2), 848; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28020848 - 14 Jan 2023
Cited by 9 | Viewed by 1943
Abstract
In this study, (Z)-2-(benzylamino)-5-benzylidenethiazol-4(5H)-one (BABT) derivatives were designed as tyrosinase inhibitors based on the structure of MHY2081, using a simplified approach. Of the 14 BABT derivatives synthesized, two derivatives ((Z)-2-(benzylamino)-5-(3-hydroxy-4-methoxybenzylidene)thiazol-4(5H)-one [7] and ( [...] Read more.
In this study, (Z)-2-(benzylamino)-5-benzylidenethiazol-4(5H)-one (BABT) derivatives were designed as tyrosinase inhibitors based on the structure of MHY2081, using a simplified approach. Of the 14 BABT derivatives synthesized, two derivatives ((Z)-2-(benzylamino)-5-(3-hydroxy-4-methoxybenzylidene)thiazol-4(5H)-one [7] and (Z)-2-(benzylamino)-5-(2,4-dihydroxybenzylidene)thiazol-4(5H)-one [8]) showed more potent mushroom tyrosinase inhibitory activities than kojic acid, regardless of the substrate used; in particular, compound 8 was 106-fold more potent than kojic acid when l-tyrosine was used as the substrate. Analysis of Lineweaver–Burk plots for 7 and 8 indicated that they were competitive inhibitors, which was confirmed via in silico docking. In experiments using B16F10 cells, 8 exerted a greater ability to inhibit melanin production than kojic acid, and it inhibited cellular tyrosinase activity in a concentration-dependent manner, indicating that the anti-melanogenic effect of 8 is attributable to its ability to inhibit tyrosinase. In addition, 8 exhibited strong antioxidant activity to scavenge 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals and peroxynitrite and inhibited the expression of melanogenesis-associated proteins (tyrosinase and microphthalmia-associated transcription factor). These results suggest that BABT derivative 8 is a promising candidate for the treatment of hyperpigmentation-related diseases, owing to its inhibition of melanogenesis-associated protein expression, direct tyrosinase inhibition, and antioxidant activity. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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16 pages, 2863 KiB  
Article
Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone
by Adrien Djiemeny Ngueta, Jenny Roy, René Maltais and Donald Poirier
Molecules 2023, 28(2), 632; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28020632 - 7 Jan 2023
Cited by 1 | Viewed by 2576
Abstract
Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting [...] Read more.
Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrogen-dependent diseases. In order to obtain new inhibitors of 17β-HSD1, the impact of a m-carbamoylphenyloxy group at position three of an estrane nucleus was evaluated by preparing three derivatives of estrone (E1) and E2 using a microwave-assisted synthesis of diaryl ethers. Their inhibitory activity was addressed on two cell lines (T-47D and Z-12) representative of breast cancer and endometriosis, respectively, but unlike T-47D cells, Z-12 cells were not found suitable for testing potential 17β-HSD1 inhibitors. Thus, the addition of the m-carbamoylphenyl group at C3 of E1 (compound 5) did not increase the inhibition of E1 to E2 transformation by 17β-HSD1 present in T-47D cells (IC50 = 0.31 and 0.21 μM for 5 and E1, respectively), and this negative effect was more obvious for E2 derivatives 6 and 10 (IC50 = 1.2 and 1.3 μM, respectively). Molecular docking allowed us to identify key interactions with 17β-HSD1 and to highlight these new inhibitors’ actions through an opposite orientation than natural enzyme substrate E1′s classical one. Furthermore, molecular modeling experiments explain the better inhibitory activity of E1-ether derivative 5, as opposed to the E2-ether derivatives 6 and 10. Finally, when tested on T-47D and Z-12 cells, compounds 5, 6 and 10 did not stimulate the proliferation of these two estrogen-dependent cell lines. In fact, they reduced it. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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19 pages, 9624 KiB  
Article
Investigation on Hydrazonobenzenesulfonamides as Human Carbonic Anhydrase I, II, IX and XII Inhibitors
by Davide Moi, Serena Vittorio, Andrea Angeli, Gianfranco Balboni, Claudiu T. Supuran and Valentina Onnis
Molecules 2023, 28(1), 91; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010091 - 22 Dec 2022
Cited by 7 | Viewed by 1666
Abstract
A small series of hydrazonobenzenesulfonamides was designed, synthesized and studied for their human carbonic anhydrase (hCA) inhibitory activity. The synthesized compounds were evaluated against hCA I, II, IX and XII isoforms using acetazolamide (AAZ) as the standard inhibitor. Various hydrazonosulfonamide derivatives showed inhibitory [...] Read more.
A small series of hydrazonobenzenesulfonamides was designed, synthesized and studied for their human carbonic anhydrase (hCA) inhibitory activity. The synthesized compounds were evaluated against hCA I, II, IX and XII isoforms using acetazolamide (AAZ) as the standard inhibitor. Various hydrazonosulfonamide derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The most potent and selective hydrazones 8, 9, 10, 11, 19 and 24 were docked into isoforms I, II, IX and XII to better understand their activity and selectivity for the different CA isoforms. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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20 pages, 2736 KiB  
Article
Straightforward Access to a New Class of Dual DYRK1A/CLK1 Inhibitors Possessing a Simple Dihydroquinoline Core
by Mihaela-Liliana Ţînţaş, Ludovic Peauger, Florent Alix, Cyril Papamicaël, Thierry Besson, Jana Sopková-de Oliveira Santos, Vincent Gembus and Vincent Levacher
Molecules 2023, 28(1), 36; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28010036 - 21 Dec 2022
Viewed by 1922
Abstract
The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer’s disease (AD) and Down syndrome, and as such, has emerged as [...] Read more.
The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer’s disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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15 pages, 4016 KiB  
Article
Quinoxalinones as A Novel Inhibitor Scaffold for EGFR (L858R/T790M/C797S) Tyrosine Kinase: Molecular Docking, Biological Evaluations, and Computational Insights
by Utid Suriya, Panupong Mahalapbutr, Watchara Wimonsong, Sirilata Yotphan, Kiattawee Choowongkomon and Thanyada Rungrotmongkol
Molecules 2022, 27(24), 8901; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27248901 - 14 Dec 2022
Cited by 4 | Viewed by 2101
Abstract
Combating acquired drug resistance of EGFR tyrosine kinase (TK) is a great challenge and an urgent necessity in the management of non-small cell lung cancers. The advanced EGFR (L858R/T790M/C797S) triple mutation has been recently reported, and there have been no specific drugs approved [...] Read more.
Combating acquired drug resistance of EGFR tyrosine kinase (TK) is a great challenge and an urgent necessity in the management of non-small cell lung cancers. The advanced EGFR (L858R/T790M/C797S) triple mutation has been recently reported, and there have been no specific drugs approved for this strain. Therefore, our research aimed to search for effective agents that could impede the function of EGFR (L858R/T790M/C797S) TK by the integration of in silico and in vitro approaches. Our in-house quinoxalinone-containing compounds were screened through molecular docking and their biological activity was then verified by enzyme- and cell-based assay. We found that the four quinoxalinone-containing compounds including CPD4, CPD15, CPD16, and CPD21 were promising to be novel EGFR (L858R/T790M/C797S) TK inhibitors. The IC50 values measured by the enzyme-based assay were 3.04 ± 1.24 nM; 6.50 ± 3.02 nM,10.50 ± 1.10 nM; and 3.81 ± 1.80 nM, respectively, which are at a similar level to a reference drug; osimertinib (8.93 ± 3.01 nM). Besides that, they displayed cytotoxic effects on a lung cancer cell line (H1975) with IC50 values in the range of 3.47 to 79.43 μM. In this proposed study, we found that all screened compounds could interact with M793 at the hinge regions and two mutated residues including M790 and S797; which may be the main reason supporting the inhibitory activity in vitro. The structural dynamics revealed that the screened compounds have sufficient non-native contacts with surrounding amino acids and could be well-buried in the binding site’s cleft. In addition, all predicted physicochemical parameters were favorable to be drug-like based on Lipinski’s rule of five, and no extreme violation of toxicity features was found. Altogether, this study proposes a novel EGFR (L858R/T790M/C797S) TK inhibitor scaffold and provides a detailed understanding of compounds’ recognition and susceptibility at the molecular level. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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16 pages, 1480 KiB  
Article
Cholinesterases Inhibition, Anticancer and Antioxidant Activity of Novel Benzoxazole and Naphthoxazole Analogs
by Alicja Skrzypek, Monika Karpińska, Małgorzata Juszczak, Aneta Grabarska, Joanna Wietrzyk, Elżbieta Krajewska-Kułak, Marek Studziński, Tadeusz Paszko and Joanna Matysiak
Molecules 2022, 27(23), 8511; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27238511 - 3 Dec 2022
Cited by 4 | Viewed by 1429
Abstract
Benzoxazole and naphthoxazole fused systems are found in many biologically active molecules. Novel benzoxazole and naphthoxazole analogs functionalized by the 2,4-dihydroxyphenyl moiety were designed, obtained and evaluated as a broad spectrum of biological potency compounds. Sulfinylbis[(2,4-dihydroxyphenyl)methanethione] or its analogs and 2-aminophenols or 1-amino-2-naphthol [...] Read more.
Benzoxazole and naphthoxazole fused systems are found in many biologically active molecules. Novel benzoxazole and naphthoxazole analogs functionalized by the 2,4-dihydroxyphenyl moiety were designed, obtained and evaluated as a broad spectrum of biological potency compounds. Sulfinylbis[(2,4-dihydroxyphenyl)methanethione] or its analogs and 2-aminophenols or 1-amino-2-naphthol were used as starting reagents. 4-(Naphtho[1,2-d][1,3]oxazol-2-yl)benzene-1,3-diol was identified as the most promising compound of the nanomolar activity against AChE (IC50 = 58 nM) of the mixed-type inhibition and of the moderate activity against BChE (IC50 = 981 nM). The higher antiproliferative potency against a panel of human cancer cell lines for naphtho[1,2-d][1,3]oxazoles than for benzoxazoles was found. The activity of the analog with chlorine atom was in the range of 2.18–2.89 µM (IC50) against all studied cells and it is similar to that of cisplatin studied comparatively. Moreover, this compound was not toxic at this concentration to human normal breast cells and keratinocytes. For some compounds it also has proved antioxidant properties at the level of IC50 = 0.214 µM, for the most active compound. The lipophilicity of all compounds, expressed as log p values, is within the range recommended for potential drugs. The biological activity profile of the considered analogs and their lipophilic level justify the search for agents used in AD or in anticancer therapy in this group of compounds. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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13 pages, 993 KiB  
Article
Design, Synthesis and Biological Assessment of Rhodanine-Linked Benzenesulfonamide Derivatives as Selective and Potent Human Carbonic Anhydrase Inhibitors
by Baijayantimala Swain, Abrar Khan, Priti Singh, Vaibhav S. Marde, Andrea Angeli, Krishna Kartheek Chinchilli, Venkata Madhavi Yaddanapudi, Simone Carradori, Claudiu T. Supuran and Mohammed Arifuddin
Molecules 2022, 27(22), 8028; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27228028 - 18 Nov 2022
Cited by 2 | Viewed by 1652
Abstract
A novel series of twenty-five rhodamine-linked benzenesulfonamide derivatives (7a–u and 9a–d) were synthesized and screened for their inhibitory action against four physiologically relevant human (h) carbonic anhydrase (CA) isoforms, namely hCA I, hCA II, hCA IX, and [...] Read more.
A novel series of twenty-five rhodamine-linked benzenesulfonamide derivatives (7a–u and 9a–d) were synthesized and screened for their inhibitory action against four physiologically relevant human (h) carbonic anhydrase (CA) isoforms, namely hCA I, hCA II, hCA IX, and hCA XII. All the synthesized molecules showed good to excellent inhibition against all the tested isoforms in the nanomolar range due to the presence of the sulfonamide as a zinc binding group. The target compounds were developed from indol-3-ylchalcone-linked benzenesulfonamide where the indol-3-ylchalcone moiety was replaced with rhodanine-linked aldehydes or isatins to improve the inhibition. Interestingly, the molecules were slightly more selective towards hCA IX and XII compared to hCA I and II. The most potent and efficient ones against hCA I were 7h (KI 22.4 nM) and 9d (KI 35.8 nM) compared to the standard drug AAZ (KI 250.0 nM), whereas in case of hCA II inhibition, the derivatives containing the isatin nucleus as a tail were preferred. Collectively, all compounds were endowed with better inhibition against hCA IX compared to AAZ (KI 25.8 nM) as well as strong potency against hCA XII. Finally, these newly synthesized molecules could be taken as potential leads for the development of isoform selective hCA IX and XII inhibitors. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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18 pages, 1310 KiB  
Article
Carbonic Anhydrase Inhibition Activities of Schiff’s Bases Based on Quinazoline-Linked Benzenesulfonamide
by Adel S. El-Azab, Alaa A.-M. Abdel-Aziz, Hazem A. Ghabbour, Silvia Bua, Alessio Nocentini, Hamad M. Alkahtani, Nawaf A. Alsaif, Mohamed H. M. Al-Agamy and Claudiu T. Supuran
Molecules 2022, 27(22), 7703; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27227703 - 9 Nov 2022
Cited by 6 | Viewed by 1344
Abstract
Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff’s bases based on quinazoline scaffold 4–27. The hCA I isoform was efficiently inhibited by Schiff’s [...] Read more.
Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff’s bases based on quinazoline scaffold 4–27. The hCA I isoform was efficiently inhibited by Schiff’s bases 4–6, 10–19, 22–27 and had an inhibition constant (Ki) value of 52.8–991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2, 3, 4, 10, 11, 16, 18, 24, 26, and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8–52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2–27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5–99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3, 10, 11, 13, 15–19, and 24 possessed potent hCA XII inhibitory activities with KI values of 5.4–25.5 nM vs. 5.7 nM of AAZ. Schiff’s bases 7, 8, 9, and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with KI rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5, 7, 8, 9, 14, 18, 19, and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46–107, while derivatives 12, 14, and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04–58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2, 5, 7–14, 19–23, and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02–19.67, whereas derivatives 5, 7, 8, 13, 14, 15, 17, 20, 21, and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84–26.60 balanced to AAZ (SI, 0.48 and 2.10). Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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38 pages, 17868 KiB  
Article
Preliminary Structure–Activity Relationship Study of the MMV Pathogen Box Compound MMV675968 (2,4-Diaminoquinazoline) Unveils Novel Inhibitors of Trypanosoma brucei brucei
by Darline Dize, Rolland Bantar Tata, Rodrigue Keumoe, Rufin Marie Kouipou Toghueo, Mariscal Brice Tchatat, Cyrille Ngansop Njanpa, Vianey Claire Tchuenguia, Lauve Tchokouaha Yamthe, Patrick Valere Tsouh Fokou, Benoît Laleu, James Duffy, Ozlem Tastan Bishop and Fabrice Fekam Boyom
Molecules 2022, 27(19), 6574; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27196574 - 4 Oct 2022
Cited by 6 | Viewed by 2132
Abstract
New drugs are urgently needed for the treatment of human African trypanosomiasis (HAT). In line with our quest for novel inhibitors of trypanosomes, a small library of analogs of the antitrypanosomal hit (MMV675968) available at MMV as solid materials was screened for antitrypanosomal [...] Read more.
New drugs are urgently needed for the treatment of human African trypanosomiasis (HAT). In line with our quest for novel inhibitors of trypanosomes, a small library of analogs of the antitrypanosomal hit (MMV675968) available at MMV as solid materials was screened for antitrypanosomal activity. In silico exploration of two potent antitrypanosomal structural analogs (7-MMV1578647 and 10-MMV1578445) as inhibitors of dihydrofolate reductase (DHFR) was achieved, together with elucidation of other antitrypanosomal modes of action. In addition, they were assessed in vitro for tentative inhibition of DHFR in a crude trypanosome extract. Their ADMET properties were also predicted using dedicated software. Overall, the two diaminoquinazoline analogs displayed approximately 40-fold and 60-fold more potency and selectivity in vitro than the parent hit, respectively (MMV1578445 (10): IC50 = 0.045 µM, SI = 1737; MMV1578467 (7): IC50 = 0.06 µM; SI = 412). Analogs 7 and 10 were also strong binders of the DHFR enzyme in silico, in all their accessible protonation states, and interacted with key DHFR ligand recognition residues Val32, Asp54, and Ile160. They also exhibited significant activity against trypanosome protein isolate. MMV1578445 (10) portrayed fast and irreversible trypanosome growth arrest between 4–72 h at IC99. Analogs 7 and 10 induced in vitro ferric iron reduction and DNA fragmentation or apoptosis induction, respectively. The two potent analogs endowed with predicted suitable physicochemical and ADMET properties are good candidates for further deciphering their potential as starting points for new drug development for HAT. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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26 pages, 9135 KiB  
Article
Resveratrol–Maltol and Resveratrol–Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure
by Milena Mlakić, Lajos Fodor, Ilijana Odak, Ottó Horváth, Marija Jelena Lovrić, Danijela Barić, Valentina Milašinović, Krešimir Molčanov, Željko Marinić, Zlata Lasić and Irena Škorić
Molecules 2022, 27(19), 6379; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27196379 - 27 Sep 2022
Cited by 3 | Viewed by 1663
Abstract
New resveratrol–thiophene and resveratrol–maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol–thiophene hybrids have excellent inhibitory and antioxidant properties (similar to [...] Read more.
New resveratrol–thiophene and resveratrol–maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol–thiophene hybrids have excellent inhibitory and antioxidant properties (similar to the activity of reference drug galantamine), maltols have been proven to be weaker inhibitors and antioxidants. The molecular docking of selected active ligands gave insight into the structures of docked enzymes. It enabled the identification of interactions between the ligand and the active site of both cholinesterases. The maltols that proved to be active cholinesterase inhibitors were able to coordinate Fe3+ ion, forming complexes of 1:1 composition. Their formation constants, determined by spectrophotometry, are very similar, lgK = 11.6–12.6, suggesting that Fe3+ binds to the common hydroxy-pyranone moiety and is hardly affected by the other aromatic part of the ligand. Accordingly, the characteristic bands in their individual absorption spectra are uniformly red-shifted relative to those of the free ligands. The crystal structures of two new resveratrol–maltol hybrids were recorded, giving additional information on the molecules’ intermolecular hydrogen bonds and packing. In this way, several functionalities of these new resveratrol hybrids were examined as a necessary approach to finding more effective drugs for complicated neurodegenerative diseases. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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14 pages, 2484 KiB  
Article
Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII
by Arzu Gumus, Murat Bozdag, Atilla Akdemir, Andrea Angeli, Silvia Selleri, Fabrizio Carta and Claudiu T. Supuran
Molecules 2022, 27(14), 4610; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27144610 - 19 Jul 2022
Cited by 5 | Viewed by 1448
Abstract
A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a [...] Read more.
A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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17 pages, 2703 KiB  
Article
Continued Structural Exploration of Sulfocoumarin as Selective Inhibitor of Tumor-Associated Human Carbonic Anhydrases IX and XII
by Simone Giovannuzzi, Clemente Capasso, Alessio Nocentini and Claudiu T. Supuran
Molecules 2022, 27(13), 4076; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27134076 - 24 Jun 2022
Cited by 6 | Viewed by 1291
Abstract
A series of new 3- and 7-substituted sulfocoumarins was obtained by several cyclization reactions and subsequent derivatization for screening as prodrug inhibitors of the human (h) cancer-associated carbonic anhydrases (CAs) IX and XII. All products were ineffective inhibitors against the off-target hCA I [...] Read more.
A series of new 3- and 7-substituted sulfocoumarins was obtained by several cyclization reactions and subsequent derivatization for screening as prodrug inhibitors of the human (h) cancer-associated carbonic anhydrases (CAs) IX and XII. All products were ineffective inhibitors against the off-target hCA I and II, whilst hCAs IX and XII were inhibited with inhibition constants (KIs) spanning from low nanomolar to the high micromolar range, according to the sulfocoumarin derivatization pattern. In particular, sulfocoumarin 15 turned out to be the most potent and selective inhibitor herein reported (hCA I and II: KI > 100 µM; hCA IX: KI = 22.9 nM; hCA XII: KI = 19.2 nM). Considering that hCA IX and XII validated anti-tumor targets, such prodrug, isoform-selective inhibitors as the sulfocoumarins reported here may be useful for identifying suitable drug candidates for clinical trials. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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20 pages, 6041 KiB  
Article
HDAC Inhibitory and Anti-Cancer Activities of Curcumin and Curcumin Derivative CU17 against Human Lung Cancer A549 Cells
by Narissara Namwan, Gulsiri Senawong, Chanokbhorn Phaosiri, Pakit Kumboonma, La-or Somsakeesit, Arunta Samankul, Chadaporn Leerat and Thanaset Senawong
Molecules 2022, 27(13), 4014; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27134014 - 22 Jun 2022
Cited by 16 | Viewed by 2760
Abstract
Previous research reported that the curcumin derivative (CU17) inhibited several cancer cell growths in vitro. However, its anticancer potential against human lung cancer cells (A549 cell lines) has not yet been evaluated. The purpose of this research was to examine the HDAC inhibitory [...] Read more.
Previous research reported that the curcumin derivative (CU17) inhibited several cancer cell growths in vitro. However, its anticancer potential against human lung cancer cells (A549 cell lines) has not yet been evaluated. The purpose of this research was to examine the HDAC inhibitory and anti-cancer activities of CU17 compared to curcumin (CU) in A549 cells. An in vitro study showed that CU17 had greater HDAC inhibitory activity than CU. CU17 inhibited HDAC activity in a dose dependent manner with the half-maximal inhibitory concentration (IC50) value of 0.30 ± 0.086 µg/mL against HDAC enzymes from HeLa nuclear extract. In addition, CU17 could bind at the active pockets of both human class I HDACs (HDAC1, 2, 3, and 8) and class II HDACs (HDAC4, 6, and 7) demonstrated by molecular docking studies, and caused hyperacetylation of histone H3 (Ac-H3) in A549 cells shown by Western blot analysis. MTT assay indicated that both CU and CU17 suppressed A549 cell growth in a dose- and time-dependent manner. Besides, CU and CU17 induced G2/M phase cell cycle arrest and p53-independent apoptosis in A549 cells. Both CU and CU17 down-regulated the expression of p53, p21, Bcl-2, and pERK1/2, but up-regulated Bax expression in this cell line. Although CU17 inhibited the growth of lung cancer cells less effectively than CU, it showed less toxicity than CU for non-cancer cells. Accordingly, CU17 is a promising agent for lung cancer treatment. Additionally, CU17 synergized the antiproliferative activity of Gem in A549 cells, indicating the possibility of employing CU17 as an adjuvant treatment to enhance the chemotherapeutic effect of Gem in lung cancer. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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21 pages, 10015 KiB  
Article
Catalytic Properties of Caseinolytic Protease Subunit of Plasmodium knowlesi and Its Inhibition by a Member of δ-Lactone, Hyptolide
by Cahyo Budiman, Raimalynah Abd Razak, Angelesa Runin Anak Unggit, Rafida Razali, Meiny Suzery, Ruzaidi Azli Mohd Mokhtar, Ping-Chin Lee and Didik Huswo Utomo
Molecules 2022, 27(12), 3787; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27123787 - 12 Jun 2022
Cited by 3 | Viewed by 1857
Abstract
The caseinolytic protease (Clp) system plays an essential role in the protein homeostasis of the malaria parasite, particularly at the stage of apicoplast development. The inhibition of this protein is known to have a lethal effect on the parasite and is therefore considered [...] Read more.
The caseinolytic protease (Clp) system plays an essential role in the protein homeostasis of the malaria parasite, particularly at the stage of apicoplast development. The inhibition of this protein is known to have a lethal effect on the parasite and is therefore considered an interesting avenue for antimalaria drugs discovery. The catalytic activity of the Clp system is modulated by its proteolytic subunit (ClpP), which belongs to the serine protease family member and is therefore extensively studied for further inhibitors development. Among many inhibitors, the group of β-lactone is known to be a specific inhibitor for ClpP. Nevertheless, other groups of lactones have never been studied. This study aims to characterize the catalytic properties of ClpP of Plasmodium knowlesi (Pk-ClpP) and the inhibition properties of a δ-lactone hyptolide against this protein. Accordingly, a codon-optimized synthetic gene encoding Pk-ClpP was expressed in Escherichia coli BL21(DE3) and purified under a single step of Ni2+-affinity chromatography, yielding a 2.20 mg from 1 L culture. Meanwhile, size-exclusion chromatography indicated that Pk-ClpP migrated primarily as homoheptameric with a size of 205 kDa. The specific activity of pure Pk-ClpP was 0.73 U µg−1, with a catalytic efficiency kcat/KM of 0.05 µM−1 s−1, with optimum temperature and pH of 50 °C and 7.0–7.5, respectively. Interestingly, hyptolide, a member of δ-lactone, was shown to inhibit Pk-ClpP with an IC50 value of 17.36 ± 1.44 nM. Structural homology modelling, secondary structure prediction, and far-UV CD spectra revealed that helical structures dominate this protein. In addition, the structural homology modeling showed that this protein forms a barrel-shaped homoheptamer. Docking simulation revealed that the inhibition was found to be a competitive inhibition in which hyptolide was able to dock into the catalytic site and block the substrate. The competitiveness of hyptolide is due to the higher binding affinity of this molecule than the substrate. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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19 pages, 3568 KiB  
Article
Bis-Cinnamamide Derivatives as APE/Ref-1 Inhibitors for the Treatment of Human Melanoma
by Razan Alhazmi, Shirley Tong, Shaban Darwish, Elina Khanjani, Bharti Khungar, Swati Chawla, Zhonghui Zheng, Richard Chamberlin, Keykavous Parang and Sun Yang
Molecules 2022, 27(9), 2672; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27092672 - 21 Apr 2022
Viewed by 2235
Abstract
Human malignant melanoma exhibits imbalances in redox status, leading to activation of many redox-sensitive signaling pathways. APE/Ref-1 is a multifunctional protein that serves as a redox chaperone that regulates many nuclear transcription factors and is an important mechanism in cancer cell survival of [...] Read more.
Human malignant melanoma exhibits imbalances in redox status, leading to activation of many redox-sensitive signaling pathways. APE/Ref-1 is a multifunctional protein that serves as a redox chaperone that regulates many nuclear transcription factors and is an important mechanism in cancer cell survival of oxidative stress. Previous studies showed that APE/Ref-1 is a potential druggable target for melanoma therapy. In this study, we synthesized a novel APE/Ref-1 inhibitor, bis-cinnamoyl-1,12-dodecamethylenediamine (2). In a xenograft mouse model, compound 2 treatment (5 mg/kg) significantly inhibited tumor growth compared to the control group, with no significant systemic toxicity observed. We further synthesized compound 2 analogs to determine the structure-activity relationship based on their anti-melanoma activities. Among those, 4-hydroxyphenyl derivative (11) exhibited potent anti-melanoma activities and improved water solubility compared to its parental compound 2. The IC50 of compound 11 was found to be less than 0.1 μM. Compared to other known APE/Ref-1 inhibitors, compound 11 exhibited increased potency in inhibiting melanoma proliferation. As determined by luciferase reporter analyses, compound 2 was shown to effectively inhibit H2O2-activated AP-1 transcription activities. Targeting APE/Ref-1-mediated signaling using pharmaceutical inhibitors is a novel and effective strategy for melanoma treatment with potentially high impact. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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Review

Jump to: Research

12 pages, 1629 KiB  
Review
Research on Diffusible Signal Factor-Mediated Quorum Sensing in Xanthomonas: A Mini-Review
by Yu-Mei Feng, Zhou-Qing Long, Hong-Mei Xiang, Jun-Ning Ran, Xiang Zhou and Song Yang
Molecules 2023, 28(2), 876; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules28020876 - 15 Jan 2023
Cited by 6 | Viewed by 2518
Abstract
Xanthomonas spp. are important plant pathogens that seriously endanger crop yields and food security. RpfF is a key enzyme that is involved in the synthesis of diffusible signal factor (DSF) signals and predominates in the signaling pathway regulating quorum sensing (QS) in Xanthomonas [...] Read more.
Xanthomonas spp. are important plant pathogens that seriously endanger crop yields and food security. RpfF is a key enzyme that is involved in the synthesis of diffusible signal factor (DSF) signals and predominates in the signaling pathway regulating quorum sensing (QS) in Xanthomonas. Currently, novel RpfF enzyme-based quorum sensing agents have been proposed as a promising strategy for the development of new pesticides. However, few reports are available that comprehensively summarize the progress in this field. Therefore, we provide a comprehensive review of the recent advances in DSF-mediated QS and recently reported inhibitors that are proposed as bactericide candidates to target the RpfF enzyme and control plant bacterial diseases. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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25 pages, 4329 KiB  
Review
An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022
by Letizia Crocetti, Giuseppe Floresta, Agostino Cilibrizzi and Maria Paola Giovannoni
Molecules 2022, 27(15), 4964; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27154964 - 4 Aug 2022
Cited by 37 | Viewed by 10063
Abstract
Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of [...] Read more.
Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)
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