Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
6.1
4.3
Journals
Pharmaceuticals
Special Issues
Enzyme Inhibitors: Potential Therapeutic Approaches
share announcement

Enzyme Inhibitors: Potential Therapeutic Approaches

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (25 October 2024) | Viewed by 24581

Special Issue Editor

Dr. Phaedra Eleftheriou

E-Mail Website
Guest Editor
Department of Biomedical Sciences, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece
Interests: medicinal chemistry; enzymology; biochemistry; COX inhibitors; LOX inhibitors; HIV-1 RT inhibitors; HIV-1 integrase inhibitors; PTP1b inhibitors; HIV-1 protease inhibitors; anti-inflammatory; antidiabetic; antiviral; antibacterial; antifungal; food-derived antigens; anti-Neu5Gc

Special Issue Information

Dear Colleagues,

Enzymes are involved in all biochemical processes; thus, they constitute the second greatest drug target after receptors. The dysregulation of enzyme activity has been related to several pathologic disorders. Apart from specific cases which demand enzyme administration to counteract the lack or reduced action of an enzyme, small molecules that moderate enzyme activity are broadly used. However, the enhancement of enzyme expression or activity is the aim in only certain cases, while enzyme inhibition is the most common drug target. Inhibitors of human enzymes are used to fight many common disorders, such as inflammation, hypertension and hypercholesterolemia, and are one of the medications for the treatment of diabetes. Moreover, most antiviral, antibacterial and antifungal agents also act as enzyme inhibitors. Despite approximately 790 enzyme inhibitors having been approved since 2021, the search for novel inhibitors for known enzyme drug targets continues, targeting the development of novel agents with improved properties, less side effects and ones appropriate for resistant strains. In addition, novel enzymes are added each year to the catalogue of drug targets for the anticipation of untreated diseases. Among the fourteen drugs for novel drug targets approved in 2021, four were enzymes and three of the approved drugs were enzyme inhibitors.

This Special Issue aims to gather research and review articles on enzymes and enzyme inhibitors with pharmaceutical interest, covering a hot and developing area of medical research.

Dr. Phaedra Eleftheriou
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 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 targets
  • therapeutic approaches

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (10 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

19 pages, 764 KiB  
Article
Algerian Prickly Pear Seed By-Products: Fatty Acids Composition, Antioxidant, Enzyme Inhibitory Activities towards Tyrosinase, Urease, α-Amylase, and Cholinesterase, along with the Ability to Protect from Thermal Protein Denaturation
by Nassiba Chafaa, Camelia Mosbah, Latifa Khattabi, Karima Malaoui, Wafa Zahnit, Mohamed El Amine Smaali, Faiza Houri, Yazid Medfouni, Khalid Mashay Al-Anazi and Ahmad Ali
Pharmaceuticals 2024, 17(9), 1145; https://doi.org/10.3390/ph17091145 - 30 Aug 2024
Viewed by 1533
Abstract
Prickly pear seed is a source of the most expensive oil in the world, which is rich in vitamins and polyunsaturated fatty acids. Its extraction generates a large quantity of press cake. These two by-products need to be valued. The current study aimed [...] Read more.
Prickly pear seed is a source of the most expensive oil in the world, which is rich in vitamins and polyunsaturated fatty acids. Its extraction generates a large quantity of press cake. These two by-products need to be valued. The current study aimed to assess the fatty acid composition of oil and the phytochemical composition of press cake. In addition, the antioxidant and the inhibition of thermal protein denaturation effects of both Algerian seed by-products were evaluated with their inhibitory action against the activities of urease, tyrosinase, α-amylase, and cholinesterase enzymes. The GC MS analysis result revealed the richness of our oil in linoleic (74%) and palmitic (13%) acids methyl esters, respectively. The chemical composition of press cake was characterized by a high value of dry matter (94.94 ± 0.05%), especially the carbohydrates (85.13 ± 0.94%). The results of antioxidant activity presented by IC50 and A0.5 ranged from 7.51 ± 0.03 to 88.10 ± 0.92 µg/mL. Furthermore, the IC50 values were 40.19 ± 1.21 and 61.18 ± 0.03 µg/mL in thermal protein denaturation assay, and ranging from 22.97 ± 0.72 to 385.99 ± 0.27 µg/mL for the inhibition of enzymatic activities. These results indicate that the studied oil can be one of the strongest oils for its impressive effects and also encourage us to reuse its press cake in feed livestock. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

19 pages, 7047 KiB  
Article
Azobenzenesulfonamide Carbonic Anhydrase Inhibitors as New Weapons to Fight Helicobacter pylori: Synthesis, Bioactivity Evaluation, In Vivo Toxicity, and Computational Studies
by Letizia Giampietro, Beatrice Marinacci, Alice Della Valle, Ilaria D’Agostino, Aldo Lauro, Mattia Mori, Simone Carradori, Alessandra Ammazzalorso, Barbara De Filippis, Cristina Maccallini, Andrea Angeli, Clemente Capasso, Santolo Francati, Adriano Mollica, Rossella Grande and Claudiu T. Supuran
Pharmaceuticals 2024, 17(8), 1027; https://doi.org/10.3390/ph17081027 - 5 Aug 2024
Viewed by 1053
Abstract
Research into novel anti-Helicobacter pylori agents represents an important approach for the identification of new treatments for chronic gastritis and peptic ulcers, which are associated with a high risk of developing gastric carcinoma. In this respect, two series of azobenzenesulfonamides were designed, [...] Read more.
Research into novel anti-Helicobacter pylori agents represents an important approach for the identification of new treatments for chronic gastritis and peptic ulcers, which are associated with a high risk of developing gastric carcinoma. In this respect, two series of azobenzenesulfonamides were designed, synthesized, and tested against a large panel of human and bacterial CAs to evaluate their inhibitory activity. In addition, computational studies of the novel primary benzenesulfonamides (4a–j) were performed to predict the putative binding mode to both HpCAs. Then, the antimicrobial activity versus H. pylori of the two series was also studied. The best-in-class compounds were found to be 4c and 4e among the primary azobenzenesulfonamides and 5c and 5f belonging to the secondary azobenzenesulfonamides series, showing themselves to exert a promising anti-H. pylori activity, with MIC values of 4–8 μg/mL and MBCs between 4 and 16 μg/mL. Moreover, the evaluation of their toxicity on a G. mellonella larva in vivo model indicated a safe profile for 4c,e and 5c,f. The collected results warrant considering these azobenzenesulfonamides as an interesting starting point for the development of a new class of anti-H. pylori agents. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

21 pages, 3217 KiB  
Article
Investigation of the Effects of a Novel NOX2 Inhibitor, GLX7013170, against Glutamate Excitotoxicity and Diabetes Insults in the Retina
by Stavroula Dionysopoulou, Per Wikstrom, Erik Walum, Spiros Georgakis and Kyriaki Thermos
Pharmaceuticals 2024, 17(3), 393; https://doi.org/10.3390/ph17030393 - 19 Mar 2024
Cited by 1 | Viewed by 1421
Abstract
Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress is correlated to NADPH oxidase (NOX), a major source of Reactive Oxygen Species (ROS), and glutamate metabolism impairments. This study investigated the role [...] Read more.
Glutamate excitotoxicity and oxidative stress represent two major pathological mechanisms implicated in retinal disorders. In Diabetic Retinopathy (DR), oxidative stress is correlated to NADPH oxidase (NOX), a major source of Reactive Oxygen Species (ROS), and glutamate metabolism impairments. This study investigated the role of NOX2 and the novel NOX2 inhibitor, GLX7013170, in two models of a) retinal AMPA excitotoxicity [AMPA+GLX7013170 (10−4 M, intravitreally)] and b) early-stage DR paradigm (ESDR), GLX7013170: 14-day therapeutic treatment (topically, 20 μL/eye, 10 mg/mL (300 × 10−4 M), once daily) post-streptozotocin (STZ)-induced DR. Immunohistochemical studies for neuronal markers, nitrotyrosine, micro/macroglia, and real-time PCR, Western blot, and glutamate colorimetric assays were conducted. Diabetes increased NOX2 expression in the retina. NOX2 inhibition limited the loss of NOS-positive amacrine cells and the overactivation of micro/macroglia in both models. In the diabetic retina, GLX7013170 had no effect on retinal ganglion cell axons, but reduced oxidative damage, increased Bcl-2, reduced glutamate levels, and partially restored excitatory amino acid transporter (EAAT1) expression. These results suggest that NOX2 in diabetes is part of the triad, oxidative stress, NOX, and glutamate excitotoxicity, key players in the induction of DR. GLX7013170 is efficacious as a neuroprotective/anti-inflammatory agent and a potential therapeutic in retinal diseases, including ESDR. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

18 pages, 4514 KiB  
Article
s-Triazine Derivatives Functionalized with Alkylating 2-Chloroethylamine Fragments as Promising Antimicrobial Agents: Inhibition of Bacterial DNA Gyrases, Molecular Docking Studies, and Antibacterial and Antifungal Activity
by Dawid Maliszewski, Rasime Demirel, Agnieszka Wróbel, Maciej Baradyn, Artur Ratkiewicz and Danuta Drozdowska
Pharmaceuticals 2023, 16(9), 1248; https://doi.org/10.3390/ph16091248 - 4 Sep 2023
Cited by 5 | Viewed by 1582
Abstract
The spectrum of biological properties of s-triazine derivatives is broad and includes anti-microbial, anti-cancer, and anti-neurodegenerative activities, among others. The s-triazine molecule, due to the possibility of substituting three substituents, offers many opportunities to obtain hybrid compounds with a wide variety of activities. [...] Read more.
The spectrum of biological properties of s-triazine derivatives is broad and includes anti-microbial, anti-cancer, and anti-neurodegenerative activities, among others. The s-triazine molecule, due to the possibility of substituting three substituents, offers many opportunities to obtain hybrid compounds with a wide variety of activities. A group of 1,3,5 triazine derivatives containing a dipeptide, 2-ethylpiperazine, and a methoxy group as substituents was screened for their antimicrobial activity. An in vitro study was conducted on pathogenic bacteria (E. coli, S. aureus, B. subtilis, and M. luteus), yeasts (C. albicans), and filamentous fungi (A. fumigatus, A. flavus, F. solani, and P. citrinum) via microdilution in broth, and the results were compared with antibacterial (Streptomycin) and antifungal (Ketoconazole and Nystatin) antibiotics. Several s-triazine analogues have minimal inhibitory concentrations lower than the standard. To confirm the inhibitory potential of the most active compounds against gyrases E. coli and S. aureus, a bacterial gyrases inhibition assay, and molecular docking studies were performed. The most active s-triazine derivatives contained the -NH-Trp(Boc)-AlaOMe, -NH-Asp(OtBu)-AlaOMe, and -NH-PheOMe moieties in their structures. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

25 pages, 6178 KiB  
Article
Discovery of New Uracil and Thiouracil Derivatives as Potential HDAC Inhibitors
by Omnia R. Elbatrawy, Mohamed Hagras, Moshira A. El Deeb, Fatimah Agili, Maghawry Hegazy, Ahmed A. El-Husseiny, Mahmoud Mohamed Mokhtar, Samy Y. Elkhawaga, Ibrahim H. Eissa and Samar El-Kalyoubi
Pharmaceuticals 2023, 16(7), 966; https://doi.org/10.3390/ph16070966 - 6 Jul 2023
Cited by 5 | Viewed by 2162
Abstract
Background: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. Aim: Discovery of new anticancer agents targeting HDAC. Methods: New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized [...] Read more.
Background: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. Aim: Discovery of new anticancer agents targeting HDAC. Methods: New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized compounds were tested against MCF-7, HepG2, and HCT-116. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. The most active member was tested for its potential against cell cycle, apoptosis, caspase-3, and caspase-8. Docking studies were carried out against HDAC1. Results: Compounds 5a, 5b, 5f, 5i, 5k, and 5m exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound 5m was the most potent member (IC50 = 0.05 µg/mL) compared to trichostatin A (IC50 = 0.0349 µg/mL). For HDAC4, compound 5m showed superior activity (IC50 = 2.83 µg/mL) than trichostatin A (IC50 = 3.349 µg/mL). Compound 5m showed a high potential to arrest the HCT116 cell cycle at the G0-G1 phase. In addition, it showed an almost 17 times apoptotic effect (37.59%) compared to the control cells (2.17%). Furthermore, Compound 5m showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. Conclusions: Compound 5m has potential anticancer activity targeting HDAC with a significant apoptotic effect. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

20 pages, 7315 KiB  
Article
Screening and Elucidation of Chemical Structures of Novel Mammalian α-Glucosidase Inhibitors Targeting Anti-Diabetes Drug from Herbals Used by E De Ethnic Tribe in Vietnam
by Van Bon Nguyen, San-Lang Wang, Tu Quy Phan, Thi Huyen Thoa Pham, Hung-Tse Huang, Chia-Ching Liaw and Anh Dzung Nguyen
Pharmaceuticals 2023, 16(5), 756; https://doi.org/10.3390/ph16050756 - 17 May 2023
Cited by 4 | Viewed by 1934
Abstract
Among ten extracts of indigenous medicinal plants, the MeOH extract of Terminalia triptera Stapf. (TTS) showed the most efficient mammalian α-glucosidase inhibition for the first time. The data of screening bioactive parts used indicated that the TTS trunk bark and leaves extracts demonstrated [...] Read more.
Among ten extracts of indigenous medicinal plants, the MeOH extract of Terminalia triptera Stapf. (TTS) showed the most efficient mammalian α-glucosidase inhibition for the first time. The data of screening bioactive parts used indicated that the TTS trunk bark and leaves extracts demonstrated comparable and higher effects compared to acarbose, a commercial anti-diabetic drug, with half-maximal inhibitory concentration (IC50) values of 181, 331, and 309 µg/mL, respectively. Further bioassay-guided purification led to the isolation of three active compounds from the TTS trunk bark extract and identified as (−)-epicatechin (1), eschweilenol C (2), and gallic acid (3). Of these, compounds 1 and 2 were determined as novel and potent mammalian α-glucosidase inhibitors. The virtual study indicated that these compounds bind to α-glucosidase (Q6P7A9) with acceptable RMSD values (1.16–1.56 Å) and good binding energy (DS values in the range of −11.4 to −12.8 kcal/mol) by interacting with various prominent amino acids to generate five and six linkages, respectively. The data of Lipinski’s rule of five and absorption, distribution, metabolism, excretion and toxicity (ADMET)-based pharmacokinetics and pharmacology revealed that these purified compounds possess anti-diabetic drug properties, and the compounds are almost not toxic for human use. Thus, the findings of this work suggested that (−)-epicatechin and eschweilenol C are novel potential mammalian α-glucosidase inhibitor candidates for type 2 diabetes treatment. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

12 pages, 1176 KiB  
Article
Association between Gallstone Disease and Statin Use: A Nested Case—Control Study in Korea
by Mi Jung Kwon, Jung Woo Lee, Ho Suk Kang, Hyun Lim, Eun Soo Kim, Nan Young Kim, Hyo Geun Choi and Min-Jeong Kim
Pharmaceuticals 2023, 16(4), 536; https://doi.org/10.3390/ph16040536 - 3 Apr 2023
Cited by 3 | Viewed by 3472
Abstract
The correlation between statin use and the development of gallstone disease remains controversial. Existing data, primarily based on Caucasian populations, are biased, thus necessitating validation studies involving Asian cohorts. We conducted a nested case–control study using data from the Korean National Health Insurance [...] Read more.
The correlation between statin use and the development of gallstone disease remains controversial. Existing data, primarily based on Caucasian populations, are biased, thus necessitating validation studies involving Asian cohorts. We conducted a nested case–control study using data from the Korean National Health Insurance Service Health Screening Cohort (2002–2019) to determine the likelihood of gallstone disease according to periods of previous statin use and type of statin. Among the 514,866 participants, 22,636 diagnosed with gallstones at ≥2 clinic visits (using the International Classification of Diseases, 10th revision, code K80) were matched 1:4 to 90,544 controls for age, sex, income, and residential area, and their statin prescription history for 2 years prior to the index date was examined. Propensity-score-weighted odds ratios (ORs) for gallstone disease were calculated using conditional logistic regression. Long-term use (>545 days) of any statin or lipophilic statins was associated with lower odds of incident gallstones (OR = 0.91, 95% confidence interval [CI] = 0.86–0.96, p < 0.001 and OR = 0.88, 95% CI = 0.83–0.93, p < 0.001, respectively) after adjusting for confounders. Short-term use (180–545 days) of any statin or hydrophilic statins was not statistically related to incident gallstones. In summary, prior statin medication, particularly long-term lipophilic statin use, may confer a preventive advantage against gallstone disease. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Graphical abstract

19 pages, 6058 KiB  
Article
Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling
by Bilal Ahmad Khan, Syeda Shamila Hamdani, Muhammad Khalid, Muhammad Ashfaq, Khurram Shahzad Munawar, Muhammad Nawaz Tahir, Ataualpa A. C. Braga, Ahmed M. Shawky, Alaa M. Alqahtani, Mohammed A. S. Abourehab, Gamal A. Gabr, Mahmoud A. A. Ibrahim and Peter A. Sidhom
Pharmaceuticals 2023, 16(3), 424; https://doi.org/10.3390/ph16030424 - 10 Mar 2023
Cited by 7 | Viewed by 2425
Abstract
1,3,4-Oxadiazole moiety is a crucial pharmacophore in many biologically active compounds. In a typical synthesis, probenecid was subjected to a sequence of reactions to obtain a 1,3,4-oxadiazole–phthalimide hybrid (PESMP) in high yields. The NMR (1H and 13C) spectroscopic [...] Read more.
1,3,4-Oxadiazole moiety is a crucial pharmacophore in many biologically active compounds. In a typical synthesis, probenecid was subjected to a sequence of reactions to obtain a 1,3,4-oxadiazole–phthalimide hybrid (PESMP) in high yields. The NMR (1H and 13C) spectroscopic analysis initially confirmed the structure of PESMP. Further spectral aspects were validated based on a single-crystal XRD analysis. Experimental findings were confirmed afterwards by executing a Hirshfeld surface (HS) analysis and quantum mechanical computations. The HS analysis showed the role of the π⋯π stacking interactions in PESMP. PESMP was found to have a high stability and lower reactivity in terms of global reactivity parameters. α-Amylase inhibition studies revealed that the PESMP was a good inhibitor of α-amylase with an s value of 10.60 ± 0.16 μg/mL compared with that of standard acarbose (IC50 = 8.80 ± 0.21 μg/mL). Molecular docking was also utilized to reveal the binding pose and features of PESMP against the α-amylase enzyme. Via docking computations, the high potency of PESMP and acarbose towards the α-amylase enzyme was unveiled and confirmed by docking scores of −7.4 and −9.4 kcal/mol, respectively. These findings shine a new light on the potential of PESMP compounds as α-amylase inhibitors. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

25 pages, 13890 KiB  
Article
Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives
by Ahmed Elkamhawy, Seohyun Son, Hwa Young Lee, Mahmoud H. El-Maghrabey, Mohamed A. El Hamd, Saud O. Alshammari, Abeer A. Abdelhameed, Qamar A. Alshammari, Ahmed Abdeen, Samah F. Ibrahim, Wael A. Mahdi, Sultan Alshehri, Radwan Alnajjar, Won Jun Choi, Ahmed A. Al-Karmalawy and Kyeong Lee
Pharmaceuticals 2023, 16(1), 43; https://doi.org/10.3390/ph16010043 - 28 Dec 2022
Cited by 10 | Viewed by 3832
Abstract
Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to [...] Read more.
Co-expression of the epidermal growth factor receptor (EGFR, also known as ErbB1) and human epidermal growth factor receptor 2 (HER2) has been identified as a diagnostic or prognostic sign in various tumors. Despite the fact that lapatinib (EGFR/HER2 dual inhibitor) has shown to be successful, many patients do not respond to it or develop resistance for a variety of reasons that are still unclear. As a result, new approaches and inhibitory small molecules are still needed for EGFR/HER2 inhibition. Herein, novel lapatinib derivatives possessing 4-anilinoquinazoline and imidazole scaffolds (6a–l) were developed and screened as EGFR/HER2 dual inhibitors. In vitro and in silico investigations revealed that compound 6j has a high affinity for the ATP-binding regions of EGFR and HER2. All of the designed candidates were predicted to not penetrate the BBB, raising the expectation for the absence of CNS side effects. At 10 µM, derivatives possessing 3-chloro-4-(pyridin-2-ylmethoxy)aniline moiety (6i–l) demonstrated outstanding ranges of percentage inhibition against EGFR (97.65–99.03%) and HER2 (87.16–96.73%). Compound 6j showed nanomolar IC50 values over both kinases (1.8 nM over EGFR and 87.8 nM over HER2). Over EGFR, compound 6j was found to be 50-fold more potent than staurosporine and 6-fold more potent than lapatinib. A kinase selectivity panel of compound 6j showed poor to weak inhibitory activity over CDK2/cyclin A, c-MET, FGFR1, KDR/VEGFR2, and P38a/MAPK14, respectively. Structure–activity relationship (SAR) that were obtained with different substitutions were justified. Additionally, molecular docking and molecular dynamics studies revealed insights into the binding mode of the target compounds. Thus, compound 6j was identified as a highly effective and dual EGFR/HER2 inhibitor worthy of further investigation. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

21 pages, 6652 KiB  
Article
Synthesis and Evaluation of Novel S-alkyl Phthalimide- and S-benzyl-oxadiazole-quinoline Hybrids as Inhibitors of Monoamine Oxidase and Acetylcholinesterase
by Bilal Ahmad Khan, Syeda Shamila Hamdani, Saquib Jalil, Syeda Abida Ejaz, Jamshed Iqbal, Ahmed M. Shawky, Alaa M. Alqahtani, Gamal A. Gabr, Mahmoud A. A. Ibrahim and Peter A. Sidhom
Pharmaceuticals 2023, 16(1), 11; https://doi.org/10.3390/ph16010011 - 22 Dec 2022
Cited by 6 | Viewed by 2721
Abstract
New S-alkyl phthalimide 5a–f and S-benzyl 6a–d analogs of 5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2-thiol (4) were prepared by reacting 4 with N-bromoalkylphthalimide and CF3-substituted benzyl bromides in excellent yields. Spectroscopic techniques were employed to elucidate the [...] Read more.
New S-alkyl phthalimide 5a–f and S-benzyl 6a–d analogs of 5-(2-phenylquinolin-4-yl)-1,3,4-oxadiazole-2-thiol (4) were prepared by reacting 4 with N-bromoalkylphthalimide and CF3-substituted benzyl bromides in excellent yields. Spectroscopic techniques were employed to elucidate the structures of the synthesized molecules. The inhibition activity of newly synthesized molecules toward MAO-A, MAO-B, and AChE enzymes, was also assessed. All these compounds showed activity in the submicromolar range against all enzymes. Compounds 5a and 5f were found to be the most potent compounds against MAO-A (IC50 = 0.91 ± 0.15 nM) and MAO-B (IC50 = 0.84 ± 0.06 nM), while compound 5c showed the most efficient acetylcholinesterase inhibition (IC50 = 1.02± 0.65 μM). Docking predictions disclosed the docking poses of the synthesized molecules with all enzymes and demonstrated the outstanding potency of compounds 5a, 5f, and 5c (docking scores = −11.6, −15.3, and −14.0 kcal/mol against MAO-A, MAO-B, and AChE, respectively). These newly synthesized analogs act as up-and-coming candidates for the creation of safer curative use against Alzheimer’s illness. Full article
(This article belongs to the Special Issue Enzyme Inhibitors: Potential Therapeutic Approaches)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-10
Back to TopTop