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Special Issue "Enzyme Inhibitors: Potential Therapeutic Approaches"

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

Deadline for manuscript submissions: 20 February 2024 | Viewed by 9123

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Dr. Phaedra Eleftheriou

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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

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Keywords

enzyme inhibitors
drug targets
therapeutic approaches

Published Papers (7 papers)

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Research

Open AccessArticle

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

and

Pharmaceuticals 2023, 16(9), 1248; https://doi.org/10.3390/ph16091248 - 04 Sep 2023

Viewed by 330

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. 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)

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Open AccessArticle

Discovery of New Uracil and Thiouracil Derivatives as Potential HDAC Inhibitors

Mahmoud Mohamed Mokhtar

Samy Y. Elkhawaga

Ibrahim H. Eissa

and

Samar El-Kalyoubi

Pharmaceuticals 2023, 16(7), 966; https://doi.org/10.3390/ph16070966 - 06 Jul 2023

Viewed by 873

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 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)

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Open AccessArticle

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

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Pharmaceuticals 2023, 16(5), 756; https://doi.org/10.3390/ph16050756 - 17 May 2023

Viewed by 875

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 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)

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Open AccessArticle

Association between Gallstone Disease and Statin Use: A Nested Case—Control Study in Korea

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Pharmaceuticals 2023, 16(4), 536; https://doi.org/10.3390/ph16040536 - 03 Apr 2023

Viewed by 1421

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 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)

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Open AccessArticle

Exploring Probenecid Derived 1,3,4-Oxadiazole-Phthalimide Hybrid as α-Amylase Inhibitor: Synthesis, Structural Investigation, and Molecular Modeling

Bilal Ahmad Khan

Syeda Shamila Hamdani

Muhammad Khalid

Muhammad Ashfaq

Khurram Shahzad Munawar

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 1 | Viewed by 1113

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 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)

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Open AccessArticle

Design, Synthesis, Biological Evaluation, and Molecular Dynamics Studies of Novel Lapatinib Derivatives

Ahmed Elkamhawy

Seohyun Son

Hwa Young Lee

Mahmoud H. El-Maghrabey

Ahmed A. Al-Karmalawy

and

Kyeong Lee

Pharmaceuticals 2023, 16(1), 43; https://doi.org/10.3390/ph16010043 - 28 Dec 2022

Cited by 3 | Viewed by 2110

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 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)

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Open AccessArticle

Synthesis and Evaluation of Novel S-alkyl Phthalimide- and S-benzyl-oxadiazole-quinoline Hybrids as Inhibitors of Monoamine Oxidase and Acetylcholinesterase

Bilal Ahmad Khan

Syeda Shamila Hamdani

Mahmoud A. A. Ibrahim

and

Peter A. Sidhom

Pharmaceuticals 2023, 16(1), 11; https://doi.org/10.3390/ph16010011 - 22 Dec 2022

Cited by 2 | Viewed by 1707

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 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)

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