Research

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17 pages, 2249 KiB

Open AccessArticle

Design, Synthesis, In Vitro and In Silico Studies of New Thiazolylhydrazine-Piperazine Derivatives as Selective MAO-A Inhibitors

by Begüm Nurpelin Sağlık, Osman Cebeci, Ulviye Acar Çevik, Derya Osmaniye, Serkan Levent, Betül Kaya Çavuşoğlu, Sinem Ilgın, Yusuf Özkay and Zafer Asım Kaplancıklı

Molecules 2020, 25(18), 4342; https://doi.org/10.3390/molecules25184342 - 22 Sep 2020

Cited by 7 | Viewed by 2469

Abstract

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such [...] Read more.

Monoamine oxidase (MAO) isoenzymes are very important drug targets among neurological disorders. Herein, novel series of thiazolylhydrazine-piperazine derivatives were designed, synthesized and evaluated for their MAO-A and -B inhibitory activity. The structures of the synthesized compounds were assigned using different spectroscopic techniques such as ¹H-NMR, ¹³C-NMR and HRMS. Moreover, the prediction of ADME (Absorption, Distribution, Metabolism, Elimination) parameters for all of the compounds were performed using in silico method. According to the enzyme inhibition results, the synthesized compounds showed the selectivity against MAO-A enzyme inhibition. Compounds 3c, 3d and 3e displayed significant MAO-A inhibition potencies. Among them, compound 3e was found to be the most effective derivative with an IC₅₀ value of 0.057 ± 0.002 µM. Moreover, it was seen that this compound has a more potent inhibition profile than the reference inhibitors moclobemide (IC₅₀ = 6.061 ± 0.262 µM) and clorgiline (IC₅₀ = 0.062 ± 0.002 µM). In addition, the enzyme kinetics were performed for compound 3e and it was determined that this compound had a competitive and reversible inhibition type. Molecular modeling studies aided in the understanding of the interaction modes between this compound and MAO-A. It was found that compound 3e had significant and important binding property. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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22 pages, 5771 KiB

Open AccessArticle

Enhanced Antigiardial Effect of Omeprazole Analog Benzimidazole Compounds

by Beatriz Hernández-Ochoa, Saúl Gómez-Manzo, Adrián Sánchez-Carrillo, Jaime Marcial-Quino, Luz María Rocha-Ramírez, Araceli Santos-Segura, Edson Jiovany Ramírez-Nava, Roberto Arreguin-Espinosa, Miguel Cuevas-Cruz, Alfonso Méndez-Tenorio and Ernesto Calderón-Jaimes

Molecules 2020, 25(17), 3979; https://doi.org/10.3390/molecules25173979 - 01 Sep 2020

Cited by 10 | Viewed by 2610

Abstract

Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating [...] Read more.

Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating the need to find new alternative treatments. In this study, we synthesized a series of 2-mercaptobenzimidazoles that are derivatives of omeprazole, and the chemical structures were confirmed through mass, ¹H NMR, and ¹³C NMR techniques. The in vitro efficacy compounds against Giardia, as well as its effect on the inhibition of triosephosphate isomerase (TPI) recombinant, were investigated, the inactivation assays were performed with 0.2 mg/mL of the enzyme incubating for 2 h at 37 °C in TE buffer, pH 7.4 with increasing concentrations of the compounds. Among the target compounds, H-BZM2, O₂N-BZM7, and O₂N-BZM9 had greater antigiardial activity (IC₅₀: 36, 14, and 17 µM on trophozoites), and inhibited the TPI enzyme (K₂: 2.3, 3.2, and 2.8 M⁻¹ s⁻¹) respectively, loading alterations on the secondary structure, global stability, and tertiary structure of the TPI protein. Finally, we demonstrated that it had low toxicity on Caco-2 and HT29 cells. This finding makes it an attractive potential starting point for new antigiardial drugs. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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13 pages, 2979 KiB

Open AccessArticle

Discovery of Novel Integrase Inhibitors Acting outside the Active Site Through High-Throughput Screening

by Cindy Aknin, Elena A. Smith, Christophe Marchand, Marie-Line Andreola, Yves Pommier and Mathieu Metifiot

Molecules 2019, 24(20), 3675; https://doi.org/10.3390/molecules24203675 - 12 Oct 2019

Cited by 6 | Viewed by 2505

Abstract

Currently, an increasing number of drugs are becoming available to clinics for the treatment of HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients, due to resistance with or without [...] Read more.

Currently, an increasing number of drugs are becoming available to clinics for the treatment of HIV infection. Even if this targeted therapy is highly effective at suppressing viral replication, caregivers are facing growing therapeutic failures in patients, due to resistance with or without treatment adherence concerns. Accordingly, it is important to continue to discover small molecules that have a novel mechanism of inhibition. In this work, HIV integrase inhibitors were selected by high-throughput screening. Chemical structure comparisons enabled the identification of stilbene disulfonic acids as a potential new chemotype. Biochemical characterization of the lead compound stilbenavir (NSC34931) and a few derivatives was performed. Stilbene disulfonic acid derivatives exhibit low to sub-micromolar antiviral activity, and they inhibit integrase through DNA-binding inhibition. They probably bind to the C-terminal domain of integrase, in the cavity normally occupied by the noncleaved strand of the viral DNA substrate. Because of this original mode of action compared to active site strand transfer inhibitors, they do not exhibit cross-resistance to the three main resistance pathways to integrase inhibitors (G140S-Q148H, N155H, and Y143R). Further structure–activity optimization should enable the development of more active and less toxic derivatives with potential clinical relevance. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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21 pages, 7011 KiB

Open AccessArticle

Design, Synthesis, Docking Studies and Monoamine Oxidase Inhibition of a Small Library of 1-acetyl- and 1-thiocarbamoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazoles

by Paolo Guglielmi, Simone Carradori, Giulio Poli, Daniela Secci, Roberto Cirilli, Giulia Rotondi, Paola Chimenti, Anél Petzer and Jacobus P. Petzer

Molecules 2019, 24(3), 484; https://doi.org/10.3390/molecules24030484 - 29 Jan 2019

Cited by 24 | Viewed by 3998

Abstract

New N-acetyl/N-thiocarbamoylpyrazoline derivatives were designed and synthesized in high yields to assess their inhibitory activity and selectivity against human monoamine oxidase A and B. The most important chiral compounds were separated into their single enantiomers and tested. The impact of [...] Read more.

New N-acetyl/N-thiocarbamoylpyrazoline derivatives were designed and synthesized in high yields to assess their inhibitory activity and selectivity against human monoamine oxidase A and B. The most important chiral compounds were separated into their single enantiomers and tested. The impact of the substituents at N1, C3 and C5 positions as well the influence of the configuration of the C5 on the biological activity were analyzed. Bulky aromatic groups at C5 were not tolerated. p-Prenyloxyaryl moiety at C3 oriented the selectivity toward the B isoform. The results were also corroborated by molecular modelling studies providing new suggestions for the synthesis of privileged structures to serve as lead compounds for the treatment of mood disorders and neurodegenerative diseases. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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13 pages, 1582 KiB

Open AccessArticle

Effectiveness of Prenyl Group on Flavonoids from Epimedium koreanum Nakai on Bacterial Neuraminidase Inhibition

by Hong Min Choi, Jeong Yoon Kim, Zuo Peng Li, Janar Jenis, Yeong Jun Ban, Aizhamal Baiseitova and Ki Hun Park

Molecules 2019, 24(2), 317; https://doi.org/10.3390/molecules24020317 - 16 Jan 2019

Cited by 21 | Viewed by 3668

Abstract

In this study, the inhibitory potential of bacterial neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The [...] Read more.

In this study, the inhibitory potential of bacterial neuraminidase (NA) was observed on the leaves of Epimedium koreanum Nakai, which is a popular ingredient in traditional herbal medicine. This study attempted to isolate the relevant, responsible metabolites and elucidate their inhibition mechanism. The methanol extraction process yielded eight flavonoids (1–8), of which compounds 7 and 8 were new compounds named koreanoside F and koreanoside G, respectively. All the compounds (1–8) showed a significant inhibition to bacterial NA with IC₅₀ values of 0.17–106.3 µM. In particular, the prenyl group on the flavonoids played a critical role in bacterial NA inhibition. Epimedokoreanin B (compound 1, IC₅₀ = 0.17 µM) with two prenyl groups on C8 and C5′ of luteolin was 500 times more effective than luteolin (IC₅₀ = 85.6 µM). A similar trend was observed on compound 2 (IC₅₀ = 0.68 µM) versus dihydrokaempferol (IC₅₀ = 500.4 µM) and compound 3 (IC₅₀ = 12.6 µM) versus apigenin (IC₅₀ = 107.5 µM). Kinetic parameters (K_m, V_max, and K_ik/K_iv) evaluated that all the compounds apart from compound 5 showed noncompetitive inhibition. Compound 5 was proven to be a mixed type inhibitor. In an enzyme binding affinity experiment using fluorescence, affinity constants (K_SV) were tightly related to inhibitory activities. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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10 pages, 1788 KiB

Open AccessArticle

Cloning, Characterization and Anion Inhibition Studies of a β-Carbonic Anhydrase from the Pathogenic Protozoan Entamoeba histolytica

by Susanna Haapanen, Silvia Bua, Marianne Kuuslahti, Seppo Parkkila and Claudiu T. Supuran

Molecules 2018, 23(12), 3112; https://doi.org/10.3390/molecules23123112 - 28 Nov 2018

Cited by 9 | Viewed by 2449

Abstract

We report the cloning and catalytic activity of a β-carbonic anhydrase (CA, EC 4.2.1.1), isolated from the pathogenic protozoan Entamoeba histolytica, EhiCA. This enzyme has a high catalytic activity for the physiologic CO₂ hydration reaction, with a k_cat of 6.7 [...] Read more.

We report the cloning and catalytic activity of a β-carbonic anhydrase (CA, EC 4.2.1.1), isolated from the pathogenic protozoan Entamoeba histolytica, EhiCA. This enzyme has a high catalytic activity for the physiologic CO₂ hydration reaction, with a k_cat of 6.7 × 10⁵ s⁻¹ and a k_cat/K_m of 8.9 × 10⁷ M⁻¹ × s⁻¹. An anion inhibition study of EhiCA with inorganic/organic anions and small molecules revealed that fluoride, chloride, cyanide, azide, pyrodiphosphate, perchlorate, tetrafluoroborate and sulfamic acid did not inhibit the enzyme activity, whereas pseudohalides (cyanate and thiocyanate), bicarbonate, nitrate, nitrite, diethyldithiocarbamate, and many complex inorganic anions showed inhibition in the millimolar range (K_Is of 0.51–8.4 mM). The best EhiCA inhibitors were fluorosulfonate, sulfamide, phenylboronic acid and phenylarsonic acid (K_Is in the range of 28–86 μM). Since β-CAs are not present in vertebrates, the present study may be useful for detecting lead compounds for the design of effective enzyme inhibitors, with potential to develop anti-infectives with alternative mechanisms of action. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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15 pages, 4741 KiB

Open AccessArticle

Screening of Angiotensin-I Converting Enzyme Inhibitory Peptides Derived from Caulerpa lentillifera

by Cesarea Hulda Joel, Christoper C. Y. Sutopo, Arief Prajitno, Jui-Hsin Su and Jue-Liang Hsu

Molecules 2018, 23(11), 3005; https://doi.org/10.3390/molecules23113005 - 16 Nov 2018

Cited by 30 | Viewed by 5366

Abstract

Peptides with angiotensin-I converting enzyme (ACE) inhibitory activity have received considerable interest due to their potential as antihypertensive agents and consumer concern over the safety of synthetic drugs. The objective of this study was to isolate ACE inhibitory (ACEI) peptides from Caulerpa lentillifera [...] Read more.

Peptides with angiotensin-I converting enzyme (ACE) inhibitory activity have received considerable interest due to their potential as antihypertensive agents and consumer concern over the safety of synthetic drugs. The objective of this study was to isolate ACE inhibitory (ACEI) peptides from Caulerpa lentillifera (known commonly as sea grape) protein hydrolysate. In this study, short-chain peptides were obtained after hydrolysis by various enzymes and subsequently by ultrafiltration. Thermolysin hydrolysate showed the highest ACEI activity. Bioassay-guided fractionation was performed using reversed-phase high performance liquid chromatography (RP-HPLC) to uncover the fraction 9 with the highest ACE inhibitory activity from thermolysin hydrolysate. Peptides in this fraction were further identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis coupled with de novo sequencing, which gave two oligopeptides, FDGIP (FP-5) and AIDPVRA (AA-7). The identities and activities of these two peptides were further confirmed using synthetic peptides. Their IC₅₀ values were determined as 58.89 ± 0.68 µM and 65.76 ± 0.92 µM, respectively. Moreover, the inhibition kinetics revealed that both FP-5 and AA-7 are competitive inhibitors. These activities were further explained using molecular docking simulation. The present study is the first report about ACEI peptides derived from Caulerpa lentillifera and it shows the potential for preventing hypertension and for functional food development. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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17 pages, 3033 KiB

Open AccessArticle

Optimization of Aminoimidazole Derivatives as Src Family Kinase Inhibitors

by Cinzia Maria Francini, Francesca Musumeci, Anna Lucia Fallacara, Lorenzo Botta, Alessio Molinari, Roberto Artusi, Laura Mennuni, Adriano Angelucci and Silvia Schenone

Molecules 2018, 23(9), 2369; https://doi.org/10.3390/molecules23092369 - 17 Sep 2018

Cited by 6 | Viewed by 3398

Abstract

Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. [...] Read more.

Protein kinases have emerged as crucial targets for cancer therapy over the last decades. Since 2001, 40 and 39 kinase inhibitors have been approved by FDA and EMA, respectively, and the majority are antineoplastic drugs. Morevoer, many candidates are currently in clinical trials. We previously reported a small library of 4-aminoimidazole and 2-aminothiazole derivatives active as Src family kinase (SFK) inhibitors. Starting from these results, we decided to perform an optimization study applying a mix and match strategy to identify a more potent generation of 4-aminoimidazoles. Firstly, a computational study has been performed, then compounds showing the best predicted docking scores were synthesized and screened in a cell-free assay for their SFK inhibitory activity. All the new chemical entities showed IC₅₀s in the nanomolar range, with 2–130 fold increased activities compared to the previously reported inhibitors. Finally, the most active compounds have been tested on three cancer cell lines characterized by Src hyperactivation. Compounds 4k and 4l showed an interesting antiproliferative activity on SH-SY5Y neuroblastoma (NB) cell line. In this assay, the compounds resulted more potent than dasatinib, a tyrosine kinase inhibitor approved for the treatment of leukemias and in clinical trials for NB. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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Review

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20 pages, 2676 KiB

Open AccessReview

Pharmacological Inhibition of LSD1 for Cancer Treatment

by Guan-Jun Yang, Pui-Man Lei, Suk-Yu Wong, Dik-Lung Ma and Chung-Hang Leung

Molecules 2018, 23(12), 3194; https://doi.org/10.3390/molecules23123194 - 04 Dec 2018

Cited by 96 | Viewed by 8211

Abstract

Lysine-specific demethylase 1A (LSD1, also named KDM1A) is a demethylase that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is [...] Read more.

Lysine-specific demethylase 1A (LSD1, also named KDM1A) is a demethylase that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is aberrantly expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. Pharmacological inhibition of LSD1 has been reported to significantly attenuate tumor progression in vitro and in vivo in a range of solid tumors and acute myeloid leukemia. This review will present the structural aspects of LSD1, its role in carcinogenesis, a comparison of currently available approaches for screening LSD1 inhibitors, a classification of LSD1 inhibitors, and its potential as a drug target in cancer therapy. Full article

(This article belongs to the Special Issue Trends in the Development of Enzyme Inhibitors)

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