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12 pages, 3613 KiB

Open AccessArticle

Exploring Novel Pyridine Carboxamide Derivatives as Urease Inhibitors: Synthesis, Molecular Docking, Kinetic Studies and ADME Profile

by Ayesha Naseer, Faisal Abdulrhman Osra, Asia Naz Awan, Aqeel Imran, Abdul Hameed, Syed Adnan Ali Shah, Jamshed Iqbal and Zainul Amiruddin Zakaria

Pharmaceuticals 2022, 15(10), 1288; https://doi.org/10.3390/ph15101288 - 19 Oct 2022

Cited by 7 | Viewed by 3208

Abstract

The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide [...] Read more.

The rapid development of resistance by ureolytic bacteria which are involved in various life-threatening conditions such as gastric and duodenal cancer has induced the need to develop a new line of therapy which has anti-urease activity. A series of pyridine carboxamide and carbothioamide derivatives which also have some novel structures were synthesized via condensation reaction and investigated against urease for their inhibitory action. Among the series, 5-chloropyridine-2 yl-methylene hydrazine carbothioamide (Rx-6) and pyridine 2-yl-methylene hydrazine carboxamide (Rx-7) IC50 = 1.07 ± 0.043 µM, 2.18 ± 0.058 µM both possessed significant activity. Furthermore, molecular docking and kinetic studies were performed for the most potent inhibitors to demonstrate the binding mode of the active pyridine carbothioamide with the enzyme urease and its mode of interaction. The ADME profile also showed that all the synthesized molecules present oral bioavailability and high GI absorption. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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20 pages, 4010 KiB

Open AccessArticle

Rational Design and Synthesis of New Selective COX-2 Inhibitors with In Vivo PGE2-Lowering Activity by Tethering Benzenesulfonamide and 1,2,3-Triazole Pharmacophores to Some NSAIDs

by Nada H. El-Dershaby, Soad A. El-Hawash, Shaymaa E. Kassab, Hoda G. Daabees, Ahmed E. Abdel Moneim and Mostafa M. M. El-Miligy

Pharmaceuticals 2022, 15(10), 1165; https://doi.org/10.3390/ph15101165 - 20 Sep 2022

Cited by 3 | Viewed by 2157

Abstract

New selective COX-2 inhibitors were designed and synthesized by tethering 1,2,3-triazole and benzenesulfonamide pharmacophores to some NSAIDs. Compounds 6b and 6j showed higher in vitro COX-2 selectivity and inhibitory activity (IC₅₀ = 0.04 µM and S.I. = 329 and 312, respectively) than [...] Read more.

New selective COX-2 inhibitors were designed and synthesized by tethering 1,2,3-triazole and benzenesulfonamide pharmacophores to some NSAIDs. Compounds 6b and 6j showed higher in vitro COX-2 selectivity and inhibitory activity (IC₅₀ = 0.04 µM and S.I. = 329 and 312, respectively) than celecoxib (IC₅₀ = 0.05 µM and S.I. = 294). Compound 6e revealed equipotent in vitro COX-2 inhibitory activity to celecoxib. Furthermore, 6b and 6j expressed more potent relief of carrageenan-induced paw edema thickness in mice than celecoxib, with ED₅₀ values of 11.74 µmol/kg and 13.38 µmol/kg vs. 16.24 µmol/kg, respectively. Compounds 6b and 6j inhibited the production of PGE2 with a % inhibition of PGE2 production of 90.70% and 86.34%, respectively, exceeding celecoxib’s percentage (78.62%). Moreover, 6b and 6j demonstrated a gastric safety profile comparable to celecoxib. In conclusion, compounds 6b and 6j better achieved the target goal as more potent and selective COX-2 inhibitors than celecoxib in vitro and in vivo. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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17 pages, 3354 KiB

Open AccessArticle

Identification of a Dual Inhibitor of Secreted Phospholipase A₂ (GIIA sPLA₂) and SARS-CoV-2 Main Protease

by Maria A. Theodoropoulou, Giorgos S. Koutoulogenis, Linlin Zhang, Ifigeneia Akrani, Emmanuel Mikros, Rolf Hilgenfeld and George Kokotos

Pharmaceuticals 2022, 15(8), 961; https://doi.org/10.3390/ph15080961 - 3 Aug 2022

Cited by 5 | Viewed by 2194

Abstract

The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (M^pro) is a highly attractive target for the development of novel antivirals and a variety of inhibitors have already been developed. Accumulating evidence on the pathobiology [...] Read more.

The development of novel agents to combat COVID-19 is of high importance. SARS-CoV-2 main protease (M^pro) is a highly attractive target for the development of novel antivirals and a variety of inhibitors have already been developed. Accumulating evidence on the pathobiology of COVID-19 has shown that lipids and lipid metabolizing enzymes are critically involved in the severity of the infection. The purpose of the present study was to identify an inhibitor able to simultaneously inhibit both SARS-CoV-2 M^pro and phospholipase A₂ (PLA₂), an enzyme which plays a significant role in inflammatory diseases. Evaluating several PLA₂ inhibitors, we demonstrate that the previously known potent inhibitor of Group IIA secretory PLA₂, GK241, may also weakly inhibit SARS-CoV-2 M^pro. Molecular mechanics docking and molecular dynamics calculations shed light on the interactions between GK241 and SARS-CoV-2 M^pro. 2-Oxoamide GK241 may represent a lead molecular structure for the development of dual PLA₂ and SARS-CoV-2 M^pro inhibitors. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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34 pages, 19728 KiB

Open AccessArticle

Design, Synthesis, and Development of pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part I—Indole Derivatives

by Mariola Stypik, Marcin Zagozda, Stanisław Michałek, Barbara Dymek, Daria Zdżalik-Bielecka, Maciej Dziachan, Nina Orłowska, Paweł Gunerka, Paweł Turowski, Joanna Hucz-Kalitowska, Aleksandra Stańczak, Paulina Stańczak, Krzysztof Mulewski, Damian Smuga, Filip Stefaniak, Lidia Gurba-Bryśkiewicz, Arkadiusz Leniak, Zbigniew Ochal, Mateusz Mach, Karolina Dzwonek, Monika Lamparska-Przybysz, Krzysztof Dubiel and Maciej Wieczorek Show full author list Hide full author list

Pharmaceuticals 2022, 15(8), 949; https://doi.org/10.3390/ph15080949 - 30 Jul 2022

Cited by 2 | Viewed by 2680

Abstract

Phosphoinositide 3-kinase δ (PI3Kδ), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for [...] Read more.

Phosphoinositide 3-kinase δ (PI3Kδ), a member of the class I PI3K family, is an essential signaling biomolecule that regulates the differentiation, proliferation, migration, and survival of immune cells. The overactivity of this protein causes cellular dysfunctions in many human disorders, for example, inflammatory and autoimmune diseases, including asthma or chronic obstructive pulmonary disease (COPD). In this work, we designed and synthesized a new library of small-molecule inhibitors based on indol-4-yl-pyrazolo[1,5-a]pyrimidine with IC₅₀ values in the low nanomolar range and high selectivity against the PI3Kδ isoform. CPL302253 (54), the most potent compound of all the structures obtained, with IC₅₀ = 2.8 nM, is a potential future candidate for clinical development as an inhaled drug to prevent asthma. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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35 pages, 15684 KiB

Open AccessArticle

Design, Synthesis, and Development of Pyrazolo[1,5-a]pyrimidine Derivatives as a Novel Series of Selective PI3Kδ Inhibitors: Part II—Benzimidazole Derivatives

by Mariola Stypik, Stanisław Michałek, Nina Orłowska, Marcin Zagozda, Maciej Dziachan, Martyna Banach, Paweł Turowski, Paweł Gunerka, Daria Zdżalik-Bielecka, Aleksandra Stańczak, Urszula Kędzierska, Krzysztof Mulewski, Damian Smuga, Wioleta Maruszak, Lidia Gurba-Bryśkiewicz, Arkadiusz Leniak, Wojciech Pietruś, Zbigniew Ochal, Mateusz Mach, Beata Zygmunt, Jerzy Pieczykolan, Krzysztof Dubiel and Maciej Wieczorek Show full author list Hide full author list

Pharmaceuticals 2022, 15(8), 927; https://doi.org/10.3390/ph15080927 - 27 Jul 2022

Cited by 7 | Viewed by 2433

Abstract

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, [...] Read more.

Phosphoinositide 3-kinase (PI3K) is the family of lipid kinases participating in vital cellular processes such as cell proliferation, growth, migration, or cytokines production. Due to the high expression of these proteins in many human cells and their involvement in metabolism regulation, normal embryogenesis, or maintaining glucose homeostasis, the inhibition of PI3K (especially the first class which contains four subunits: α, β, γ, δ) is considered to be a promising therapeutic strategy for the treatment of inflammatory and autoimmune diseases such as systemic lupus erythematosus (SLE) or multiple sclerosis. In this work, we synthesized a library of benzimidazole derivatives of pyrazolo[1,5-a]pyrimidine representing a collection of new, potent, active, and selective inhibitors of PI3Kδ, displaying IC₅₀ values ranging from 1.892 to 0.018 μM. Among all compounds obtained, CPL302415 (6) showed the highest activity (IC₅₀ value of 18 nM for PI3Kδ), good selectivity (for PI3Kδ relative to other PI3K isoforms: PI3Kα/δ = 79; PI3Kβ/δ = 1415; PI3Kγ/δ = 939), and promising physicochemical properties. As a lead compound synthesized on a relatively large scale, this structure is considered a potential future candidate for clinical trials in SLE treatment. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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30 pages, 4152 KiB

Open AccessArticle

Design and Synthesis of New Pyrimidine-Quinolone Hybrids as Novel hLDHA Inhibitors

by Iván Díaz, Sofia Salido, Manuel Nogueras and Justo Cobo

Pharmaceuticals 2022, 15(7), 792; https://doi.org/10.3390/ph15070792 - 24 Jun 2022

Cited by 6 | Viewed by 2732

Abstract

A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (hLDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (10-21 and 24–31) were studied in silico, [...] Read more.

A battery of novel pyrimidine-quinolone hybrids was designed by docking scaffold replacement as lactate dehydrogenase A (hLDHA) inhibitors. Structures with different linkers between the pyrimidine and quinolone scaffolds (10-21 and 24–31) were studied in silico, and those with the 2-aminophenylsulfide (U-shaped) and 4-aminophenylsulfide linkers (24–31) were finally selected. These new pyrimidine-quinolone hybrids (24–31)(a–c) were easily synthesized in good to excellent yields by a green catalyst-free microwave-assisted aromatic nucleophilic substitution reaction between 3-(((2/4-aminophenyl)thio)methyl)quinolin-2(1H)-ones 22/23(a–c) and 4-aryl-2-chloropyrimidines (1–4). The inhibitory activity against hLDHA of the synthesized hybrids was evaluated, resulting IC₅₀ values of the U-shaped hybrids 24–27(a–c) much better than the ones of the 1,4-linked hybrids 28–31(a–c). From these results, a preliminary structure–activity relationship (SAR) was established, which enabled the design of novel 1,3-linked pyrimidine-quinolone hybrids (33–36)(a–c). Compounds 35(a–c), the most promising ones, were synthesized and evaluated, fitting the experimental results with the predictions from docking analysis. In this way, we obtained novel pyrimidine-quinolone hybrids (25a, 25b, and 35a) with good IC₅₀ values (<20 μM) and developed a preliminary SAR. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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27 pages, 3625 KiB

Open AccessArticle

Substrate-Based Design of Cytosolic Nucleotidase IIIB Inhibitors and Structural Insights into Inhibition Mechanism

by Dorota Kubacka, Mateusz Kozarski, Marek R. Baranowski, Radoslaw Wojcik, Joanna Panecka-Hofman, Dominika Strzelecka, Jerome Basquin, Jacek Jemielity and Joanna Kowalska

Pharmaceuticals 2022, 15(5), 554; https://doi.org/10.3390/ph15050554 - 29 Apr 2022

Cited by 1 | Viewed by 2511

Abstract

Cytosolic nucleotidases (cNs) catalyze dephosphorylation of nucleoside 5’-monophosphates and thereby contribute to the regulation of nucleotide levels in cells. cNs have also been shown to dephosphorylate several therapeutically relevant nucleotide analogues. cN-IIIB has shown in vitro a distinctive activity towards 7-mehtylguanosine monophosphate (m [...] Read more.

Cytosolic nucleotidases (cNs) catalyze dephosphorylation of nucleoside 5’-monophosphates and thereby contribute to the regulation of nucleotide levels in cells. cNs have also been shown to dephosphorylate several therapeutically relevant nucleotide analogues. cN-IIIB has shown in vitro a distinctive activity towards 7-mehtylguanosine monophosphate (m⁷GMP), which is one key metabolites of mRNA cap. Consequently, it has been proposed that cN-IIIB participates in mRNA cap turnover and prevents undesired accumulation and salvage of m⁷GMP. Here, we sought to develop molecular tools enabling more advanced studies on the cellular role of cN-IIIB. To that end, we performed substrate and inhibitor property profiling using a library of 41 substrate analogs. The most potent hit compounds (identified among m⁷GMP analogs) were used as a starting point for structure–activity relationship studies. As a result, we identified several 7-benzylguanosine 5’-monophosphate (Bn⁷GMP) derivatives as potent, unhydrolyzable cN-IIIB inhibitors. The mechanism of inhibition was elucidated using X-ray crystallography and molecular docking. Finally, we showed that compounds that potently inhibit recombinant cN-IIIB have the ability to inhibit m⁷GMP decay in cell lysates. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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21 pages, 5339 KiB

Open AccessArticle

Covalent Inhibition of the Human 20S Proteasome with Homobelactosin C Inquired by QM/MM Studies

by Natalia Serrano-Aparicio, Silvia Ferrer and Katarzyna Świderek

Pharmaceuticals 2022, 15(5), 531; https://doi.org/10.3390/ph15050531 - 25 Apr 2022

Cited by 4 | Viewed by 2891

Abstract

20S proteasome is a main player in the protein degradation pathway in the cytosol, thus intervening in multiple pivotal cellular processes. Over the years the proteasome has emerged as a crucial target for the treatment of many diseases such as neurodegenerative diseases, cancer, [...] Read more.

20S proteasome is a main player in the protein degradation pathway in the cytosol, thus intervening in multiple pivotal cellular processes. Over the years the proteasome has emerged as a crucial target for the treatment of many diseases such as neurodegenerative diseases, cancer, autoimmune diseases, developmental disorders, cystic fibrosis, diabetes, cardiac diseases, atherosclerosis, and aging. In this work, the mechanism of proteasome covalent inhibition with bisbenzyl-protected homobelactosin C (hBelC) was explored using quantum mechanics/molecular mechanics (QM/MM) methods. Molecular dynamic simulations were used to describe key interactions established between the hBelC and its unique binding mode in the primed site of the β5 subunit. The free energy surfaces were computed to characterize the kinetics and thermodynamics of the inhibition process. This study revealed that although the final inhibition product for hBelC is formed according to the same molecular mechanism as one described for hSalA, the free energy profile of the reaction pathway differs significantly from the one previously reported for γ-lactam-β-lactone containing inhibitors in terms of the height of the activation barrier as well as the stabilization of the final product. Moreover, it was proved that high stabilization of the covalent adduct formed between β5-subunit and hBelC, together with the presence of aminocarbonyl side chain in the structure of the inhibitor which prevents the hydrolysis of the ester bond from taking place, determines its irreversible character. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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20 pages, 2911 KiB

Open AccessArticle

Uracil as a Zn-Binding Bioisostere of the Allergic Benzenesulfonamide in the Design of Quinoline–Uracil Hybrids as Anticancer Carbonic Anhydrase Inhibitors

by Samar A. El-Kalyoubi, Ehab S. Taher, Tarek S. Ibrahim, Mohammed Farrag El-Behairy and Amany M. M. Al-Mahmoudy

Pharmaceuticals 2022, 15(5), 494; https://doi.org/10.3390/ph15050494 - 19 Apr 2022

Cited by 11 | Viewed by 2496

Abstract

A series of quinoline–uracil hybrids (10a–l) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds 10a–l demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound 10h displayed the best selectivity [...] Read more.

A series of quinoline–uracil hybrids (10a–l) has been rationalized and synthesized. The inhibitory activity against hCA isoforms I, II, IX, and XII was explored. Compounds 10a–l demonstrated powerful inhibitory activity against all tested hCA isoforms. Compound 10h displayed the best selectivity profile with good activity. Compound 10d displayed the best activity profile with minimal selectivity. Compound 10l emerged as the best congener considering both activity (IC₅₀ = 140 and 190 nM for hCA IX and hCA XII, respectively) and selectivity (S.I. = 13.20 and 9.75 for II/IX, and II/XII, respectively). The most active hybrids were assayed for antiproliferative and pro-apoptotic activities against MCF-7 and A549. In silico studies, molecular docking, physicochemical parameters, and ADMET analysis were performed to explain the acquired CA inhibitory action of all hybrids. A study of the structure–activity relationship revealed that bulky substituents at uracil N-1 were unfavored for activity while substituted quinoline and thiouracil were effective for selectivity. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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23 pages, 9486 KiB

Open AccessArticle

Pyrazolo[4,3-c]pyridine Sulfonamides as Carbonic Anhydrase Inhibitors: Synthesis, Biological and In Silico Studies

by Andrea Angeli, Victor Kartsev, Anthi Petrou, Boris Lichitsky, Andrey Komogortsev, Mariana Pinteala, Athina Geronikaki and Claudiu T. Supuran

Pharmaceuticals 2022, 15(3), 316; https://doi.org/10.3390/ph15030316 - 7 Mar 2022

Cited by 15 | Viewed by 3236

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO₂ hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On [...] Read more.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO₂ hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On the other hand, in microorganisms, the β- and γ- classes are expressed in addition to the α- class, showing substantial structural differences to the human isoforms. In this scenario, not only human but also bacterial CAs are of particular interest as new antibacterial agents with an alternative mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Pyrazolo[4,3-c]pyridine sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX and XII, and β- and γ-CAs from three different bacterial strains, was evaluated by a stopped-flow CO₂ hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the 3β- and 3γ-CAs. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX. Four compounds (1f, 1g, 1h and 1k) were more potent than AAZ against hCA I. Furthermore, compound 1f also showed better activity than AAZ against the hCA II isoform. Moreover, ten compounds out of eleven appeared to be very potent against the γ-CA from E.coli, with a Ki much lower than that of the reference drug. Most of the compounds showed better activity than AAZ against hCA I as well as the γ-CA from E.coli and the β-CA from Burkholderia pseudomallei (BpsCAβ). Compounds 1f and 1k showed a good selectivity index against hCA I and hCA XII, while 1b was selective against all 3β-CA isoforms from E.coli, BpsCA, and VhCA and all 3γ-CA isoforms from E.coli, BpsCA and PgiCA. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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17 pages, 23130 KiB

Open AccessArticle

Discovery of Kinase and Carbonic Anhydrase Dual Inhibitors by Machine Learning Classification and Experiments

by Min-Jeong Kim, Sarita Pandit and Jun-Goo Jee

Pharmaceuticals 2022, 15(2), 236; https://doi.org/10.3390/ph15020236 - 16 Feb 2022

Viewed by 2493

Abstract

A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine [...] Read more.

A multi-target small molecule modulator is advantageous for treating complicated diseases such as cancers. However, the strategy and application for discovering a multi-target modulator have been less reported. This study presents the dual inhibitors for kinase and carbonic anhydrase (CA) predicted by machine learning (ML) classifiers, and validated by biochemical and biophysical experiments. ML trained by CA I and CA II inhibitor molecular fingerprints predicted candidates from the protein-specific bioactive molecules approved or under clinical trials. For experimental tests, three sulfonamide-containing kinase inhibitors, 5932, 5946, and 6046, were chosen. The enzyme assays with CA I, CA II, CA IX, and CA XII have allowed the quantitative comparison in the molecules’ inhibitory activities. While 6046 inhibited weakly, 5932 and 5946 exhibited potent inhibitions with 100 nM to 1 μM inhibitory constants. The ML screening was extended for finding CAs inhibitors of all known kinase inhibitors. It found XMU-MP-1 as another potent CA inhibitor with an approximate 30 nM inhibitory constant for CA I, CA II, and CA IX. Differential scanning fluorimetry confirmed the direct interaction between CAs and small molecules. Cheminformatics studies, including docking simulation, suggest that each molecule possesses two separate functional moieties: one for interaction with kinases and the other with CAs. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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17 pages, 3685 KiB

Open AccessArticle

Increasing Inhibition of the Rat Brain 2-Oxoglutarate Dehydrogenase Decreases Glutathione Redox State, Elevating Anxiety and Perturbing Stress Adaptation

by Artem V. Artiukhov, Anastasia V. Graf, Alexey V. Kazantsev, Alexandra I. Boyko, Vasily A. Aleshin, Alexander L. Ksenofontov and Victoria I. Bunik

Pharmaceuticals 2022, 15(2), 182; https://doi.org/10.3390/ph15020182 - 31 Jan 2022

Cited by 7 | Viewed by 3482

Abstract

Specific inhibitors of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) are administered to animals to model the downregulation of the enzyme as observed in neurodegenerative diseases. Comparison of the effects of succinyl phosphonate (SP, 0.02 mmol/kg) and its uncharged precursor, triethyl succinyl phosphonate (TESP, 0.02 and [...] Read more.

Specific inhibitors of mitochondrial 2-oxoglutarate dehydrogenase (OGDH) are administered to animals to model the downregulation of the enzyme as observed in neurodegenerative diseases. Comparison of the effects of succinyl phosphonate (SP, 0.02 mmol/kg) and its uncharged precursor, triethyl succinyl phosphonate (TESP, 0.02 and 0.1 mmol/kg) reveals a biphasic response of the rat brain metabolism and physiology to increasing perturbation of OGDH function. At the low (TE)SP dose, glutamate, NAD⁺, and the activities of dehydrogenases of 2-oxoglutarate and malate increase, followed by their decreases at the high TESP dose. The complementary changes, i.e., an initial decrease followed by growth, are demonstrated by activities of pyruvate dehydrogenase and glutamine synthetase, and levels of oxidized glutathione and citrulline. While most of these indicators return to control levels at the high TESP dose, OGDH activity decreases and oxidized glutathione increases, compared to their control values. The first phase of metabolic perturbations does not cause significant physiological changes, but in the second phase, the ECG parameters and behavior reveal decreased adaptability and increased anxiety. Thus, lower levels of OGDH inhibition are compensated by the rearranged metabolic network, while the increased levels induce a metabolic switch to a lower redox state of the brain, associated with elevated stress of the animals. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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17 pages, 2455 KiB

Open AccessArticle

In-Silico Screening of Novel Synthesized Thienopyrimidines Targeting Fms Related Receptor Tyrosine Kinase-3 and Their In-Vitro Biological Evaluation

by Elshaymaa I. Elmongy, Najla Altwaijry, Nashwah G. M. Attallah, Manal Mubarak AlKahtani and Hanan Ali Henidi

Pharmaceuticals 2022, 15(2), 170; https://doi.org/10.3390/ph15020170 - 29 Jan 2022

Cited by 21 | Viewed by 3148

Abstract

The present investigation describes the design strategy and synthesis of novel thienopyrimidine compounds in addition to their anticancer activity targeting tyrosine kinase FLT3 enzyme. The synthesized compounds were subjected to a cytotoxic study where compounds 9a and 9b showed the most potent cytotoxicity [...] Read more.

The present investigation describes the design strategy and synthesis of novel thienopyrimidine compounds in addition to their anticancer activity targeting tyrosine kinase FLT3 enzyme. The synthesized compounds were subjected to a cytotoxic study where compounds 9a and 9b showed the most potent cytotoxicity against HT-29, HepG-2, and MCF-7 cell lines reflected by their IC₅₀ values for 9a (1.21 ± 0.34, 6.62 ± 0.7 and 7.2 ± 1.9 μM), for 9b (0.85 ± 0.16, 9.11 ± 0.3 and 16.26 ± 2.3 μM) and better than that of reference standard which recorded (1.4 ± 1.16, 13.915 ± 2.2, and 8.43 ± 0.5 μM), respectively. Compounds’ selectivity to malignant cells was determined using selectivity assay, interestingly, all the tested compounds demonstrated an excellent selectivity index (SI) range from 20.2 to 99.7. Target in-silico prediction revealed the FLT3 kinase enzyme was the kinase enzyme of highest probability. Molecular docking studies were performed on the prepared compounds which showed promising binding affinity for FLT3 kinase enzyme and the main interactions between the synthesized ligands and kinase active site were similar to those between the co-crystallized ligand and the receptor. Further biological exploration was performed using in-vitro FLT3 kinase enzyme inhibition assay. The results showed that the 2-morpholinoacetamido derivative 10a exhibited highest FLT3 inhibitory activity among the tested compounds followed by compound 9a then 12. Pharmacokinetic assessment disclosed that all the investigated compounds were considered as “drug-like” molecules with promising bioavailability. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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22 pages, 12635 KiB

Open AccessArticle

Exploring Toxins for Hunting SARS-CoV-2 Main Protease Inhibitors: Molecular Docking, Molecular Dynamics, Pharmacokinetic Properties, and Reactome Study

by Mahmoud A. A. Ibrahim, Alaa H. M. Abdelrahman, Laila A. Jaragh-Alhadad, Mohamed A. M. Atia, Othman R. Alzahrani, Muhammad Naeem Ahmed, Moustafa Sherief Moustafa, Mahmoud E. S. Soliman, Ahmed M. Shawky, Paul W. Paré, Mohamed-Elamir F. Hegazy and Peter A. Sidhom

Pharmaceuticals 2022, 15(2), 153; https://doi.org/10.3390/ph15020153 - 27 Jan 2022

Cited by 15 | Viewed by 4428

Abstract

The main protease (M^pro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for M^pro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards [...] Read more.

The main protease (M^pro) is a potential druggable target in SARS-CoV-2 replication. Herein, an in silico study was conducted to mine for M^pro inhibitors from toxin sources. A toxin and toxin-target database (T3DB) was virtually screened for inhibitor activity towards the M^pro enzyme utilizing molecular docking calculations. Promising toxins were subsequently characterized using a combination of molecular dynamics (MD) simulations and molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. According to the MM-GBSA binding energies over 200 ns MD simulations, three toxins—namely philanthotoxin (T3D2489), azaspiracid (T3D2672), and taziprinone (T3D2378)—demonstrated higher binding affinities against SARS-CoV-2 M^pro than the co-crystalized inhibitor XF7 with MM-GBSA binding energies of −58.9, −55.9, −50.1, and −43.7 kcal/mol, respectively. The molecular network analyses showed that philanthotoxin provides a ligand lead using the STRING database, which includes the biochemical top 20 signaling genes CTSB, CTSL, and CTSK. Ultimately, pathway enrichment analysis (PEA) and Reactome mining results revealed that philanthotoxin could prevent severe lung injury in COVID-19 patients through the remodeling of interleukins (IL-4 and IL-13) and the matrix metalloproteinases (MMPs). These findings have identified that philanthotoxin—a venom of the Egyptian solitary wasp—holds promise as a potential M^pro inhibitor and warrants further in vitro/in vivo validation. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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21 pages, 1889 KiB

Open AccessArticle

2-(Piperidin-4-yl)acetamides as Potent Inhibitors of Soluble Epoxide Hydrolase with Anti-Inflammatory Activity

by Juan Martín-López, Sandra Codony, Clara Bartra, Christophe Morisseau, María Isabel Loza, Coral Sanfeliu, Bruce D. Hammock, José Brea and Santiago Vázquez

Pharmaceuticals 2021, 14(12), 1323; https://doi.org/10.3390/ph14121323 - 17 Dec 2021

Cited by 2 | Viewed by 3285

Abstract

The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of endogenous epoxyeicosatrienoic acids. Numerous potent sEH inhibitors (sEHI) have been developed, however many contain highly lipophilic [...] Read more.

The pharmacological inhibition of soluble epoxide hydrolase (sEH) has been suggested as a potential therapy for the treatment of pain and inflammatory diseases through the stabilization of endogenous epoxyeicosatrienoic acids. Numerous potent sEH inhibitors (sEHI) have been developed, however many contain highly lipophilic substituents limiting their availability. Recently, a new series of benzohomoadamantane-based ureas endowed with potent inhibitory activity for the human and murine sEH was reported. However, their very low microsomal stability prevented further development. Herein, a new series of benzohomoadamantane-based amides were synthetized, fully characterized, and evaluated as sEHI. Most of these amides were endowed with excellent inhibitory potencies. A selected compound displayed anti-inflammatory effects with higher effectiveness than the reference sEHI, TPPU. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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18 pages, 3594 KiB

Open AccessArticle

Design and Synthesis of Highly Active Antimycobacterial Mutual Esters of 2-(2-Isonicotinoylhydrazineylidene)propanoic Acid

by Václav Pflégr, Jana Maixnerová, Jiřina Stolaříková, Adrián Pál, Jana Korduláková, František Trejtnar, Jarmila Vinšová and Martin Krátký

Pharmaceuticals 2021, 14(12), 1302; https://doi.org/10.3390/ph14121302 - 14 Dec 2021

Cited by 3 | Viewed by 2758

Abstract

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including [...] Read more.

The combination of two active scaffolds into one molecule represents a proven approach in drug design to overcome microbial drug resistance. We designed and synthesized more lipophilic esters of 2-(2-isonicotinoylhydrazineylidene)propanoic acid, obtained from antitubercular drug isoniazid, with various alcohols, phenols and thiols, including several drugs, using carbodiimide-mediated coupling. Nineteen new esters were evaluated as potential antimycobacterial agents against drug-sensitive Mycobacterium tuberculosis (Mtb.) H₃₇Rv, Mycobacterium avium and Mycobacterium kansasii. Selected derivatives were also tested for inhibition of multidrug-resistant (MDR) Mtb., and their mechanism of action was investigated. The esters exhibited high activity against Mtb. (minimum inhibitory concentrations, MIC, from ≤0.125 μM), M. kansasii, M. avium as well as MDR strains (MIC from 0.25, 32 and 8 µM, respectively). The most active mutual derivatives were derived from 4-chloro/phenoxy-phenols, triclosan, quinolin-8-ol, naphthols and terpene alcohols. The experiments identified enoyl-acyl carrier protein reductase (InhA), and thus mycobacterial cell wall biosynthesis, as the main target of the molecules that are activated by KatG, but for some compounds can also be expected adjunctive mechanism(s). Generally, the mutual esters have also avoided cytotoxicity and are promising hits for the discovery of antimycobacterial drugs with improved properties compared to parent isoniazid. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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15 pages, 2623 KiB

Open AccessEditor’s ChoiceArticle

Discovery of SARS-CoV-2 Nsp14 and Nsp16 Methyltransferase Inhibitors by High-Throughput Virtual Screening

by Raitis Bobrovs, Iveta Kanepe, Nauris Narvaiss, Liene Patetko, Gints Kalnins, Mihails Sisovs, Anna L. Bula, Solveiga Grinberga, Martins Boroduskis, Anna Ramata-Stunda, Nils Rostoks, Aigars Jirgensons, Kaspars Tars and Kristaps Jaudzems

Pharmaceuticals 2021, 14(12), 1243; https://doi.org/10.3390/ph14121243 - 30 Nov 2021

Cited by 26 | Viewed by 3916

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses mRNA capping to evade the human immune system. The cap formation is performed by the SARS-CoV-2 mRNA cap methyltransferases (MTases) nsp14 and nsp16, which are emerging targets for the development of broad-spectrum antiviral agents. Here, we report results from high-throughput virtual screening against these two enzymes. The docking of seven million commercially available drug-like compounds and S-adenosylmethionine (SAM) co-substrate analogues against both MTases resulted in 80 virtual screening hits (39 against nsp14 and 41 against nsp16), which were purchased and tested using an enzymatic homogeneous time-resolved fluorescent energy transfer (HTRF) assay. Nine compounds showed micromolar inhibition activity (IC₅₀ < 200 μM). The selectivity of the identified inhibitors was evaluated by cross-checking their activity against human glycine N-methyltransferase. The majority of the compounds showed poor selectivity for a specific MTase, no cytotoxic effects, and rather poor cell permeability. Nevertheless, the identified compounds represent good starting points that have the potential to be developed into efficient viral MTase inhibitors. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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11 pages, 2218 KiB

Open AccessCommunication

Investigation of Thiocarbamates as Potential Inhibitors of the SARS-CoV-2 Mpro

by Katarzyna Papaj, Patrycja Spychalska, Katarzyna Hopko, Patryk Kapica, Andre Fisher, Markus A. Lill, Weronika Bagrowska, Jakub Nowak, Katarzyna Szleper, Martin Smieško, Anna Kasprzycka and Artur Góra

Pharmaceuticals 2021, 14(11), 1153; https://doi.org/10.3390/ph14111153 - 12 Nov 2021

Cited by 2 | Viewed by 2996

Abstract

In the present study we tested, using the microscale thermophoresis technique, a small library of thionocarbamates, thiolocarbamates, sulfide and disulfide as potential lead compounds for SARS-CoV-2 Mpro drug design. The successfully identified binder is a representative of the thionocarbamates group with a high [...] Read more.

In the present study we tested, using the microscale thermophoresis technique, a small library of thionocarbamates, thiolocarbamates, sulfide and disulfide as potential lead compounds for SARS-CoV-2 Mpro drug design. The successfully identified binder is a representative of the thionocarbamates group with a high potential for future modifications aiming for higher affinity and solubility. The experimental analysis was extended by computational studies that show insufficient accuracy of the simplest and widely applied approaches and underline the necessity of applying more advanced methods to properly evaluate the affinity of potential SARS-CoV-2 Mpro binders. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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29 pages, 6150 KiB

Open AccessArticle

4-(Indol-3-yl)thiazole-2-amines and 4-ιndol-3-yl)thiazole Acylamines as Νovel Antimicrobial Agents: Synthesis, In Silico and In Vitro Evaluation

by Sergei Simakov, Victor Kartsev, Anthi Petrou, Ioannis Nicolaou, Athina Geronikaki, Marija Ivanov, Marina Kostic, Jasmina Glamočlija, Marina Soković, Despoina Talea and Ioannis S. Vizirianakis

Pharmaceuticals 2021, 14(11), 1096; https://doi.org/10.3390/ph14111096 - 28 Oct 2021

Cited by 10 | Viewed by 2855

Abstract

This manuscript deals with the synthesis and computational and experimental evaluation of the antimicrobial activity of twenty-nine 4-(indol-3-yl)thiazole-2-amines and 4-ιndol-3-yl)thiazole acylamines. An evaluation of antibacterial activity against Gram (+) and Gram (−) bacteria revealed that the MIC of indole derivatives is in the [...] Read more.

This manuscript deals with the synthesis and computational and experimental evaluation of the antimicrobial activity of twenty-nine 4-(indol-3-yl)thiazole-2-amines and 4-ιndol-3-yl)thiazole acylamines. An evaluation of antibacterial activity against Gram (+) and Gram (−) bacteria revealed that the MIC of indole derivatives is in the range of 0.06–1.88 mg/mL, while among fourteen methylindole derivatives, only six were active, with an MIC in the range of of 0.47–1.88 mg/mL. S. aureus appeared to be the most resistant strain, while S. Typhimurium was the most sensitive. Compound 5x was the most promising, with an MIC in the range of 0.06–0.12 mg/mL, followed by 5d and 5m. An evaluation of these three compounds against resistant strains, namely MRSA P. aeruginosa and E. coli, revealed that they were more potent against MRSA than ampicillin. Furthermore, compounds 5m and 5x were superior inhibitors of biofilm formation, compared to ampicillin and streptomycin, in terms Compounds 5d, 5m, and 5x interact with streptomycin in additive manner. The antifungal activity of some compounds exceeded or was equipotent to those of the reference antifungal agents bifonazole and ketoconazole. The most potent antifungal agent was found to be compound 5g. Drug likeness scores of compounds was in a range of −0.63 to 0.29, which is moderate to good. According to docking studies, E. coli MurB inhibition is probably responsible for the antibacterial activity of compounds, whereas CYP51 inhibition was implicated in antifungal activity. Compounds appeared to be non-toxic, according to the cytotoxicity assessment in MRC-5 cells. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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Review

Jump to: Research, Other

22 pages, 5695 KiB

Open AccessReview

Computational Methods in Cooperation with Experimental Approaches to Design Protein Tyrosine Phosphatase 1B Inhibitors in Type 2 Diabetes Drug Design: A Review of the Achievements of This Century

by Mara Ibeth Campos-Almazán, Alicia Hernández-Campos, Rafael Castillo, Erick Sierra-Campos, Mónica Valdez-Solana, Claudia Avitia-Domínguez and Alfredo Téllez-Valencia

Pharmaceuticals 2022, 15(7), 866; https://doi.org/10.3390/ph15070866 - 14 Jul 2022

Cited by 17 | Viewed by 2971

Abstract

Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates phosphotyrosine residues and is an important regulator of several signaling pathways, such as insulin, leptin, and the ErbB signaling network, among others. Therefore, this enzyme is considered an attractive target to design new drugs against type 2 [...] Read more.

Protein tyrosine phosphatase 1B (PTP1B) dephosphorylates phosphotyrosine residues and is an important regulator of several signaling pathways, such as insulin, leptin, and the ErbB signaling network, among others. Therefore, this enzyme is considered an attractive target to design new drugs against type 2 diabetes, obesity, and cancer. To date, a wide variety of PTP1B inhibitors that have been developed by experimental and computational approaches. In this review, we summarize the achievements with respect to PTP1B inhibitors discovered by applying computer-assisted drug design methodologies (virtual screening, molecular docking, pharmacophore modeling, and quantitative structure–activity relationships (QSAR)) as the principal strategy, in cooperation with experimental approaches, covering articles published from the beginning of the century until the time this review was submitted, with a focus on studies conducted with the aim of discovering new drugs against type 2 diabetes. This review encourages the use of computational techniques and includes helpful information that increases the knowledge generated to date about PTP1B inhibition, with a positive impact on the route toward obtaining a new drug against type 2 diabetes with PTP1B as a molecular target. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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55 pages, 12417 KiB

Open AccessReview

β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

by Silvana Alfei and Anna Maria Schito

Pharmaceuticals 2022, 15(4), 476; https://doi.org/10.3390/ph15040476 - 13 Apr 2022

Cited by 31 | Viewed by 9869

Abstract

β-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing β-lactamase enzymes (BLEs), is becoming one of the major warnings to the global public health. Since only a small number of novel [...] Read more.

β-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing β-lactamase enzymes (BLEs), is becoming one of the major warnings to the global public health. Since only a small number of novel antibiotics are in development, a current clinical approach to limit this phenomenon consists of administering proper combinations of β-lactam antibiotics (BLAs) and β-lactamase inhibitors (BLEsIs). Unfortunately, while few clinically approved BLEsIs are capable of inhibiting most class-A and -C serine β-lactamases (SBLEs) and some carbapenemases of class D, they are unable to inhibit most part of the carbapenem hydrolyzing enzymes of class D and the worrying metallo-β-lactamases (MBLEs) of class B. Particularly, MBLEs are a set of enzymes that catalyzes the hydrolysis of a broad range of BLAs by a zinc-mediated mechanism, and currently no clinically available molecule capable of inhibiting MBLEs exists. Additionally, new types of alarming “superbugs”, were found to produce the New Delhi metallo-β-lactamases (NDMs) encoded by increasing variants of a plasmid-mediated gene capable of rapidly spreading among bacteria of the same species and even among different species. Particularly, NDM-1 possesses a flexible hydrolysis mechanism that inactivates all BLAs, except for aztreonam. The present review provides first an overview of existing BLAs and the most clinically relevant BLEs detected so far. Then, the BLEsIs and their most common associations with BLAs already clinically applied and those still in development are reviewed. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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50 pages, 9734 KiB

Open AccessReview

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

by Silvana Alfei and Guendalina Zuccari

Pharmaceuticals 2022, 15(3), 384; https://doi.org/10.3390/ph15030384 - 21 Mar 2022

Cited by 16 | Viewed by 5743 | Correction

Abstract

The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of [...] Read more.

The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of class A, C, and D, and metal-BLEs (MBLEs) of class B. A current strategy to restore no longer functioning BLAs consists of associating them to β-lactamase enzymes inhibitors (BLEsIs), which, interacting with BLEs, prevent them hydrolyzing to the associated antibiotic. Worryingly, the inhibitors that are clinically approved are very few and inhibit only most of class A and C SBLEs, leaving several class D and all MBLEs of class B untouched. Numerous non-clinically approved new molecules are in development, which have shown broad and ultra-broad spectrum of action, some of them also being active on the New Delhi metal-β-lactamase-1 (NDM-1), which can hydrolyze all available BLAs except for aztreonam. To not duplicate the existing review concerning this topic, we have herein examined BLEsIs by a chemistry approach. To this end, we have reviewed both the long-established synthesis adopted to prepare the old BLEsIs, those proposed to achieve the BLEsIs that are newly approved, and those recently reported to prepare the most relevant molecules yet in development, which have shown high potency, providing for each synthesis the related reaction scheme. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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19 pages, 4909 KiB

Open AccessReview

Recent Advances in the Biological Activity of s-Triazine Core Compounds

by Dawid Maliszewski and Danuta Drozdowska

Pharmaceuticals 2022, 15(2), 221; https://doi.org/10.3390/ph15020221 - 12 Feb 2022

Cited by 34 | Viewed by 3976

Abstract

An effective strategy for successful chemotherapy relies on creating compounds with high selectivity against cancer cells compared to normal cells and relatively low cytotoxicity. One such approach is the discovery of critical points in cancer cells, i.e., where specific enzymes that are potential [...] Read more.

An effective strategy for successful chemotherapy relies on creating compounds with high selectivity against cancer cells compared to normal cells and relatively low cytotoxicity. One such approach is the discovery of critical points in cancer cells, i.e., where specific enzymes that are potential therapeutic targets are generated. Triazine is a six-membered heterocyclic ring compound with three nitrogen replacing carbon-hydrogen units in the benzene ring structure. The subject of this review is the symmetrical 1,3,5-triazine, known as s-triazine. 1,3,5-triazine is one of the oldest heterocyclic compounds available. Because of its low cost and high availability, it has attracted researcher attention for novel synthesis. s-Triazine has a weak base, it has much weaker resonance energy than benzene, therefore, nucleophilic substitution is preferred to electrophilic substitution. Heterocyclic bearing a symmetrical s-triazine core represents an interesting class of compounds possessing a wide spectrum of biological properties such as anti-cancer, antiviral, fungicidal, insecticidal, bactericidal, herbicidal and antimicrobial, antimalarial agents. They also have applications as dyes, lubricants, and analytical reagents. Hence, the group of 1,3,5-triazine derivatives has developed over the years. Triazine is not only the core amongst them, but is also a factor increasing the kinetic potential of the entire derivatives. Modifying the structure and introducing new substituents makes it possible to obtain compounds with broad inhibitory activity on processes such as proliferation. In some cases, s-triazine derivatives induce cell apoptosis. In this review we will present currently investigated 1,3,5-triazine derivatives with anti-cancer activities, with particular emphasis on their inhibition of enzymes involved in the process of tumorigenesis. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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27 pages, 67784 KiB

Open AccessReview

Design and Development of Autotaxin Inhibitors

by Yi Jia, Yan Li, Xu-Dong Xu, Yu Tian and Hai Shang

Pharmaceuticals 2021, 14(11), 1203; https://doi.org/10.3390/ph14111203 - 22 Nov 2021

Cited by 22 | Viewed by 5036

Abstract

Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and [...] Read more.

Autotaxin (ATX) is the only enzyme of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP2) family with lysophospholipase D (lysoPLD) activity, which is mainly responsible for the hydrolysis of extracellular lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA). LPA can induce various responses, such as cell proliferation, migration, and cytokine production, through six G protein-coupled receptors (LPA1-6). This signaling pathway is associated with metabolic and inflammatory disorder, and inhibiting this pathway has a positive effect on the treatment of related diseases, while ATX, as an important role in the production of LPA, has been shown to be associated with the occurrence and metastasis of tumors, fibrosis and cardiovascular diseases. From mimics of ATX natural lipid substrates to the rational design of small molecule inhibitors, ATX inhibitors have made rapid progress in structural diversity and design over the past 20 years, and three drugs, GLPG1690, BBT-877, and BLD-0409, have entered clinical trials. In this paper, we will review the structure of ATX inhibitors from the perspective of the transformation of design ideas, discuss the advantages and disadvantages of each inhibitor type, and put forward prospects for the development of ATX inhibitors in the future. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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