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22 pages, 5922 KiB

Open AccessArticle

Exploring the Anticancer Effects of Brominated Plastoquinone Analogs with Promising Cytotoxic Activity in MCF-7 Breast Cancer Cells via Cell Cycle Arrest and Oxidative Stress Induction

by Ayse Tarbin Jannuzzi, Ayse Mine Yilmaz Goler, Nilüfer Bayrak, Mahmut Yıldız, Hatice Yıldırım, Betul Karademir Yilmaz, Deepak Shilkar, Raghusrinivasan Jayaprakash Venkatesan, Venkatesan Jayaprakash and Amaç Fatih TuYuN

Pharmaceuticals 2022, 15(7), 777; https://doi.org/10.3390/ph15070777 - 22 Jun 2022

Cited by 4 | Viewed by 2170

Abstract

Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the [...] Read more.

Plastoquinone analogs are privileged structures among the known antiproliferative natural product-based compound families. Exploiting one of these analogs as a lead structure, we report the investigation of the brominated PQ analogs (BrPQ) in collaboration with the National Cancer Institute of Bethesda within the Developmental Therapeutics Program (DTP). These analogs exhibited growth inhibition in the micromolar range across leukemia, non-small cell lung cancer (EKVX, HOP-92, and NCI-H522), colon cancer (HCT-116, HOP-92), melanoma (LOX IMVI), and ovarian cancer (OVCAR-4) cell lines. One brominated PQ analog (BrPQ5) was selected for a full panel five-dose in vitro assay by the NCI’s Development Therapeutic Program (DTP) division to determine GI₅₀, TGI, and LC₅₀ parameters. The brominated PQ analog (BrPQ5) displayed remarkable activity against most tested cell lines, with GI₅₀ values ranging from 1.55 to 4.41 µM. The designed molecules (BrPQ analogs) obeyed drug-likeness rules, displayed a favorable predictive Absorption, Distribution, Metabolism, and Excretion (ADME) profile, and an in silico simulation predicted a possible BrPQ5 interaction with proteasome catalytic subunits. Furthermore, the in vitro cytotoxic activity of BrPQ5 was assessed, and IC₅₀ values for U-251 glioma, MCF-7 and MDA-MB-231 breast cancers, DU145 prostate cancer, HCT-116 colon cancer, and VHF93 fibroblast cell lines were evaluated using an MTT assay. MCF-7 was the most affected cell line, and the effects of BrPQ5 on cell proliferation, cell cycle, oxidative stress, apoptosis/necrosis induction, and proteasome activity were further investigated in MCF-7 cells. The in vitro assay results showed that BrPQ5 caused cytotoxicity in MCF-7 breast cancer cells via cell cycle arrest and oxidative stress induction. However, BrPQ5 did not inhibit the catalytic activity of the proteasome. These results provide valuable insights for further discovery of novel antiproliferative agents. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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22 pages, 2075 KiB

Open AccessArticle

Promising Antibacterial and Antifungal Agents Based on Thiolated Vitamin K3 Analogs: Synthesis, Bioevaluation, Molecular Docking

by Hatice Yıldırım, Mahmut Yıldız, Nilüfer Bayrak, Emel Mataracı-Kara, Mohamed Osman Radwan, Ayse Tarbin Jannuzzi, Masami Otsuka, Mikako Fujita and Amaç Fatih TuYuN

Pharmaceuticals 2022, 15(5), 586; https://doi.org/10.3390/ph15050586 - 10 May 2022

Cited by 6 | Viewed by 2380

Abstract

In the present study, we designed and synthesized thiolated VK3 analogs (VK3a–g) along with an extensive antimicrobial study. After the evaluation of the antibacterial and antifungal activity against various bacterial and fungal strains, we presented an initial structure–activity relationship study on [...] Read more.

In the present study, we designed and synthesized thiolated VK3 analogs (VK3a–g) along with an extensive antimicrobial study. After the evaluation of the antibacterial and antifungal activity against various bacterial and fungal strains, we presented an initial structure–activity relationship study on these VK3 analogs. In particular, four thiolated VK3 analogs exhibited superior biological potency against some Gram-positive bacterial strains, including Staphylococcus aureus (ATCC^® 29213) and Enterococcus faecalis (ATCC^® 29212). Next, all thiolated VK3 analogs were evaluated for their potential of cell growth inhibition on the NCI-60 cancer cell lines panel. This screening underlined that the thiolated VK3 analogs have no visible cytotoxicity on different cancer cell lines. The selected two thiolated VK3 analogs (VK3a and VK3b), having minimal hemolytic activity, which also have the lowest MIC values on S. aureus and E. faecalis, were further evaluated for their inhibition capacities on biofilm formation after evaluating their potential in vitro antimicrobial activity against each of the 20 clinically obtained resistant strains of Staphylococcus aureus. VK3b showed excellent antimicrobial activity against clinically resistant S. aureus isolates. Furthermore, the tested molecules showed nearly two log₁₀ reduction in the viable cell count at six hours according to the time kill curve studies. Although these molecules decreased biofilm attachment about 50%, when sub-MIC concentrations were used these molecules increased the percentage of biofilm formation. The molecular docking of VK3a and VK3b in S. aureus thymidylate kinase was conducted in order to predict their molecular interactions. VK3a and VK3b exhibited excellent lead-likeness properties and pharmacokinetic profiles that qualify them for further optimization and development. In conclusion, since investigating efficient novel antimicrobial molecules is quite difficult, these studies are of high importance, especially in the present era of antimicrobial resistance. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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24 pages, 5778 KiB

Open AccessArticle

Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CL^pro Main Protease

by Barbara Herlah, Andrej Hoivik, Luka Jamšek, Katja Valjavec, Norio Yamamoto, Tyuji Hoshino, Krištof Kranjc and Andrej Perdih

Pharmaceuticals 2022, 15(5), 539; https://doi.org/10.3390/ph15050539 - 27 Apr 2022

Cited by 6 | Viewed by 3092

Abstract

The emergence of SARS-CoV-2, responsible for the global COVID-19 pandemic, requires the rapid development of novel antiviral drugs that would contribute to an effective treatment alongside vaccines. Drug repurposing and development of new molecules targeting numerous viral targets have already led to promising [...] Read more.

The emergence of SARS-CoV-2, responsible for the global COVID-19 pandemic, requires the rapid development of novel antiviral drugs that would contribute to an effective treatment alongside vaccines. Drug repurposing and development of new molecules targeting numerous viral targets have already led to promising drug candidates. To this end, versatile molecular scaffolds with high functionalization capabilities play a key role. Starting with the clinically used conformationally flexible HIV-1 protease inhibitors that inhibit replication of SARS-CoV-2 and bind major protease 3CL^pro, we designed and synthesized a series of rigid bicyclo[2.2.2]octenes fused to N-substituted succinimides to test whether this core scaffold could support the development of non-covalent 3CL^pro inhibitors. Inhibition assays confirmed that some compounds can inhibit the SARS-CoV-2 main protease; the most promising compound 11a inhibited 3CL^pro in micromolar range (IC₅₀ = 102.2 μM). Molecular simulations of the target-ligand complex in conjunction with dynophore analyses and endpoint free energy calculations provide additional insight and first recommendations for future optimization. The fused bicyclo[2.2.2]octenes can be used as a new potential starting point in the development of non-covalent SARS-CoV-2 3CL^pro protease inhibitors and the study also substantiates the potential of this versatile scaffold for the development of biologically active molecules. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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19 pages, 5457 KiB

Open AccessArticle

Discovery of Azaindolin-2-One as a Dual Inhibitor of GSK3β and Tau Aggregation with Potential Neuroprotective Activity

by Taha F. S. Ali, Halil I. Ciftci, Mohamed O. Radwan, Eslam Roshdy, Ahmed M. Shawky, Mohammed A. S. Abourehab, Hiroshi Tateishi, Masami Otsuka and Mikako Fujita

Pharmaceuticals 2022, 15(4), 426; https://doi.org/10.3390/ph15040426 - 31 Mar 2022

Cited by 2 | Viewed by 2759

Abstract

The inhibition of glycogen synthase kinase 3β (GSK3β) activity through pharmacological intervention represents a promising approach for treating challenging neurodegenerative disorders like Alzheimer’s disease. Similarly, abnormal tau aggregate accumulation in neurons is a hallmark of various neurodegenerative diseases. We introduced new dual GSK3β/tau [...] Read more.

The inhibition of glycogen synthase kinase 3β (GSK3β) activity through pharmacological intervention represents a promising approach for treating challenging neurodegenerative disorders like Alzheimer’s disease. Similarly, abnormal tau aggregate accumulation in neurons is a hallmark of various neurodegenerative diseases. We introduced new dual GSK3β/tau aggregation inhibitors due to the excellent clinical outcome of multitarget drugs. Compound (E)-2f stands out among the synthesized inhibitors as a promising GSK3β inhibitor (IC₅₀ 1.7 µM) with a pronounced tau anti-aggregation effect in a cell-based model of tauopathy. Concurrently, (E)-2f was demonstrated to be non-toxic to normal cells, making it a promising neuroprotective lead compound that needs further investigation. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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24 pages, 3869 KiB

Open AccessArticle

Hybrids of Imatinib with Quinoline: Synthesis, Antimyeloproliferative Activity Evaluation, and Molecular Docking

by Carine Santos, Luiz Pimentel, Henayle Canzian, Andressa Oliveira, Floriano Junior, Rafael Dantas, Lucas Hoelz, Debora Marinho, Anna Cunha, Monica Bastos and Nubia Boechat

Pharmaceuticals 2022, 15(3), 309; https://doi.org/10.3390/ph15030309 - 03 Mar 2022

Cited by 2 | Viewed by 2648

Abstract

Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as [...] Read more.

Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as a pharmacophore in the structure of the TKI inhibitor bosutinib (BST), have been widely applied. Thus, this work aimed to obtain new hybrids of imatinib containing quinoline moieties and evaluate them against K562 cells. The compounds were synthesized with a high purity degree. Among the produced molecules, the inhibitor 4-methyl-N3-(4-(pyridin-3-yl)pyrimidin-2-yl)-N1-(quinolin-4-yl)benzene-1,3-diamine (2g) showed a suitable reduction in cell viability, with a CC₅₀ value of 0.9 µM (IMT, CC₅₀ = 0.08 µM). Molecular docking results suggest that the interaction between the most active inhibitor 2g and the BCR-ABL1 enzyme occurs at the bosutinib binding site through a competitive inhibition mechanism. Despite being less potent and selective than IMT, 2g is a suitable prototype for use in the search for new drugs against chronic myeloid leukemia (CML), especially in patients with acquired resistance to IMT. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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22 pages, 4813 KiB

Open AccessArticle

Two out of Three Musketeers Fight against Cancer: Synthesis, Physicochemical, and Biological Properties of Phosphino Cu^I, Ru^II, Ir^III Complexes

by Urszula K. Komarnicka, Alessandro Niorettini, Sandra Kozieł, Barbara Pucelik, Agata Barzowska, Daria Wojtala, Aleksandra Ziółkowska, Monika Lesiów, Agnieszka Kyzioł, Stefano Caramori, Marina Porchia and Alina Bieńko

Pharmaceuticals 2022, 15(2), 169; https://doi.org/10.3390/ph15020169 - 29 Jan 2022

Cited by 5 | Viewed by 3505

Abstract

Two novel phosphine ligands, Ph₂PCH₂N(CH₂CH₃)₃ (1) and Ph₂PCH₂N(CH₂CH₂CH₂CH₃)₂ (2), and six new metal (Cu(I), Ir(III) and Ru(II)) [...] Read more.

Two novel phosphine ligands, Ph₂PCH₂N(CH₂CH₃)₃ (1) and Ph₂PCH₂N(CH₂CH₂CH₂CH₃)₂ (2), and six new metal (Cu(I), Ir(III) and Ru(II)) complexes with those ligands: iridium(III) complexes: Ir(η5-Cp*)Cl₂(1) (1a), Ir(η5-Cp*)Cl₂(2) (2a) (Cp*: Pentamethylcyclopentadienyl); ruthenium(II) complexes: Ru(η6-p-cymene)Cl₂(1) (1b), Ru(η6-p-cymene)Cl₂(2) (2b) and copper(I) complexes: [Cu(CH₃CN)₂(1)BF₄] (1c), [Cu(CH₃CN)₂(2)BF₄] (2c) were synthesized and characterized using elemental analysis, NMR spectroscopy, and ESI-MS spectrometry. Copper(I) complexes turned out to be highly unstable in the presence of atmospheric oxygen in contrast to ruthenium(II) and iridium(III) complexes. The studied Ru(II) and Ir(III) complexes exhibited promising cytotoxicity towards cancer cells in vitro with IC₅₀ values significantly lower than that of the reference drug—cisplatin. Confocal microscopy analysis showed that Ru(II) and Ir(III) complexes effectively accumulate inside A549 cells with localization in cytoplasm and nuclei. A precise cytometric analysis provided clear evidence for the predominance of apoptosis in induced cell death. Furthermore, the complexes presumably induce the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. Gel electrophoresis experiments revealed that Ru(II) and Ir(III) inorganic compounds showed their unusual low genotoxicity towards plasmid DNA. Additionally, metal complexes were able to generate reactive oxygen species as a result of redox processes, proved by gel electrophoresis and cyclic voltamperometry. In vitro cytotoxicity assays were also carried out within multicellular tumor spheroids and efficient anticancer action on these 3D assemblies was demonstrated. It was proven that the hydrocarbon chain elongation of the phosphine ligand coordinated to the metal ions does not influence the cytotoxic effect of resulting complexes in contrast to metal ions type. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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14 pages, 2811 KiB

Open AccessArticle

Coumarin Derivatives Exert Anti-Lung Cancer Activity by Inhibition of Epithelial–Mesenchymal Transition and Migration in A549 Cells

by Rodrigo Santos Aquino de Araújo, Julianderson de Oliveira dos Santos Carmo, Simone Lara de Omena Silva, Camila Radelley Azevedo Costa da Silva, Tayhana Priscila Medeiros Souza, Natália Barbosa de Mélo, Jean-Jacques Bourguignon, Martine Schmitt, Thiago Mendonça de Aquino, Renato Santos Rodarte, Ricardo Olímpio de Moura, José Maria Barbosa Filho, Emiliano Barreto and Francisco Jaime Bezerra Mendonça-Junior

Pharmaceuticals 2022, 15(1), 104; https://doi.org/10.3390/ph15010104 - 17 Jan 2022

Cited by 11 | Viewed by 2392

Abstract

A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung [...] Read more.

A series of coumarin derivatives and isosteres were synthesized from the reaction of triflic intermediates with phenylboronic acids, terminal alkynes, and organozinc compounds through palladium-catalyzed cross-coupling reactions. The in vitro cytotoxic effect of the compounds was evaluated against two non-small cell lung carcinoma (NSCLC) cell lines (A-549 and H2170) and a normal cell line (NIH-3T3) using cisplatin as a reference drug. Additionally, the effects of the most promising coumarin derivative (9f) in reversing the epithelial-to-mesenchymal transition (EMT) in IL-1β-stimulated A549 cells and in inhibiting the EMT-associated migratory ability in A549 cells were also evaluated. 9f had the greatest cytotoxic effect (CC₅₀ = 7.1 ± 0.8 and 3.3 ± 0.5 μM, respectively against A549 and H2170 cells) and CC₅₀ value of 25.8 µM for NIH-3T3 cells. 9f inhibited the IL-1β-induced EMT in epithelial cells by inhibiting the F-actin reorganization, attenuating changes in the actin cytoskeleton reorganization, and downregulating vimentin in A549 cells stimulated by IL-1β. Treatment of A549 cells with 9f at 7 µM for 24 h significantly reduced the migration of IL-1β-stimulated cells, which is a phenomenon confirmed by qualitative assessment of the wound closure. Taken together, our findings suggest that coumarin derivatives, especially compound 9f, may become a promising candidate for lung cancer therapy, especially in lung cancer promoted by NSCLC cell lines. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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29 pages, 11523 KiB

Open AccessArticle

Probing In Silico the Benzimidazole Privileged Scaffold for the Development of Drug-like Anti-RSV Agents

by Elena Cichero, Alessio Calautti, Valeria Francesconi, Michele Tonelli, Silvia Schenone and Paola Fossa

Pharmaceuticals 2021, 14(12), 1307; https://doi.org/10.3390/ph14121307 - 15 Dec 2021

Cited by 18 | Viewed by 2447

Abstract

Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV [...] Read more.

Targeting the fusion (F) protein has been recognized as a fruitful strategy for the development of anti-RSV agents. Despite the considerable efforts so far put into the development of RSV F protein inhibitors, the discovery of adequate therapeutics for the treatment of RSV infections is still awaiting a positive breakthrough. Several benzimidazole-containing derivatives have been discovered and evaluated in clinical trials, with only some of them being endowed with a promising pharmacokinetic profile. In this context, we applied a computational study based on a careful analysis of a number of X-ray crystallographic data of the RSV F protein, in the presence of different clinical candidates. A deepen comparison of the related electrostatic features and H-bonding motifs allowed us to pave the way for the following molecular dynamic simulation of JNJ-53718678 and then to perform docking studies of the in-house library of potent benzimidazole-containing anti-RSV agents. The results revealed not only the deep flexibility of the biological target but also the most relevant and recurring key contacts supporting the benzimidazole F protein inhibitor ability. Among them, several hydrophobic interactions and π-π stacking involving F140 and F488 proved to be mandatory, as well as H-bonding to D486. Specific requirements turning in RSV F protein binding ability were also explored thanks to structure-based pharmacophore analysis. Along with this, in silico prediction of absorption, distribution, metabolism, excretion (ADME) properties, and also of possible off-target events was performed. The results highlighted once more that the benzimidazole ring represents a privileged scaffold whose properties deserve to be further investigated for the rational design of novel and orally bioavailable anti-RSV agents. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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21 pages, 4784 KiB

Open AccessArticle

New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

by Milena Mlakić, Tena Čadež, Danijela Barić, Ivana Puček, Ana Ratković, Željko Marinić, Kornelija Lasić, Zrinka Kovarik and Irena Škorić

Pharmaceuticals 2021, 14(11), 1147; https://doi.org/10.3390/ph14111147 - 11 Nov 2021

Cited by 6 | Viewed by 2291

Abstract

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime [...] Read more.

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight trans,anti- and trans,syn-isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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28 pages, 3155 KiB

Open AccessArticle

Three-Component Synthesis of 2-Amino-3-cyano-4H-chromenes, In Silico Analysis of Their Pharmacological Profile, and In Vitro Anticancer and Antifungal Testing

by Alberto Feliciano, Omar Gómez-García, Carlos H. Escalante, Mario A. Rodríguez-Hernández, Mariana Vargas-Fuentes, Dulce Andrade-Pavón, Lourdes Villa-Tanaca, Cecilio Álvarez-Toledano, María Teresa Ramírez-Apan, Miguel A. Vázquez, Joaquín Tamariz and Francisco Delgado

Pharmaceuticals 2021, 14(11), 1110; https://doi.org/10.3390/ph14111110 - 30 Oct 2021

Cited by 6 | Viewed by 2416

Abstract

Chromenes are compounds that may be useful for inhibiting topoisomerase and cytochrome, enzymes involved in the growth of cancer and fungal cells, respectively. The aim of this study was to synthesize a series of some novel 2-amino-3-cyano-4-aryl-6,7-methylendioxy-4H-chromenes 4a–o and 2-amino-3-cyano-5,7-dimethoxy-4-aryl-4H [...] Read more.

Chromenes are compounds that may be useful for inhibiting topoisomerase and cytochrome, enzymes involved in the growth of cancer and fungal cells, respectively. The aim of this study was to synthesize a series of some novel 2-amino-3-cyano-4-aryl-6,7-methylendioxy-4H-chromenes 4a–o and 2-amino-3-cyano-5,7-dimethoxy-4-aryl-4H-chromenes 6a–h by a three-component reaction, and test these derivatives for anticancer and antifungal activity. Compounds 4a and 4b were more active than cisplatin (9) and topotecan (7) in SK-LU-1 cells, and more active than 9 in PC-3 cells. An evaluation was also made of the series of compounds 4 and 6 as potential antifungal agents against six Candida strains, finding their MIC₅₀ to be less than or equal to that of fluconazole (8). Molecular docking studies are herein reported, for the interaction of 4 and 6 with topoisomerase IB and the active site of CYP51 of Candida spp. Compounds 4a–o and 6a–h interacted in a similar way as 7 with key amino acids of the active site of topoisomerase IB and showed better binding energy than 8 at the active site of CYP51. Hence, 4a–o and 6a–h are good candidates for further research, having demonstrated their dual inhibition of enzymes that participate in the growth of cancer and fungal cells. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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12 pages, 1470 KiB

Open AccessArticle

Inhibition of Matrix Metalloproteinases and Cancer Cell Detachment by Ru(II) Polypyridyl Complexes Containing 4,7-Diphenyl-1,10-phenanthroline Ligands—New Candidates for Antimetastatic Agents

by Przemysław Gajda-Morszewski, Ilona Gurgul, Ewelina Janczy-Cempa, Olga Mazuryk, Michał Łomzik and Małgorzata Brindell

Pharmaceuticals 2021, 14(10), 1014; https://doi.org/10.3390/ph14101014 - 01 Oct 2021

Cited by 8 | Viewed by 1919

Abstract

Primary tumor targeting is the dominant approach in drug development, while metastasis is the leading cause of cancer death. Therefore, in addition to the cytotoxic activity of a series of Ru(II) polypyridyl complexes of the type [Ru(dip)₂L]²⁺ (dip: 4,7-diphenyl-1,10-phenanthroline while [...] Read more.

Primary tumor targeting is the dominant approach in drug development, while metastasis is the leading cause of cancer death. Therefore, in addition to the cytotoxic activity of a series of Ru(II) polypyridyl complexes of the type [Ru(dip)₂L]²⁺ (dip: 4,7-diphenyl-1,10-phenanthroline while L = dip; bpy: 2,2′-bipyridine; bpy-SC: bipyridine derivative bearing a semicarbazone 2-formylopyridine moiety; dpq, dpq(CH₃)₂, dpb: quinoxaline derivatives) their ability to inhibit cell detachment was investigated. In vitro studies performed on lung cancer A549 cells showed that they accumulate in cells very well and exhibit moderate cytotoxicity with IC₅₀ ranging from 4 to 13 µM. Three of the studied compounds that have dip, bpy-SC, or dpb ligands after treatment of the cells with a non-toxic dose (<¹/₂IC₅₀) enhanced their adhesion properties demonstrated by lower detachment in the trypsin resistance assay. The same complexes inhibited both MMP-2 and MMP-9 enzyme activities with IC₅₀ ranging from 2 to 12 µM; however, the MMP-9 inhibition was stronger. More detailed studies for [Ru(dip)₂(bpy-SC)]²⁺, which induced the greatest increase in cell adhesion, revealed that it is predominately accumulated in the cytoskeletal fraction of A549 cells. Moreover, cells treated with this compound showed the localization of MMP-9 to a greater extent also in the cytoskeleton. Taken together, our results indicate the possibility of a reduction of metastatic cells escaping from the primary lesion to the surrounding tissue by prevention of their detachment and by influencing the activity of MMP-2 and MMP-9. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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11 pages, 1536 KiB

Open AccessArticle

Privileged Quinolylnitrones for the Combined Therapy of Ischemic Stroke and Alzheimer’s Disease

by José M. Alonso, Alejandro Escobar-Peso, Alejandra Palomino-Antolín, Daniel Diez-Iriepa, Mourad Chioua, Emma Martínez-Alonso, Isabel Iriepa, Javier Egea, Alberto Alcázar and José Marco-Contelles

Pharmaceuticals 2021, 14(9), 861; https://doi.org/10.3390/ph14090861 - 27 Aug 2021

Cited by 4 | Viewed by 1953

Abstract

Cerebrovascular diseases such as ischemic stroke are known to exacerbate dementia caused by neurodegenerative pathologies such as Alzheimer’s disease (AD). Besides, the increasing number of patients surviving stroke makes it necessary to treat the co-occurrence of these two diseases with a single and [...] Read more.

Cerebrovascular diseases such as ischemic stroke are known to exacerbate dementia caused by neurodegenerative pathologies such as Alzheimer’s disease (AD). Besides, the increasing number of patients surviving stroke makes it necessary to treat the co-occurrence of these two diseases with a single and combined therapy. For the development of new dual therapeutic agents, eight hybrid quinolylnitrones have been designed and synthesized by the juxtaposition of selected pharmacophores from our most advanced lead-compounds for ischemic stroke and AD treatment. Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen–glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or β-amyloid peptide Aβ_25–35, modeling toxic insults found among the effects of AD. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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13 pages, 5287 KiB

Open AccessArticle

New 2,3-Benzodiazepine Derivative: Synthesis, Activity on Central Nervous System, and Toxicity Study in Mice

by Amal Amaghnouje, Serhii Bohza, Nathalie Bohdan, Imane Es-Safi, Andrii Kyrylchuk, Sanae Achour, Hinde El Fatemi, Dalila Bousta and Andriy Grafov

Pharmaceuticals 2021, 14(8), 814; https://doi.org/10.3390/ph14080814 - 19 Aug 2021

Cited by 3 | Viewed by 3022

Abstract

We report the design and synthesis of a new diazepine derivative, 4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-2,3-benzodiazepin-1-one (VBZ102), and the evaluation of its anxiolytic-like profile, memory impairment effect, and toxicity in Swiss mice. VBZ102 was evaluated for central nervous system effects in an open field, light–dark box, and [...] Read more.

We report the design and synthesis of a new diazepine derivative, 4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-2,3-benzodiazepin-1-one (VBZ102), and the evaluation of its anxiolytic-like profile, memory impairment effect, and toxicity in Swiss mice. VBZ102 was evaluated for central nervous system effects in an open field, light–dark box, and novel object recognition tests under oral administration for acute and sub-acute treatment. We tested the VBZ102 toxicity in mice through a determination of LD₅₀ values and examination of the biochemical and histopathological parameters. The VBZ102 induced an anxiolytic effect at different doses both in the light–dark box and open field tests. Unlike other benzodiazepines (e.g., bromazepam), a sedative effect was noted only after administration of the VBZ102 at 10.0 mg/kg. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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24 pages, 3301 KiB

Open AccessArticle

Hybrid Quinolinyl Phosphonates as Heterocyclic Carboxylate Isosteres: Synthesis and Biological Evaluation against Topoisomerase 1B (TOP1B)

by Asier Selas, María Fuertes, Estela Melcón-Fernández, Yolanda Pérez-Pertejo, Rosa M. Reguera, Rafael Balaña-Fouce, Birgitta R. Knudsen, Francisco Palacios and Concepcion Alonso

Pharmaceuticals 2021, 14(8), 784; https://doi.org/10.3390/ph14080784 - 09 Aug 2021

Cited by 6 | Viewed by 2616

Abstract

This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by [...] Read more.

This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by a cycloaddition reaction between phosphonate aldimines and acetylenes. Based on phosphonate group structural characteristics, considered as phosphorous isosteres of carboxylic heterocycles, they may present interesting biological properties related to cell proliferation. In the current report, a new series of dialkyl (2-arylquinolin-8-yl)phosphonates have been synthesized and their antiproliferative effect evaluated on different human cancer and embryonic cells, as well as on Leishmania infantum parasites, a eukaryotic protist responsible for visceral leishmaniasis. Thereby, the antitumor effect was assessed in human lung adenocarcinoma cells (A549), human ovarian carcinoma cells (SKOV3), and human embryonic kidney cells (HEK293) versus the non-cancerous lung fibroblasts cell line (MRC5). On the other hand, the antileishmanial activity was tested against both stages of L. infantum cell cycle, namely free-living promastigotes and intramacrophage amastigotes, using a primary culture of Balb/c splenocytes to calculate the selectivity index. Besides the antiproliferative and antileishmanial capacities, their behavior as topoisomerase 1B inhibitors has been evaluated as a possible mechanism of action. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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21 pages, 2942 KiB

Open AccessArticle

A Multicomponent Protocol for the Synthesis of Highly Functionalized γ-Lactam Derivatives and Their Applications as Antiproliferative Agents

by Xabier del Corte, Adrián López-Francés, Aitor Maestro, Ilia Villate-Beitia, Myriam Sainz-Ramos, Edorta Martínez de Marigorta, José Luis Pedraz, Francisco Palacios and Javier Vicario

Pharmaceuticals 2021, 14(8), 782; https://doi.org/10.3390/ph14080782 - 09 Aug 2021

Cited by 11 | Viewed by 2950

Abstract

An efficient synthetic methodology for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones through a multicomponent reaction of amines, aldehydes, and pyruvate derivatives is reported. In addition, the densely substituted lactam substrates show in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell [...] Read more.

An efficient synthetic methodology for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones through a multicomponent reaction of amines, aldehydes, and pyruvate derivatives is reported. In addition, the densely substituted lactam substrates show in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines HEK293 (human embryonic kidney), MCF7 (human breast adenocarcinoma), HTB81 (human prostate carcinoma), HeLa (human epithelioid cervix carcinoma), RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma), and A549 (carcinomic human alveolar basal epithelial cell). Given the possibilities in the diversity of the substituents that offer the multicomponent synthetic methodology, an extensive structure-activity profile is presented. In addition, both enantiomers of phosphonate-derived γ-lactam have been synthesized and isolated and a study of the cytotoxic activity of the racemic substrate vs. its two enantiomers is also presented. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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25 pages, 7881 KiB

Open AccessArticle

Interaction between DNA, Albumin and Apo-Transferrin and Iridium(III) Complexes with Phosphines Derived from Fluoroquinolones as a Potent Anticancer Drug

by Sandra Amanda Kozieł, Monika Katarzyna Lesiów, Daria Wojtala, Edyta Dyguda-Kazimierowicz, Dariusz Bieńko and Urszula Katarzyna Komarnicka

Pharmaceuticals 2021, 14(7), 685; https://doi.org/10.3390/ph14070685 - 16 Jul 2021

Cited by 12 | Viewed by 3296

Abstract

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) [...] Read more.

A group of cytotoxic half-sandwich iridium(III) complexes with aminomethyl(diphenyl)phosphine derived from fluoroquinolone antibiotics exhibit the ability to (i) accumulate in the nucleus, (ii) induce apoptosis, (iii) activate caspase-3/7 activity, (iv) induce the changes in cell cycle leading to G2/M phase arrest, and (v) radicals generation. Herein, to elucidate the cytotoxic effects, we investigated the interaction of these complexes with DNA and serum proteins by gel electrophoresis, fluorescence spectroscopy, circular dichroism, and molecular docking studies. DNA binding experiments established that the complexes interact with DNA by moderate intercalation and predominance of minor groove binding without the capability to cause a double-strand cleavage. The molecular docking study confirmed two binding modes: minor groove binding and threading intercalation with the fluoroquinolone part of the molecule involved in pi stacking interactions and the Ir(III)-containing region positioned within the major or minor groove. Fluorescence spectroscopic data (HSA and apo-Tf titration), together with molecular docking, provided evidence that Ir(III) complexes can bind to the proteins in order to be transferred. All the compounds considered herein were found to bind to the tryptophan residues of HSA within site I (subdomain II A). Furthermore, Ir(III) complexes were found to dock within the apo-Tf binding site, including nearby tyrosine residues. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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Review

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34 pages, 5367 KiB

Open AccessReview

Pharmacological Potential of Lathyrane-Type Diterpenoids from Phytochemical Sources

by Fátima Vela, Abdellah Ezzanad, Alan Christy Hunter, Antonio José Macías-Sánchez and Rosario Hernández-Galán

Pharmaceuticals 2022, 15(7), 780; https://doi.org/10.3390/ph15070780 - 23 Jun 2022

Cited by 7 | Viewed by 2312

Abstract

Lathyrane diterpenoids are one of the primary types of secondary metabolites present in the genus Euphorbia and one of the largest groups of diterpenes. They are characterized by having a highly oxygenated tricyclic system of 5, 11 and 3 members. These natural products [...] Read more.

Lathyrane diterpenoids are one of the primary types of secondary metabolites present in the genus Euphorbia and one of the largest groups of diterpenes. They are characterized by having a highly oxygenated tricyclic system of 5, 11 and 3 members. These natural products and some synthetic derivatives have shown numerous interesting biological activities with clinical potential against various diseases, such as cytotoxic activity against cancer cell lines, multi-drug resistance reversal, antiviral properties, anti-inflammatory activity and their capability to induce proliferation or differentiation into neurons of neural progenitor cells. The structure of the lathyrane skeleton could be considered privileged because its framework is able to direct functional groups in a well-defined space. The favorable arrangement of these makes interaction possible with more than one target. This review aims to highlight the evidence of lathyranes as privileged structures in medicinal chemistry. Chemical structures of bioactive compounds, the evaluation of biological properties of natural and semisynthetic derivatives, and the exploration of the mechanisms of action as well as target identification and some aspects of their targeted delivery are discussed. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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33 pages, 2800 KiB

Open AccessReview

The Boron Advantage: The Evolution and Diversification of Boron’s Applications in Medicinal Chemistry

by Katia Messner, Billy Vuong and Geoffrey K. Tranmer

Pharmaceuticals 2022, 15(3), 264; https://doi.org/10.3390/ph15030264 - 22 Feb 2022

Cited by 57 | Viewed by 12326

Abstract

In this review, the history of boron’s early use in drugs, and the history of the use of boron functional groups in medicinal chemistry applications are discussed. This includes diazaborines, boronic acids, benzoxaboroles, boron clusters, and carboranes. Furthermore, critical developments from these functional [...] Read more.

In this review, the history of boron’s early use in drugs, and the history of the use of boron functional groups in medicinal chemistry applications are discussed. This includes diazaborines, boronic acids, benzoxaboroles, boron clusters, and carboranes. Furthermore, critical developments from these functional groups are highlighted along with recent developments, which exemplify potential prospects. Lastly, the application of boron in the form of a prodrug, softdrug, and as a nanocarrier are discussed to showcase boron’s emergence into new and exciting fields. Overall, we emphasize the evolution of organoboron therapeutic agents as privileged structures in medicinal chemistry and outline the impact that boron has had on drug discovery and development. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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13 pages, 2615 KiB

Open AccessReview

Pyrrolotriazinone as an Underexplored Scaffold in Drug Discovery

by Tony Ge and Jean-Christophe Cintrat

Pharmaceuticals 2021, 14(12), 1275; https://doi.org/10.3390/ph14121275 - 06 Dec 2021

Cited by 1 | Viewed by 2233

Abstract

Heterocyclic amino derivatives have been extensively synthesized and validated as potent bioactive compounds, and nowadays, numerous marketed drugs share these scaffolds, from very simple structures (monoamino, monocyclic compounds) to much more complex molecules (polycyclic derivatives with two or more nitrogen atoms within the [...] Read more.

Heterocyclic amino derivatives have been extensively synthesized and validated as potent bioactive compounds, and nowadays, numerous marketed drugs share these scaffolds, from very simple structures (monoamino, monocyclic compounds) to much more complex molecules (polycyclic derivatives with two or more nitrogen atoms within the (fused) rings). In a constant quest for new chemical entities in drug discovery, a few novel heterocycles have emerged in recent years as promising building blocks for the obtainment of bioactive modulators. In this context, pyrrolotriazinones have attracted attention, and some show promising biological activities. Here, we offer an extensive review of pyrrolo[2,1-f][1,2,4]triazin-4(1H)-one and pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one, describing their biological properties en route to drug discovery. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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25 pages, 3557 KiB

Open AccessReview

The Fellowship of Privileged Scaffolds—One Structure to Inhibit Them All

by Marcin Skoreński and Marcin Sieńczyk

Pharmaceuticals 2021, 14(11), 1164; https://doi.org/10.3390/ph14111164 - 16 Nov 2021

Cited by 13 | Viewed by 2754

Abstract

Over the past few years, the application of privileged structure has emerged as a powerful approach to the discovery of new biologically active molecules. Privileged structures are molecular scaffolds with binding properties to the range of different biological targets. Moreover, privileged structures typically [...] Read more.

Over the past few years, the application of privileged structure has emerged as a powerful approach to the discovery of new biologically active molecules. Privileged structures are molecular scaffolds with binding properties to the range of different biological targets. Moreover, privileged structures typically exhibit good drug-like properties, thus assuring more drug-like properties of modified compound. Our main objective is to discuss the privileged structures used for the development of antiviral agents. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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24 pages, 5813 KiB

Open AccessReview

Synthesis and Biological Activities of Pyrazino[1,2-a]indole and Pyrazino[1,2-a]indol-1-one Derivatives

by Kena Zhang, Christine Tran, Mouad Alami, Abdallah Hamze and Olivier Provot

Pharmaceuticals 2021, 14(8), 779; https://doi.org/10.3390/ph14080779 - 08 Aug 2021

Cited by 14 | Viewed by 3704

Abstract

This review concerns the synthesis and biological activities of pyrazino[1,2-a]indoles and pyrazino[1,2-a]indol-1-ones reported since 1997 and the discovery of biological activity of pyrazinoindole derivatives. In the first part, we first presented the synthetic routes that have been reported from [...] Read more.

This review concerns the synthesis and biological activities of pyrazino[1,2-a]indoles and pyrazino[1,2-a]indol-1-ones reported since 1997 and the discovery of biological activity of pyrazinoindole derivatives. In the first part, we first presented the synthetic routes that have been reported from a methodological point of view to access the pyrazinoindole unit according to cyclization reactions using or not using metal catalysts. Then, syntheses and neuropsychiatric, auto-immune, anti-infectious and anti-cancer properties of pyrazinoindoles were detailed. In the second part, we first reported the main accesses to pyrazinoindol-1-one substrates according to Michael reactions, metal-catalyzed and metal-free cyclization reactions. The syntheses and anti-cancer, anti-infectious, anti-allergenic and neuropsychiatric properties of pyrazinoindolones were next described and discussed. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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16 pages, 1696 KiB

Open AccessReview

Thiophene-Based Compounds with Potential Anti-Inflammatory Activity

by Ryldene Marques Duarte da Cruz, Francisco Jaime Bezerra Mendonça-Junior, Natália Barbosa de Mélo, Luciana Scotti, Rodrigo Santos Aquino de Araújo, Reinaldo Nóbrega de Almeida and Ricardo Olímpio de Moura

Pharmaceuticals 2021, 14(7), 692; https://doi.org/10.3390/ph14070692 - 19 Jul 2021

Cited by 45 | Viewed by 5724

Abstract

Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively [...] Read more.

Rheumatoid arthritis, arthrosis and gout, among other chronic inflammatory diseases are public health problems and represent major therapeutic challenges. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed clinical treatments, despite their severe side effects and their exclusive action in improving symptoms, without effectively promoting the cure. However, recent advances in the fields of pharmacology, medicinal chemistry, and chemoinformatics have provided valuable information and opportunities for development of new anti-inflammatory drug candidates. For drug design and discovery, thiophene derivatives are privileged structures. Thiophene-based compounds, like the commercial drugs Tinoridine and Tiaprofenic acid, are known for their anti-inflammatory properties. The present review provides an update on the role of thiophene-based derivatives in inflammation. Studies on mechanisms of action, interactions with receptors (especially against cyclooxygenase (COX) and lipoxygenase (LOX)), and structure-activity relationships are also presented and discussed. The results demonstrate the importance of thiophene-based compounds as privileged structures for the design and discovery of novel anti-inflammatory agents. The studies reveal important structural characteristics. The presence of carboxylic acids, esters, amines, and amides, as well as methyl and methoxy groups, has been frequently described, and highlights the importance of these groups for anti-inflammatory activity and biological target recognition, especially for inhibition of COX and LOX enzymes. Full article

(This article belongs to the Special Issue Privileged Structures as Leads in Medicinal Chemistry)

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