Editorial

2 pages, 171 KiB

Open AccessEditorial

by Antonio Palumbo Piccionello

Int. J. Mol. Sci. 2022, 23(7), 3841; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073841 - 31 Mar 2022

Viewed by 1128

Oxadiazoles are electron-poor, five-membered aromatic heterocycles that contain one oxygen and two nitrogen atoms [...] Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

Research

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17 pages, 26746 KiB

Open AccessArticle

Design, Synthesis and Antifungal/Nematicidal Activity of Novel 1,2,4-Oxadiazole Derivatives Containing Amide Fragments

by Dan Liu, Ling Luo, Zhengxing Wang, Xiaoyun Ma and Xiuhai Gan

Int. J. Mol. Sci. 2022, 23(3), 1596; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031596 - 29 Jan 2022

Cited by 14 | Viewed by 2895

Abstract

Plant diseases that are caused by fungi and nematodes have become increasingly serious in recent years. However, there are few pesticide chemicals that can be used for the joint control of fungi and nematodes on the market. To solve this problem, a series [...] Read more.

Plant diseases that are caused by fungi and nematodes have become increasingly serious in recent years. However, there are few pesticide chemicals that can be used for the joint control of fungi and nematodes on the market. To solve this problem, a series of novel 1,2,4-oxadiazole derivatives containing amide fragments were designed and synthesized. Additionally, the bioassays revealed that the compound F15 demonstrated excellent antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum) in vitro, and the EC₅₀ value of that was 2.9 μg/mL, which is comparable with commonly used fungicides thifluzamide and fluopyram. Meanwhile, F15 demonstrated excellent curative and protective activity against S. sclerotiorum-infected cole in vivo. The scanning electron microscopy results showed that the hyphae of S. sclerotiorum treated with F15 became abnormally collapsed and shriveled, thereby inhibiting the growth of the hyphae. Furthermore, F15 exhibited favorable inhibition against the succinate dehydrogenase (SDH) of the S. sclerotiorum (IC₅₀ = 12.5 μg/mL), and the combination mode and binding ability between compound F15 and SDH were confirmed by molecular docking. In addition, compound F11 showed excellent nematicidal activity against Meloidogyne incognita at 200 μg/mL, the corrected mortality rate was 93.2%, which is higher than that of tioxazafen. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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25 pages, 2607 KiB

Open AccessArticle

Biological Evaluation and Molecular Docking Studies of Novel 1,3,4-Oxadiazole Derivatives of 4,6-Dimethyl-2-sulfanylpyridine-3-carboxamide

by Piotr Świątek, Teresa Glomb, Agnieszka Dobosz, Tomasz Gębarowski, Kamil Wojtkowiak, Aneta Jezierska, Jarosław J. Panek, Małgorzata Świątek and Małgorzata Strzelecka

Int. J. Mol. Sci. 2022, 23(1), 549; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010549 - 04 Jan 2022

Cited by 7 | Viewed by 3215

Abstract

To date, chronic inflammation is involved in most main human pathologies such as cancer, and autoimmune, cardiovascular or neurodegenerative disorders. Studies suggest that different prostanoids, especially prostaglandin E₂, and their own synthase (cyclooxygenase enzyme-COX) can promote tumor growth by activating signaling [...] Read more.

To date, chronic inflammation is involved in most main human pathologies such as cancer, and autoimmune, cardiovascular or neurodegenerative disorders. Studies suggest that different prostanoids, especially prostaglandin E₂, and their own synthase (cyclooxygenase enzyme-COX) can promote tumor growth by activating signaling pathways which control cell proliferation, migration, apoptosis, and angiogenesis. Non-steroidal anti-inflammatory drugs (NSAIDs) are used, alongside corticosteroids, to treat inflammatory symptoms particularly in all chronic diseases. However, their toxicity from COX inhibition and the suppression of physiologically important prostaglandins limits their use. Therefore, in continuation of our efforts in the development of potent, safe, non-toxic chemopreventive compounds, we report herein the design, synthesis, biological evaluation of new series of Schiff base-type hybrid compounds containing differently substituted N-acyl hydrazone moieties, 1,3,4-oxadiazole ring, and 4,6-dimethylpyridine core. The anti-COX-1/COX-2, antioxidant and anticancer activities were studied. Schiff base 13, containing 2-bromobenzylidene residue inhibited the activity of both isoenzymes, COX-1 and COX-2 at a lower concentration than standard drugs, and its COX-2/COX-1 selectivity ratio was similar to meloxicam. Furthermore, the results of cytotoxicity assay indicated that all of the tested compounds exhibited potent anti-cancer activity against A549, MCF-7, LoVo, and LoVo/Dx cell lines, compared with piroxicam and meloxicam. Moreover, our experimental study was supported by density functional theory (DFT) and molecular docking to describe the binding mode of new structures to cyclooxygenase. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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16 pages, 821 KiB

Open AccessArticle

Biological Activity, Lipophilicity and Cytotoxicity of Novel 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazolines

by Kinga Paruch, Anna Biernasiuk, Anna Berecka-Rycerz, Anna Hordyjewska and Łukasz Popiołek

Int. J. Mol. Sci. 2021, 22(24), 13669; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413669 - 20 Dec 2021

Cited by 5 | Viewed by 2427

Abstract

Antibiotic resistance is now a global problem, and the lack of effective antimicrobial agents for the treatment of diseases caused by resistant microbes is increasing. The 3-acetyl-2,5-disubstituted-1,3,4-oxadiazolines presented in this article may provide a good starting point for the development of potential new [...] Read more.

Antibiotic resistance is now a global problem, and the lack of effective antimicrobial agents for the treatment of diseases caused by resistant microbes is increasing. The 3-acetyl-2,5-disubstituted-1,3,4-oxadiazolines presented in this article may provide a good starting point for the development of potential new effective antimicrobial agents useful in the treatment of bacterial and fungal infections. Particular attention is drawn to the 1,3,4-oxadiazole derivative marked with the number 29 with 5-nitrofuran-2-yl substituent in its chemical structure. This substance showed a strong bactericidal effect, especially against Staphylococcus spp., and no cytotoxicity to the L929 normal cell line. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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16 pages, 1907 KiB

Open AccessArticle

Ammonium Formate-Pd/C as a New Reducing System for 1,2,4-Oxadiazoles. Synthesis of Guanidine Derivatives and Reductive Rearrangement to Quinazolin-4-Ones with Potential Anti-Diabetic Activity

by Paola Marzullo, Sonya Vasto, Silvestre Buscemi, Andrea Pace, Domenico Nuzzo and Antonio Palumbo Piccionello

Int. J. Mol. Sci. 2021, 22(22), 12301; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212301 - 14 Nov 2021

Cited by 3 | Viewed by 2428

Abstract

1,2,4-Oxadiazole is a heterocycle with wide reactivity and many useful applications. The reactive O-N bond is usually reduced using molecular hydrogen to obtain amidine derivatives. NH₄CO₂H-Pd/C is here demonstrated as a new system for the O-N reduction, allowing us [...] Read more.

1,2,4-Oxadiazole is a heterocycle with wide reactivity and many useful applications. The reactive O-N bond is usually reduced using molecular hydrogen to obtain amidine derivatives. NH₄CO₂H-Pd/C is here demonstrated as a new system for the O-N reduction, allowing us to obtain differently substituted acylamidine, acylguanidine and diacylguanidine derivatives. The proposed system is also effective for the achievement of a reductive rearrangement of 5-(2′-aminophenyl)-1,2,4-oxadiazoles into 1-alkylquinazolin-4(1H)-ones. The alkaloid glycosine was also obtained with this method. The obtained compounds were preliminarily tested for their biological activity in terms of their cytotoxicity, induced oxidative stress, α-glucosidase and DPP4 inhibition, showing potential application as anti-diabetics. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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11 pages, 3650 KiB

Open AccessArticle

The Reactivity of Azidonitrobenzofuroxans towards 1,3-Dicarbonyl Compounds: Unexpected Formation of Amino Derivative via the Regitz Diazo Transfer and Tautomerism Study

by Elena Chugunova, Almir Gazizov, Daut Islamov, Alexander Burilov, Alena Tulesinova, Sergey Kharlamov, Victor Syakaev, Vasily Babaev, Nurgali Akylbekov, Nurbol Appazov, Konstantin Usachev and Rakhmetulla Zhapparbergenov

Int. J. Mol. Sci. 2021, 22(17), 9646; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179646 - 06 Sep 2021

Cited by 2 | Viewed by 2081

Abstract

Herein, we report on the reaction of nitro-substituted azidobenzofuroxans with 1,3-dicarbonyl compounds in basic media. The known reactions of benzofuroxans and azidofuroxans with 1,3-dicarbonyl compounds in the presence of bases are the 1,3-dipolar cycloaddition and the Beirut reaction. In contrast with this, azidonitrobenzofuroxan [...] Read more.

Herein, we report on the reaction of nitro-substituted azidobenzofuroxans with 1,3-dicarbonyl compounds in basic media. The known reactions of benzofuroxans and azidofuroxans with 1,3-dicarbonyl compounds in the presence of bases are the 1,3-dipolar cycloaddition and the Beirut reaction. In contrast with this, azidonitrobenzofuroxan reacts with 1,3-carbonyl compounds through Regitz diazo transfer, which is the first example of this type of reaction for furoxan derivatives. This difference is seemingly due to the strong electron-withdrawing effect of the superelectrophilic azidonitrobenzofuroxan, which serves as the azido transfer agent rather than 1,3-dipole in this case. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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21 pages, 3906 KiB

Open AccessArticle

In Vitro and In Silico Evaluation of New 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone as Promising Cyclooxygenase Inhibitors

by Krzysztof Peregrym, Łukasz Szczukowski, Benita Wiatrak, Katarzyna Potyrak, Żaneta Czyżnikowska and Piotr Świątek

Int. J. Mol. Sci. 2021, 22(17), 9130; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179130 - 24 Aug 2021

Cited by 10 | Viewed by 2271

Abstract

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, [...] Read more.

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX-2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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20 pages, 4260 KiB

Open AccessArticle

Novel Hybrid Compounds Containing Benzofuroxan and Aminothiazole Scaffolds: Synthesis and Evaluation of Their Anticancer Activity

by Elena Chugunova, Gabriele Micheletti, Dario Telese, Carla Boga, Daut Islamov, Konstantin Usachev, Alexander Burilov, Alena Tulesinova, Alexandra Voloshina, Anna Lyubina, Syumbelya Amerhanova, Tatiana Gerasimova, Aisylu Gilfanova and Victor Syakaev

Int. J. Mol. Sci. 2021, 22(14), 7497; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147497 - 13 Jul 2021

Cited by 8 | Viewed by 2266

Abstract

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray [...] Read more.

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Tamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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32 pages, 9643 KiB

Open AccessArticle

Design, Synthesis, In Silico and In Vitro Studies for New Nitric Oxide-Releasing Indomethacin Derivatives with 1,3,4-Oxadiazole-2-thiol Scaffold

by Alexandru Sava, Frederic Buron, Sylvain Routier, Alina Panainte, Nela Bibire, Sandra Mădălina Constantin, Florentina Geanina Lupașcu, Alin Viorel Focșa and Lenuţa Profire

Int. J. Mol. Sci. 2021, 22(13), 7079; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22137079 - 30 Jun 2021

Cited by 8 | Viewed by 3609

Abstract

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a–p) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries [...] Read more.

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a–p) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Moreover, their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was also performed. Based on docking results, 8k, 8l and 8m proved to be the best interaction for the COX-2 (cyclooxygense-2) target site, with an improved docking score compared with celecoxib. Referring to the thermal denaturation of serum proteins and antioxidant effects, all the tested compounds were more active than IND and aspirin, used as references. In addition, the compounds 8c, 8h, 8i, 8m, 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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Review

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23 pages, 6784 KiB

Open AccessReview

Antimicrobial Activity of 1,3,4-Oxadiazole Derivatives

by Teresa Glomb and Piotr Świątek

Int. J. Mol. Sci. 2021, 22(13), 6979; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136979 - 29 Jun 2021

Cited by 49 | Viewed by 5456

Abstract

The worldwide development of antimicrobial resistance forces scientists to search for new compounds to which microbes would be sensitive. Many new structures contain the 1,3,4-oxadiazole ring, which have shown various antimicrobial activity, e.g., antibacterial, antitubercular, antifungal, antiprotozoal and antiviral. In many publications, the [...] Read more.

The worldwide development of antimicrobial resistance forces scientists to search for new compounds to which microbes would be sensitive. Many new structures contain the 1,3,4-oxadiazole ring, which have shown various antimicrobial activity, e.g., antibacterial, antitubercular, antifungal, antiprotozoal and antiviral. In many publications, the activity of new compounds exceeds the activity of already known antibiotics and other antimicrobial agents, so their potential as new drugs is very promising. The review of active antimicrobial 1,3,4-oxadiazole derivatives is based on the literature from 2015 to 2021. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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