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Bioactive Oxadiazoles 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 7731

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Dr. Antonio Palumbo Piccionello

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Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche-STEBICEF, Università degli Studi di Palermo, Viale delle Scienze Ed. 17, 90128 Palermo, Italy
Interests: heterocyclic chemistry; drug design and synthesis; fluorinated organic compounds
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Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous Special Issues “Bioactive Oxadiazoles” and “Bioactive Oxadiazoles 2.0”.

Oxadiazoles are electron-poor five-membered aromatic heterocycles that contain one oxygen and two nitrogen atoms. The oxadiazoles, namely 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,4-regioisomers, together with N-oxides, benzo-fused, and non-aromatic derivatives, present a wide application range from material science to explosives and bioactive compounds. In the latter field, there are many possibilities, and oxadiazoles have been revealed to be active as antitumoral agents, neuroprotective compounds, antimicrobials, antivirals, antidiabetics, among others. Some bioactive oxadiazoles have reached the market or are in the advanced clinical trials stage, such as oxolamine, ataluren, raltegravir, capeserod, azilsartan, furazabol, sydnophen, zibotentan, opicabone, etc. Moreover, the oxadiazole skeleton is also present in some natural compounds, such as phidianidine and quisqualic acid, providing new inspiration for the synthesis of bio-inspired drugs. Another important issue is the use of oxadiazoles in medicinal chemistry as amide and ester isosters and as peptido-mimetics, offering a well-established tool for drug design. All of these aspects have increased interest in these heterocycles, increasing the impact of oxadiazoles in the field of bioactive compounds. This Special Issue on “Bioactive Oxadiazoles” is intended to offer a wide panorama of the potential applications of these compounds toward all diseases.

The research fields of this Special Issue include natural products, synthetic chemistry, medicinal chemistry, pharmacology, and other related research fields. Original research and review articles on all topics in these research fields are invited. I look forward to receiving many submissions from outstanding experts on these research topics.

Dr. Antonio Palumbo Piccionello
Guest Editor

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Keywords

aromatic heterocycles
bioactive compounds
drug design

Published Papers (5 papers)

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Research

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14 pages, 2861 KiB

Open AccessArticle

Synthesis and Antibacterial Activity of Mono- and Bi-Cationic Pyridinium 1,2,4-Oxadiazoles and Triazoles

by Sara Amata, Cinzia Calà, Carla Rizzo, Ivana Pibiri, Mariangela Pizzo, Silvestre Buscemi and Antonio Palumbo Piccionello

Int. J. Mol. Sci. 2024, 25(1), 377; https://doi.org/10.3390/ijms25010377 - 27 Dec 2023

Cited by 1 | Viewed by 706

Abstract

One of the main causes of mortality in humans continues to be infectious diseases. Scientists are searching for new alternatives due to the fast increase in resistance of some harmful bacteria to the frontline antibiotics. To effectively treat pathogenic infections, it is crucial to design antibiotics that can prevent the development of pathogenic resistance. For this purpose, a set of 39 quaternary pyridinium and bis-pyridinium salts with different lengths of side alkyl or fluorinated chains, heterocyclic spacers, and counter ions were tested on diverse reference bacterial ATCC (American Type Culture Collection) strains, such as S. aureus and E. coli. Subsequently, 6 out of the 39 pyridinium salts showing relevant MIC (Minimum Inhibitory Concentration) values were tested on clinically isolated, resistant strains of S. aureus, S. epidermids, S. haemolyticus, K. pneumoniae, A. baumannii, and P. aeruginosa. Additional tests have been performed to assess if the minimum concentration detected through MIC assay may limit the growth of biofilms. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 3.0)

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26 pages, 1142 KiB

Open AccessArticle

Structure–Activity Relationships and Antiplasmodial Potencies of Novel 3,4-Disubstituted 1,2,5-Oxadiazoles

by Patrick Hochegger, Theresa Hermann, Johanna Dolensky, Werner Seebacher, Robert Saf, Eva-Maria Pferschy-Wenzig, Marcel Kaiser, Pascal Mäser and Robert Weis

Int. J. Mol. Sci. 2023, 24(19), 14480; https://doi.org/10.3390/ijms241914480 - 23 Sep 2023

Viewed by 728

Abstract

The 4-substituted 3-amino-1,2,5-oxadiazole 1 from the Malaria Box Project of the Medicines for Malaria Venture foundation shows very promising selectivity and in vitro activity against Plasmodium falciparum. Within the first series of new compounds, various 3-acylamino analogs were prepared. This paper now focuses on the investigation of the importance of the aromatic substituent in ring position 4. A number of new structure–activity relationships were elaborated, showing that antiplasmodial activity and selectivity strongly depend on the substitution pattern of the 4-phenyl moiety. In addition, physicochemical parameters relevant for drug development were calculated (logP and ligand efficiency) or determined experimentally (CYP3A4-inhibition and aqueous solubility). N-[4-(3-ethoxy-4-methoxyphenyl)-1,2,5-oxadiazol-3-yl]-3-methylbenzamide 51 showed high in vitro activity against the chloroquine-sensitive strain NF54 of P. falciparum (PfNF54 IC₅₀ = 0.034 µM), resulting in a very promising selectivity index of 1526. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 3.0)

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16 pages, 5009 KiB

Open AccessArticle

Discovery of 1,2,4-Oxadiazole Derivatives Containing Haloalkyl as Potential Acetylcholine Receptor Nematicides

by Ling Luo, Yuqin Ou, Qi Zhang and Xiuhai Gan

Int. J. Mol. Sci. 2023, 24(6), 5773; https://doi.org/10.3390/ijms24065773 - 17 Mar 2023

Cited by 2 | Viewed by 1200

Abstract

Plant-parasitic nematodes pose a serious threat to crops and cause substantial financial losses due to control difficulties. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a novel broad-spectrum nematicide developed by the Monsanto Company, which shows good prevention effects on many kinds of nematodes. To discover compounds with high nematocidal activities, 48 derivatives of 1,2,4-oxadiazole were obtained by introducing haloalkyl at the 5-position of tioxazafen, and their nematocidal activities were systematically evaluated. The bioassays revealed that most of 1,2,4-oxadiazole derivatives showed remarkable nematocidal activities against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus dipsaci. Notably, compound A1 showed excellent nematocidal activity against B. xylophilus with LC₅₀ values of 2.4 μg/mL, which was superior to that of avermectin (335.5 μg/mL), tioxazafen (>300 μg/mL), and fosthiazate (436.9 μg/mL). The transcriptome and enzyme activity results indicate that the nematocidal activity of compound A1 was mainly related to the compound which affected the acetylcholine receptor of B. xylophilus. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 3.0)

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23 pages, 34217 KiB

Open AccessArticle

Synthesis, Anticancer Activity and Molecular Docking Studies of Novel N-Mannich Bases of 1,3,4-Oxadiazole Based on 4,6-Dimethylpyridine Scaffold

by Małgorzata Strzelecka, Teresa Glomb, Małgorzata Drąg-Zalesińska, Julita Kulbacka, Anna Szewczyk, Jolanta Saczko, Paulina Kasperkiewicz-Wasilewska, Nina Rembiałkowska, Kamil Wojtkowiak, Aneta Jezierska and Piotr Świątek

Int. J. Mol. Sci. 2022, 23(19), 11173; https://doi.org/10.3390/ijms231911173 - 22 Sep 2022

Cited by 8 | Viewed by 2000

Abstract

Cancer is one of the greatest challenges in modern medicine today. Difficult and long-term treatment, the many side effects of the drugs used and the growing resistance to treatment of neoplastic cells necessitate new approaches to therapy. A very promising targeted therapy is based on direct impact only on cancer cells. As a continuation of our research on new biologically active molecules, we report herein the design, synthesis and anticancer evaluation of a new series of N-Mannich-base-type hybrid compounds containing morfoline or different substituted piperazines moieties, a 1,3,4-oxadiazole ring and a 4,6-dimethylpyridine core. All compounds were tested for their potential cytotoxicity against five human cancer cell lines, A375, C32, SNB-19, MCF-7/WT and MCF-7/DX. Two of the active N-Mannich bases (compounds 5 and 6) were further evaluated for growth inhibition effects in melanoma (A375 and C32), and normal (HaCaT) cell lines using clonogenic assay and a population doubling time test. The apoptosis was determined with the neutral version of comet assay. The confocal microscopy method enabled the visualization of F-actin reorganization. The obtained results demonstrated that compounds 5 and 6 have cytotoxic and proapoptotic effects on melanoma cells and are capable of inducing F-actin depolarization in a dose-dependent manner. Moreover, computational chemistry approaches, molecular docking and electrostatic potential were employed to study non-covalent interactions of the investigated compounds with four receptors. It was found that all the examined molecules exhibit a similar binding affinity with respect to the chosen reference drugs. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 3.0)

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Review

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32 pages, 13542 KiB

Open AccessReview

Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles

by Sergey V. Baykov, Anton A. Shetnev, Artem V. Semenov, Svetlana O. Baykova and Vadim P. Boyarskiy

Int. J. Mol. Sci. 2023, 24(6), 5406; https://doi.org/10.3390/ijms24065406 - 12 Mar 2023

Cited by 4 | Viewed by 2457

Abstract

1,2,4-Oxadiazole is an essential motif in drug discovery represented in many experimental, investigational, and marketed drugs. This review covers synthetic methods that allow the conversion of different types of organic compounds into 1,2,4-oxadiazole at ambient temperature and the practical application of the latter approaches for the preparation of pharmaceutically important molecules. The discussed methods are divided into three groups. The first combines two-stage protocols requiring the preliminary preparation of O-acylamidoximes followed by cyclization under the action of organic bases. The advantages of this route are its swiftness, high efficiency of the cyclization process, and uncomplicated work-up. However, it requires the preparation and isolation of O-acylamidoximes as a separate preliminary step. The second route is a one-pot synthesis of 1,2,4-oxadiazoles directly from amidoximes and various carboxyl derivatives or aldehydes in aprotic bipolar solvents (primarily DMSO) in the presence of inorganic bases. This recently proposed pathway proved to be highly efficient in the field of medicinal chemistry. The third group of methods consists of diverse oxidative cyclizations, and these reactions have found modest application in drug design thus far. It is noteworthy that the reviewed methods allow for obtaining 1,2,4-oxadiazoles with thermosensitive functions and expand the prospects of using the oxadiazole core as an amide- or ester-like linker in the design of bioactive compounds. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 3.0)

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