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Bioactive Oxadiazoles
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Bioactive Oxadiazoles

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

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 40409

Special Issue Editor

Dr. Antonio Palumbo Piccionello

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Guest Editor
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
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Oxadiazoles are electron-poor five-membered aromatic heterocycles containing 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 revealed to be active as antitumoral agents, neuroprotective compounds, antimicrobials, antivirals, antidiabetics, and so on. 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, giving new inspiration to 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 these aspects have increased the 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.

Prof. Dr. Antonio Palumbo Piccionello
Guest Editor

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

2 pages, 155 KiB  
Editorial
Editorial for Special Issue “Bioactive Oxadiazoles”
by Antonio Palumbo Piccionello
Int. J. Mol. Sci. 2021, 22(8), 3988; https://doi.org/10.3390/ijms22083988 - 13 Apr 2021
Cited by 1 | Viewed by 1280
Abstract
Oxadiazoles are electron-poor, five-membered aromatic heterocycles containing one oxygen and two nitrogen atoms [...] Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)

Research

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23 pages, 4916 KiB  
Article
Design, Synthesis and Comprehensive Investigations of Pyrrolo[3,4-d]pyridazinone-Based 1,3,4-Oxadiazole as New Class of Selective COX-2 Inhibitors
by Łukasz Szczukowski, Edward Krzyżak, Adrianna Zborowska, Patrycja Zając, Katarzyna Potyrak, Krzysztof Peregrym, Benita Wiatrak, Aleksandra Marciniak and Piotr Świątek
Int. J. Mol. Sci. 2020, 21(24), 9623; https://doi.org/10.3390/ijms21249623 - 17 Dec 2020
Cited by 23 | Viewed by 3158
Abstract
The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have [...] Read more.
The long-term use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in treatment of different chronic inflammatory disorders is strongly restricted by their serious gastrointestinal adverse effects. Therefore, there is still an urgent need to search for new, safe, and efficient anti-inflammatory agents. Previously, we have reported the Mannich base-type derivatives of pyrrolo[3,4-d]pyridazinone which strongly inhibit cyclooxygenase, have better affinity to COX-2 isoenzyme and exert promising anti-oxidant activity. These findings encouraged us to perform further optimization of that structure. Herein, we present the design, synthesis, molecular docking, spectroscopic, and biological studies of novel pyrrolo[3,4-d]pyridazinone derivatives bearing 4-aryl-1-(1-oxoethyl)piperazine pharmacophore 5a,b–6a,b. The new compounds were obtained via convenient, efficient, one-pot synthesis. According to in vitro evaluations, novel molecules exert no cytotoxicity and act as selective COX-2 inhibitors. These findings stay in good correlation with molecular modeling results, which additionally showed that investigated compounds take a position in the active site of COX-2 very similar to Meloxicam. Moreover, all derivatives reduce the increased level of reactive oxygen and nitrogen species and prevent DNA strand breaks caused by oxidative stress. Finally, performed spectroscopic and molecular docking studies demonstrated that new compound interactions with bovine serum albumin (BSA) are moderate, formation of complexes is in one-to-one ratio, and binding site II (subdomain IIIA) is favorable. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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22 pages, 3128 KiB  
Article
New 1,3,4-Oxadiazole Derivatives of Pyridothiazine-1,1-Dioxide with Anti-Inflammatory Activity
by Teresa Glomb, Benita Wiatrak, Katarzyna Gębczak, Tomasz Gębarowski, Dorota Bodetko, Żaneta Czyżnikowska and Piotr Świątek
Int. J. Mol. Sci. 2020, 21(23), 9122; https://doi.org/10.3390/ijms21239122 - 30 Nov 2020
Cited by 28 | Viewed by 3471
Abstract
Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an [...] Read more.
Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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11 pages, 1832 KiB  
Article
Design, Synthesis and Evaluation of New Bioactive Oxadiazole Derivatives as Anticancer Agents Targeting Bcl-2
by Rania Hamdy, Samia A. Elseginy, Noha I. Ziedan, Mohamed El-Sadek, Elsaid Lashin, Arwyn T. Jones and Andrew D. Westwell
Int. J. Mol. Sci. 2020, 21(23), 8980; https://doi.org/10.3390/ijms21238980 - 26 Nov 2020
Cited by 13 | Viewed by 3048
Abstract
A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a–m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic [...] Read more.
A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a–m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a–m in the presence of phosphorus oxychloride. New compounds 4a–m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52–0.88 μM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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24 pages, 5118 KiB  
Article
Design of Novel 4-Aminobenzofuroxans and Evaluation of Their Antimicrobial and Anticancer Activity
by Elena Chugunova, Almir Gazizov, Marina Sazykina, Nurgali Akylbekov, Anastasiya Gildebrant, Ivan Sazykin, Alexander Burilov, Nurbol Appazov, Shorena Karchava, Maria Klimova, Alexandra Voloshina, Anastasia Sapunova, Syumbelya Gumerova, Ayrat Khamatgalimov, Tatiana Gerasimova, Alexey Dobrynin, Olga Gogoleva and Vladimir Gorshkov
Int. J. Mol. Sci. 2020, 21(21), 8292; https://doi.org/10.3390/ijms21218292 - 5 Nov 2020
Cited by 6 | Viewed by 2869
Abstract
A series of novel 4-aminobenzofuroxan derivatives containing aromatic/aliphatic amines fragments was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan. The quantum chemistry calculations were performed to identify the factors affecting the regioselectivity of the reaction. The formation of 4-substituted isomer is favored both [...] Read more.
A series of novel 4-aminobenzofuroxan derivatives containing aromatic/aliphatic amines fragments was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan. The quantum chemistry calculations were performed to identify the factors affecting the regioselectivity of the reaction. The formation of 4-substituted isomer is favored both by its greater stability and the lower activation barrier. Antimicrobial activity of the obtained compounds has been evaluated and some of them were found to suppress effectively bacterial biofilm growth. Fungistatic activity of 4-aminobenzofuroxans were tested on two genetically distinct isolates of M. nivale. The effect of some benzofuroxan derivatives is likely to be more universal against different varieties of M. nivale compared with benzimidazole and carbendazim. Additionally, their anti-cancer activity in vitro has been tested. 4-aminofuroxans possessing aniline moiety showed a high selectivity towards MCF-7 and M-HeLa tumor cell lines. Moreover, they exhibit a significantly lower toxicity towards normal liver cells compared to Doxorubicin and Tamoxifen. Thus, benzofuroxans containing aromatic amines fragments in their structure are promising candidates for further development both as anti-cancer and anti-microbial agents. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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10 pages, 5756 KiB  
Communication
1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer
by Anton Shetnev, Sergey Baykov, Stanislav Kalinin, Alexandra Belova, Vladimir Sharoyko, Anton Rozhkov, Lev Zelenkov, Marina Tarasenko, Evgeny Sadykov, Mikhail Korsakov and Mikhail Krasavin
Int. J. Mol. Sci. 2019, 20(7), 1699; https://doi.org/10.3390/ijms20071699 - 5 Apr 2019
Cited by 37 | Viewed by 4370
Abstract
Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative [...] Read more.
Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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17 pages, 5136 KiB  
Article
Novel 1,3,4-Oxadiazole Derivatives Containing a Cinnamic Acid Moiety as Potential Bactericide for Rice Bacterial Diseases
by Shaobo Wang, Xiuhai Gan, Yanju Wang, Shaoyuan Li, Chongfen Yi, Jixiang Chen, Fangcheng He, Yuyuan Yang, Deyu Hu and Baoan Song
Int. J. Mol. Sci. 2019, 20(5), 1020; https://doi.org/10.3390/ijms20051020 - 26 Feb 2019
Cited by 34 | Viewed by 4240
Abstract
Rice bacterial leaf blight and leaf streak are two important bacterial diseases of rice, which can result in yield loss. Currently, effective antimicrobials for rice bacterial diseases are still lacking. Thus, to develop highly effective and low-risk bactericides, 31 novel 1,3,4-oxadiazole derivatives containing [...] Read more.
Rice bacterial leaf blight and leaf streak are two important bacterial diseases of rice, which can result in yield loss. Currently, effective antimicrobials for rice bacterial diseases are still lacking. Thus, to develop highly effective and low-risk bactericides, 31 novel 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety were designed and synthesized. Bioassay results demonstrated that all compounds exhibited good antibacterial activities in vitro. Significantly, compounds 5r and 5t showed excellent antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and X. oryzae pv. oryzicola (Xoc), with the 50% effective concentration (EC50) values of 0.58 and 0.34, and 0.44 and 0.20 μg/mL, respectively. These compounds were much better than thiodiazole copper (123.10 and 161.52 μg/mL) and bismerthiazol (85.66 and 110.96 μg/mL). Moreover, compound 5t had better protective and curative activities against rice bacterial leaf blight and leaf streak than thiodiazole copper and bismerthiazol in vivo. Simultaneously, the in vivo efficacy of the compounds was demonstrated by real-time quantitative PCR to quantify bacterial titers. In addition, a three-dimensional quantitative structure–activity relationship model was created and presented good predictive ability. This work provides support for 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety as a potential new bactericide for rice bacterial diseases. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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Review

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28 pages, 4815 KiB  
Review
Groundbreaking Anticancer Activity of Highly Diversified Oxadiazole Scaffolds
by Alessandra Benassi, Filippo Doria and Valentina Pirota
Int. J. Mol. Sci. 2020, 21(22), 8692; https://doi.org/10.3390/ijms21228692 - 18 Nov 2020
Cited by 41 | Viewed by 5177
Abstract
Nowadays, an increasing number of heterocyclic-based drugs found application in medicinal chemistry and, in particular, as anticancer agents. In this context, oxadiazoles—five-membered aromatic rings—emerged for their interesting biological properties. Modification of oxadiazole scaffolds represents a valid strategy to increase their anticancer activity, especially [...] Read more.
Nowadays, an increasing number of heterocyclic-based drugs found application in medicinal chemistry and, in particular, as anticancer agents. In this context, oxadiazoles—five-membered aromatic rings—emerged for their interesting biological properties. Modification of oxadiazole scaffolds represents a valid strategy to increase their anticancer activity, especially on 1,2,4 and 1,3,4 regioisomers. In the last years, an increasing number of oxadiazole derivatives, with remarkable cytotoxicity for several tumor lines, were identified. Structural modifications, that ensure higher cytotoxicity towards malignant cells, represent a solid starting point in the development of novel oxadiazole-based drugs. To increase the specificity of this strategy, outstanding oxadiazole scaffolds have been designed to selectively interact with biological targets, including enzymes, globular proteins, and nucleic acids, showing more promising antitumor effects. In the present work, we aim to provide a comprehensive overview of the anticancer activity of these heterocycles, describing their effect on different targets and highlighting how their structural versatility has been exploited to modulate their biological properties. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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17 pages, 3018 KiB  
Review
Metal Complexes of Oxadiazole Ligands: An Overview
by Giovanni Salassa and Alessio Terenzi
Int. J. Mol. Sci. 2019, 20(14), 3483; https://doi.org/10.3390/ijms20143483 - 16 Jul 2019
Cited by 36 | Viewed by 5324
Abstract
Oxadizoles are heterocyclic ring systems that find application in different scientific disciplines, from medicinal chemistry to optoelectronics. Coordination with metals (especially the transition ones) proved to enhance the intrinsic characteristics of these organic ligands and many metal complexes of oxadiazoles showed attractive characteristics [...] Read more.
Oxadizoles are heterocyclic ring systems that find application in different scientific disciplines, from medicinal chemistry to optoelectronics. Coordination with metals (especially the transition ones) proved to enhance the intrinsic characteristics of these organic ligands and many metal complexes of oxadiazoles showed attractive characteristics for different research fields. In this review, we provide a general overview on different metal complexes and polymers containing oxadiazole moieties, reporting the principal synthetic approaches adopted for their preparation and showing the variety of applications they found in the last 40 years. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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18 pages, 2229 KiB  
Review
Strategies against Nonsense: Oxadiazoles as Translational Readthrough-Inducing Drugs (TRIDs)
by Ambra Campofelice, Laura Lentini, Aldo Di Leonardo, Raffaella Melfi, Marco Tutone, Andrea Pace and Ivana Pibiri
Int. J. Mol. Sci. 2019, 20(13), 3329; https://doi.org/10.3390/ijms20133329 - 6 Jul 2019
Cited by 33 | Viewed by 6072
Abstract
This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of [...] Read more.
This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs. Full article
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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