Editorial

2 pages, 155 KiB

Open AccessEditorial

Editorial for Special Issue “Bioactive Oxadiazoles”

by Antonio Palumbo Piccionello

Int. J. Mol. Sci. 2021, 22(8), 3988; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22083988 - 13 Apr 2021

Cited by 1 | Viewed by 1037

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249623 - 17 Dec 2020

Cited by 22 | Viewed by 2577

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

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22 pages, 3128 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239122 - 30 Nov 2020

Cited by 21 | Viewed by 2937

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21238980 - 26 Nov 2020

Cited by 10 | Viewed by 2490

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

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24 pages, 5118 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21218292 - 05 Nov 2020

Cited by 5 | Viewed by 2440

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

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10 pages, 5756 KiB

Open AccessCommunication

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20071699 - 05 Apr 2019

Cited by 33 | Viewed by 3982

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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051020 - 26 Feb 2019

Cited by 30 | Viewed by 3800

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

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228692 - 18 Nov 2020

Cited by 31 | Viewed by 4333

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

Open AccessReview

Metal Complexes of Oxadiazole Ligands: An Overview

by Giovanni Salassa and Alessio Terenzi

Int. J. Mol. Sci. 2019, 20(14), 3483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143483 - 16 Jul 2019

Cited by 29 | Viewed by 4576

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

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18 pages, 2229 KiB

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133329 - 06 Jul 2019

Cited by 31 | Viewed by 5496

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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