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Infections
Published in Evelyne Jacqz-Aigrain, Imti Choonara, Paediatric Clinical Pharmacology, 2021
Evelyne Jacqz-Aigrain, Imti Choonara
This substance, 3-[3,5dimethyl-4[[3-(3-methyl-5-isoxazolyl)propyl]oxy]phe nyl]-5-trifuoromethyl)-1,2,4-oxadiazole, has not yet received official approval. Randomised studies with adults and children have shown that it reduces the severity and duration of symptoms for meningitis due to enterovirus. A study with children under the age of 12 months suffering from enteroviral meningitis has shown good tolerance for the drug at concentrations greater than that required to cause a 90% inhibition effect for the enterovirus [3]. However, an accumulation of the drug between day 2 and day 7 and some secondary effects that were more frequent than for placebo, underscore the need to reinforce surveillance of the toxicity. Indications for this product should be limited to the rare serious cases of enterovirus infection and not for those types that are spontaneously resolving.
Hits and Lead Discovery in the Identification of New Drugs against the Trypanosomatidic Infections
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Theodora Calogeropoulou, George E. Magoulas, Ina Pöhner, Joanna Panecka-Hofman, Pasquale Linciano, Stefania Ferrari, Nuno Santarem, Ma Dolores Jiménez-Antón, Ana Isabel Olías-Molero, José María Alunda, Anabela Cordeiro da Silva, Rebecca C. Wade, Maria Paola Costi
A variety of computational chemistry methods has been used to study cruzain interactions with inhibitors, to better understand their MoA, and to design new compounds. Hologram quantitative structure- activity relationship, comparative molecular field analysis and comparative molecular similarity index analysis methods combined with docking simulations have been applied to a series of benzimidazole-based cruzain inhibitors by Pauli et al. (2017) to predict binding modes and activities. Silva et al. (2017) used docking studies and QSAR methods to study nitrile-containing cruzain inhibitors and predict their activities, leading to the proposal of new potential inhibitors. de Souza et al. (2017) used 2D- and 3D-QSAR methods to explore the interactions of oxadiazole-based compounds with different cruzain subsites. Elizondo-Jimenez et al. (2017) synthesized benzenesulfonyl and N-propionyl benzenesulfonyl hydrazone derivatives, evaluated their anti-T. cruzi activity and used docking studies to propose covalent binding to cruzain as the compounds’ MoA. Silva-Júnior et al. (2016) synthesized several trypanocidal thiophen-2-iminothiazolidines and used molecular docking to demonstrate that the most active compound likely interacts simultaneously with two subsites of cruzain.
HIV Integrase Inhibitors
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
A 2D-QSAR study was reported by Ravichandran et al. (2010) using SAR data of 67 oxadiazole substituted naphthyridine derivatives, inhibitors of the IN strand transfer mechanism (Johns et al. 2009a). The best MLR-based 2D-QSAR model indicated that high electronegativity, low dielectric constant, and highly branched, unsaturated, and long chain groups are conducive for high enzyme inhibitory activity of these derivatives. Veerasamy et al. (2011) developed a 2D-QSAR model to analyze the antiviral inhibitory activity of 63 compounds from the same series of oxadiazole-substituted naphthyridines (Johns et al. 2009b) for which Ravichandran et al. (2010) also analyzed strand transfer enzyme inhibitory activity. The authors reported that the shape index, partition coefficient, and solvent accessible surface are related descriptors and play an important role in governing the anti-HIV activities of these derivatives. These two QSAR studies (Ravichandran et al. 2010; Veerasamy et al. 2011) indicated the importance of different physicochemical parameters for improving the enzyme inhibitory activity and anti-HIV activity of these derivatives. More studies comparing two different biological end points are required to delineate the similarities and differences in these two biological activities.
Research progress on the synthesis and pharmacology of 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives: a mini review
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Jing-Jing Wang, Wen Sun, Wei-Dong Jia, Ming Bian, Li-Jun Yu
Oxadiazole is a critical component of pharmacophores and ligand binding1. It is a heterocyclic aromatic linking group capable of connecting a variety of substituents and exhibits the same biological activity as esters, amides and carbamates2. While 1,2,3-oxadiazole is unstable, 1,2,4-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole are all common and have been commercialised. Among them, 1,3,4-oxadiazole and 1,2,4-oxadiazole are important heterocyclic compounds with significant biological activity. Their synthesis has been the focus of our attention for a long time3–5. It has been reported that 1,3,4-oxadiazole and 1,2,4-oxadiazole derivatives possess antibacterial, anti-inflammatory, anti-tubercular, anti-HIV, antifungal, cathepsin K (Cat K) inhibitory, monoamine oxidase inhibitory, anti-diabetic, tyrosinase inhibitory, antioxidant and anticancer activities6–8. The majority of commercially available antihypertensive agents such as Tiodazosin and Nesapidil, as well as antibiotics such as Furamizole, contain the oxadiazole nucleus9–10. This article aims to describe the different derivatives of oxadiazole and their activities.
QSAR study of antituberculosis activity of oxadiazole derivatives using DFT calculations
Published in Journal of Receptors and Signal Transduction, 2022
Sharieh Hosseini, Sepideh Ketabi, Golnar Hasheminasab
Oxadiazoles are a class of heterocyclic aromatic chemical compounds. For the synthesis of new therapeutic compounds, oxadiazoles are at the center of researches attention. 1,3,4 oxadiazoles have special importance due to their significant biological properties, such as antibacterial, antifungal, anti-Tb, and anti-cancer, Moreover, Oxadiazole derivatives have many applications in biology. Therefore, they can be a good alternative for antimicrobial drugs [7–10]. Oxadiazole is one of the structures considered by researchers for the synthesis of new therapeutic compounds. Mandelic acid is an alpha hydroxy acid used to treat urinary tract and skin infections [10–13]. Due to the significant antimicrobial effects of many derivatives of 1, 3, and 4 oxadiazoles and Mandelic acid, several hybrid structures derived from 1, 3, and 4 oxadiazole and the benzyl ethyl mandelate group were designed and synthesized and their antibacterial and antifungal activity was investigated. Oxadiazole derivatives have many biological applications and can be a good alternative to antimicrobial drugs [14].
New 1,2,4-oxadiazole derivatives with positive mGlu4 receptor modulation activity and antipsychotic-like properties
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Anna Stankiewicz, Katarzyna Kaczorowska, Ryszard Bugno, Aneta Kozioł, Maria H. Paluchowska, Grzegorz Burnat, Barbara Chruścicka, Paulina Chorobik, Piotr Brański, Joanna M. Wierońska, Beata Duszyńska, Andrzej Pilc, Andrzej J. Bojarski
In general, it has been observed that the 1,2,4-oxadiazole derivatives exhibit variable efficacy when tested in vivo. This is most likely due to different pharmacokinetic properties of examined compounds, but firm conclusions can only be drawn after more careful profiling of their drug-like parameters. Nevertheless, the obtained results of in vivo studies clearly indicate the anxiolytic and antipsychotic properties of the tested PAMs of mGlu group III receptors. Indeed, as shown in previous literature reports, group III mGlu receptors are thought to be implicated in such pathological conditions8,70. In particular, the anxiolytic effects of the abovementioned non-selective group III agonist ACTP-I71, as well as a number of mGlu4 receptor PAMs such as Lu AF21934, have been observed in SIH and other acute models used to study anxiety-related behaviour in rodents48. Moreover, both agents have been shown to have an antipsychotic-like profile in various rodent models, including DOI-induced HTR in mice72,77. Thus, except for compound 42 which failed to alter SIH and block DOI-induced HTR in mice, the pharmacological in vivo profiles of 34, 37, 52, 60 and 62 resemble that of the non-selective group III agonist ACTP-I and various mGlu4 receptor PAMs investigated to date78. On the other hand, the lack of antidepressant-like effects of the 1,2,4-oxadiazole derivatives in the TST is similar to our earlier studies, in which we did not find such activity for either the group III agonist ACTP-I71 or the selective mGlu4 receptor PAM Lu AF2193448.