- 2-(1,2,4-Oxadiazol-5-yl)anilines Based on Amidoximes and Isatoic Anhydrides: Synthesis and Structure Features
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Abstract: An efficient one-pot method was developed for the synthesis of 2-(1,2,4-oxadiazol-5-yl)anilines via the reaction of amidoximes with isatoic anhydrides in a NaOH–DMSO medium at ambient temperature. The method allows to obtain structurally diverse
- Baykov, S. V.,Kotlyarova, V. D.,Shetnev, A. A.,Tarasenko, M. V.
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p. 768 - 778
(2021/06/26)
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- Development of Potent 3-Br-isoxazoline-Based Antimalarial and Antileishmanial Compounds
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Starting from the structure of previously reported 3-Br-isoxazoline-based covalent inhibitors of P. falciparum glyceraldehyde 3-phosphate dehydrogenase, and with the intent to improve their metabolic stability and antimalarial activity, we designed and synthesized a series of simplified analogues that are characterized by the insertion of the oxadiazole ring as a bioisosteric replacement for the metabolically labile ester/amide function. We then further replaced the oxadiazole ring with a series of five-membered heterocycles and finally combined the most promising structural features. All the new derivatives were tested in vitro for antimalarial as well as antileishmanial activity. We identified two very promising new lead compounds, endowed with submicromolar antileishmanial activity and nanomolar antiplasmodial activity, respectively, and a very high selectivity index with respect to mammalian cells.
- Basilico, Nicoletta,Conti, Paola,Coser, Consuelo,Galbiati, Andrea,Parapini, Silvia,Tamborini, Lucia,Taramelli, Donatella,Zana, Aureliano
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supporting information
p. 1726 - 1732
(2021/11/01)
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- Entry into (E)-3-(1,2,4-oxadiazol-5-yl)acrylic acids via a one-pot ring-opening/ring-closing/retro-Diels-Alder reaction sequence
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A simple and convenient one-pot method is reported for the synthesis of (E)-3-(3-aryl(heteroaryl, alkyl)-1,2,4-oxadiazole-5-yl)acrylic acids utilizing readily accessible or commercially available substituted benzamidoximes and inexpensive exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride. The method is based on the reaction of amidoximes with the anhydride in a basic medium at RT followed by an acid-catalyzed retro-Diels-Alder reaction. The observed stereoselective heterocyclization/retro-Diels-Alder cascade process is suitable for the synthesis of a wide range of substituted (E)-1,2,4-oxadiazole-5-ylacrylic acids featuring electron donating and electron withdrawing groups on the aryl moiety, as well as heteroaryl or alkyl substituents at position 3 of the 1,2,4-oxadiazole ring (42–79%; 15 examples).
- Presnukhina, Sofia,Tarasenko, Marina,Baykov, Sergey,Smirnov, Sergey N.,Boyarskiy, Vadim P.,Shetnev, Anton,Korsakov, Mikhail K.
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supporting information
(2019/12/27)
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- Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment
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An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly
- Krasavin, Mikhail,Shetnev, Anton,Sharonova, Tatyana,Baykov, Sergey,Kalinin, Stanislav,Nocentini, Alessio,Sharoyko, Vladimir,Poli, Giulio,Tuccinardi, Tiziano,Presnukhina, Sofia,Tennikova, Tatiana B.,Supuran, Claudiu T.
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- Nortopsentin alkaloid derivatives and preparation thereof, and application of nortopsentin alkaloid derivatives to prevention and treatment of diseases and insect pests
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The invention relates to nortopsentin alkaloid derivatives I and preparation thereof, and application of the nortopsentin alkaloid derivatives I to resisting of plant viruses and pathogens and killingof insects. The nortopsentin alkaloid derivatives I in
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Paragraph 0034; 0038; 0039; 0040
(2019/03/26)
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- Marine-Natural-Product Development: First Discovery of Nortopsentin Alkaloids as Novel Antiviral, Anti-phytopathogenic-Fungus, and Insecticidal Agents
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Nortopsentin alkaloids were found to have potent antiviral, anti-phytopathogenic-fungus, and insecticidal activities for the first time. Antiviral-activity tests revealed that these compounds were very sensitive to substituents, so a series of nortopsentin derivatives were designed, synthesized, and systematically evaluated for their antiviral activities against TMV, their fungicidal activities, and their insecticidal activities on the basis of a structural-diversity-derivation strategy. Compounds 2e (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 50, 59, and 56%, respectively, at 500 μg/mL) and 2k (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 60, 58, and 52%, respectively, at 500 μg/mL), with excellent antiviral activities and good physicochemical properties, emerged as new lead compounds for novel-antiviral-agent development. Further fungicidal-activity tests revealed that these alkaloids displayed broad-spectrum fungicidal activities. Compounds 2f, 2h, and 2j emerged as new lead compounds for antifungal-activity research. Additionally, all the compounds displayed good insecticidal activities against five kinds of insects, including Mythimna separate, Helicoverpa armigera, Ostrinia nubilalis, Plutella xylostella, and Culex pipiens pallens.
- Ji, Xiaofei,Guo, Jincheng,Liu, Yuxiu,Lu, Aidang,Wang, Ziwen,Li, Yongqiang,Yang, Shaoxiang,Wang, Qingmin
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p. 4062 - 4072
(2018/05/03)
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- Room-temperature synthesis of pharmaceutically important carboxylic acids bearing the 1,2,4-oxadiazole moiety
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An efficient and mild one-pot protocol has been developed for the synthesis of 1,2,4-oxadiazoles via the reaction of amidoximes with dicarboxylic acid anhydrides in a NaOH/DMSO medium. The method allows the synthesis of diversely substituted carboxylic acids bearing the 1,2,4-oxadiazole motif, – a popular building block for pharmaceutical research, in moderate to excellent yields. The reaction scope includes aromatic and heteroaromatic amidoximes as well as five-, six- and seven-membered anhydrides. The advantages of this procedure are proven gram-scalability and the use of inexpensive starting materials, which from a process chemistry point of view are essential for future industrial applications.
- Tarasenko, Marina,Duderin, Nikolay,Sharonova, Tatyana,Baykov, Sergey,Shetnev, Anton,Smirnov, Alexey V.
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supporting information
p. 3672 - 3677
(2017/08/23)
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- Expanding Synthesizable Space of Disubstituted 1,2,4-Oxadiazoles
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One-pot synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from carboxylic acids and nitriles was optimized to parallel chemistry. The method was validated on a 141 member library; the desired products were recovered with a high success rate and in moderate yields. Practical application of the approach was demonstrated in the synthesis of bioactive compound pifexole and agonists of free fatty acid receptor 1. A library of 4 948 100 synthesizable drug-like 3,5-disubstituted 1,2,4-oxadiazoles was enumerated based on the method and available validated reagents.
- Tolmachev, Andrey,Bogolubsky, Andrey V.,Pipko, Sergey E.,Grishchenko, Alexander V.,Ushakov, Dmytro V.,Zhemera, Anton V.,Viniychuk, Oleksandr O.,Konovets, Anzhelika I.,Zaporozhets, Olga A.,Mykhailiuk, Pavel K.,Moroz, Yurii S.
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p. 616 - 624
(2016/10/21)
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- Discovery of highly potent triazole antifungal agents with piperidine-oxadiazole side chains
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Due to increasing incidence and mortality of invasive fungal infections, discovery and development of new generations of antifungal agents represents a challenging task. On the basis of our previously reported triazole-benzyloxypiperidinyl lead compound, a series of novel triazole antifungal agents containing piperidine-oxadiazole side chains were rationally designed and synthesized. Most of the target compounds showed excellent inhibitory activity against clinically important fungal pathogens. In particular, compounds 6g (MIC = 0.031 μg mL-1) and 11b (MIC = 0.016 μg mL-1) were highly active against Candida albicans including fluconazole-resistant strains. Moreover, they showed inhibitory activity against hyphal formation with low toxicity, which were promising leads for further development. This journal is
- He, Xiaomeng,Jiang, Yan,Zhang, Yongqiang,Wu, Shanchao,Dong, Guoqiang,Liu, Na,Liu, Yang,Yao, Jianzhong,Miao, Zhenyuan,Wang, Yan,Zhang, Wannian,Sheng, Chunquan
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p. 653 - 664
(2015/04/27)
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- Whole cell screen based identification of spiropiperidines with potent antitubercular properties
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Abstract Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[indene-1,4′-piperidine] (abbr. spiroindenes), 4-(3-aryl-1,2,4-oxadiazol-5-yl)-1′-alkylspiro[chromene-2,4′-piperidine] (abbr. spirochromenes) and 1′-benzylspiro[indole-1,4′-piperidin]-2(1H)-one (abbr. spiroindolones). Spiroindenes showed ≥4 log10 kill (at 2-12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.
- Tantry, Subramanyam J.,Degiacomi, Giulia,Sharma, Sreevalli,Jena, Lalit Kumar,Narayan, Ashwini,Guptha, Supreeth,Shanbhag, Gajanan,Menasinakai, Sreenivasaiah,Mallya, Meenakshi,Awasthy, Disha,Balakrishnan, Gayathri,Kaur, Parvinder,Bhattacharjee, Deepa,Narayan, Chandan,Reddy, Jitendar,Naveen Kumar,Shandil, Radha,Boldrin, Francesca,Ventura, Marcello,Manganelli, Riccardo,Hartkoorn, Ruben C.,Cole, Stewart T.,Panda, Manoranjan,Markad, Shankar D.,Ramachandran, Vasanthi,Ghorpade, Sandeep R.,Dinesh, Neela
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p. 3234 - 3245
(2015/07/08)
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- Microwave-assisted synthesis, molecular docking and antiproliferative activity of (3/5-aryl-1,2,4-oxadiazole-5/3-yl)(3,4,5-trimethoxyphenyl)methanone oxime derivatives
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A series of (3/5-aryl-1,2,4-oxadiazole-5/3-yl)(3,4,5-trimethoxyphenyl)methanone oxime derivatives were synthesized via a rapid and facile microwave-assisted synthesis method of building a 1,2,4-oxadiazole skeleton using mandelic acid as the starting material. Twenty-four target compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines (SGC-7901, A549 and HT-1080). Among them, 16b exhibited the highest potency against different tumour cell lines, especially the A549 cell line (IC50 = 87 nM). Structure-activity relationship (SAR) studies revealed that the aryl substituent at the C-5 position on the 1,2,4-oxadiazole ring is superior to that at the C-3 position. An oxime as a connector can obviously increase the potency, contrary to that in SMART derivatives. Moreover, 16b significantly induced a cell cycle arrest in the G2/M phase and caused microtubule destabilization. Molecular docking studies provided a theoretical binding mode of 16b at the colchicine site in the tubulin dimer. Our work laid the foundation for further structure-guided design of novel tubulin polymerization inhibitors.
- Guan, Qi,Feng, Dongjie,Bai, Zhaoshi,Cui, Yuanhang,Zuo, Daiying,Zhai, Min'An,Jiang, Xuewei,Zhou, Wenbo,Bao, Kai,Wu, Yingliang,Zhang, Weige
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supporting information
p. 1484 - 1493
(2015/08/18)
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- 2-(3-Thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acids as inhibitors of HCV NS5B RdRp
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A series of 2-(3-thienyl)-5,6-dihydroxypyrimidine-4-carboxylic acid inhibitors of the hepatitis C virus (HCV) NS5B polymerase enzyme are reported. Sulfonyl urea substituted analogs in this series proved to be the most potent active site non-nucleoside inh
- Pacini, Barbara,Avolio, Salvatore,Ercolani, Caterina,Koch, Uwe,Migliaccio, Giovanni,Narjes, Frank,Pacini, Laura,Tomei, Licia,Harper, Steven
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scheme or table
p. 6245 - 6249
(2010/06/19)
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- NEW COMPOUNDS
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The present invention relates to new compounds of formula I, (I) a process for their preparation and new intermediates prepared therein, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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