HETEROCYCLES

■ Contents

■ Recent Advances in the Synthesis of 1,2,4-Triazolo[3,4-b][1,3,4]thiadiazole Compounds: A Mini-Review

Jin Luo,* Puqing Chen, and Chonghu Song

*Analytical and Testing Center, Jiangxi Normal University, Nanchang, Jiangxi 330022, China

Abstract

1,2,4-Triazolo[3,4-b][1,3,4]thiadiazoles are important sulphur- and nitrogen-containing fused heterocycles that can act as promising scaffolds exhibiting outstanding biological activities. Herein, we focused on the major synthetic pathways and methodologies for the synthesis of 1,2,4-triazolo[3,4-b][1,3,4]thiadiazole compounds in an attempt to facilitate the discovery of unique 1,2,4-triazolo[3,4-b]-[1,3,4]thiadiazole derivatives with improved biological activities.

■ Hydroxychloroquine: Chemistry and Medicinal Applications

Nidhi Yadav, Yogesh Kumar Tyagi,* and Ram Singh*

*Department of Applied Chemistry, Delhi Technological University, Delhi - 110042, India

Abstract

Hydroxychloroquine (HCQ) is a molecule from the 4-aminoquinoline family which is utilized for the treatment of many diseases. This is one of the essential drugs, as per WHO. HCQ has been an anti-malarial drug and is also used for the treatment of autoimmune and rheumatic diseases. This molecule is repurposed for many types of diseases, either alone or in combination with other drugs. This review article discusses its synthetic methodologies and approved applications along with repurposed studies. This article covers HCQ applications in anti-cancer activity, anti-rheumatic activity, epigenetic activity, systemic lupus erythematosus, and COVID-19.

■ Design, Synthesis, and Biological Evaluation of New Di-arylimidazole-Quinazolinone Hybrid

Parsa Moghimirad, Shahin Boumi, Seyed Nasser Ostad, Maliheh Barazandeh Tehrani,* and Mohsen Amini*

*Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran14176, Iran

Abstract

The aim of this study is synthesis of new diarylimidazole-quinazolinone hybrid derivatives to target two binding sites of tubulin, an attractive target for design of anticancer drugs. In this report, the location of the accessible space of active site was determined by comparing the crystal structure of different inhibitors in tubulin structure. The docking and molecular dynamic simulations were used to confirm the position and stability of designed compounds. Thirteen new compounds were synthesized and their cytotoxicity were studied on three types of cancerous cell lines. Some of the synthesized compounds showed remarkable anti-proliferative activity in cell culture study.

■ Sulfate Radical Anion (SO4˙ˉ) Mediated Degradation of Some Over-the-Counter Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) at Neutral pH in Aqueous Environment

Joydev K. Laha,* Neelam Manral, Sagar Badoni, Mandeep Kaur Hunjan, and Upma Gulati

*Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Punjab 160062, India

Abstract

The degradation of some common NSAIDs containing an arylacetic acid moiety via thermal oxidative decarboxylation using potassium persulfate (K2S2O8) in water at 80 °C has been investigated. A neutral pH condition is critical for efficient degradation of the drugs yielding the degraded products (corresponding carbonyl compounds). The drugs remain unaffected at lower (2-3) or higher pH (9-10). Unlike the common practice of identification of pharmaceutical degradation products by LC-MS data, the current report unveils major degradation products through isolation and identification using standard analytical techniques. The mechanism of the formation of degradation products via a radical pathway is discussed. The current report on NSAIDs degradation features a rare study in the contemporary pharmaceutical degradation dispersed in the literature.

■ Organic Base-Catalyzed Cascade Reaction of Electron-Deficient Cyclopentadienone with Prop-2-yn-1-ols: Formation of 3-Methylenetetrahydrofuran Ring Condensed with Cyclopentenone

Koki Yamaguchi*

*Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan

Abstract

2,5-Bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone (1a) reacts with prop-2-yn-1-ols (2) in the presence of 1,4-diazabicyclo[2.2.2]octane at room temperature to produce bicyclic carbocycles (4) in moderate yields, as well as tetracyclic carbocycle (5). The bicyclic carbocycle, which has a 3-methylenetetrahydrofuran moiety, is derived from the anionic cyclization of the 1,4-adducts of 1a and 2 onto a non-activated alkyne. The mechanism of the cascade reaction was discussed based on the density functional theory calculations and the X-ray crystallographic analysis.

■ Selective Synthesis of 2,2-Diamino-4,4,6,6-tetrakis(aryloxy)cyclotriphosphazenes N3P3-2,2-(NH2)2-4,4,6,6-(ArO)4

Manabu Kuroboshi,* Fumiya Nakamura, and Hideo Tanaka

*Graduate School of Natural Science and Technology, Okayama University, Tsushima-naka 3-1-1, Kita-ku, Okayama, Japan

Abstract

To synthesize cyclotriphosphazene derivatives having multi-functional groups, aryloxylation of 2,2-diamimo-4,4,6,6-tetrachlorocyclotriphosphazene 2 was examined. A mixture of gem-disubstituted N3P3(NH2)2(ArO)2Cl2 9gem, tri-substituted N3P3(NH2)2(ArO)3Cl 10, and tetra-substituted N3P3(NH2)2(ArO)4 11 was obtained, especially 11 was obtained selectively when excess amount (6 equiv.) of ArONa was used. On the other hand, mono-substituted N3P3(NH2)2(ArO)Cl3 8 and non-gem-di-substituted N3P3(NH2)2(ArO)2Cl2 9non-gem-cis and 9non-gem-trans were not detected.

■ A New Compound Embeloside A with Hypoglycemic Potential from the Fruits of Embelia oblongifolia Hemsl.

Ying Xu, Yuqi Sun, Bing Liu, Ning Chen, Yingjie Liu, Dongxue Wang, Lei Yu,* and Haifeng Wang*

*School of Pharmacy, Harbin University of Commerce, Harbin, 150076, China

Abstract

A total of eleven compounds were isolated from the ripe and dried fruits of Embelia oblongifolia Hemsl. Compound 1 was a new one named embeloside A, in addition, compounds 2-4, 6 and 10 were isolated from this genus for the first time. Their molecular structures were elucidated by 1D/2D NMR spectroscopic analysis, HR-ESI-MS spectral data and charged aerosol detector (CAD). Further, hypoglycemic activity evaluation showed that compound 1 could reduce the fasting blood glucose levels in diabetic rats. Therefore, the results suggest that compound 1 might provide a theoretical basis for the development of potential hypoglycemic drugs. The discovery of compounds 1-11 might provide experimental guidance for the further development of Embelia oblongifolia Hemsl.

■ Synthesis and Fungicidal Activities of 5-Aryl-1,3,4-oxadiazolyl 2-Thioether Derivatives Containing Strobilurin Motif

Hongtao Wang, Wenliang Zhang, and Xiaohua Du*

*Catalytic Hydrogenation Research Center, Zhejiang Key Laboratory of Green Pesticides and Cleaner Production Technology, Zhejiang University of Technology, Hangzhou 310014, China

Abstract

A novel class of 2,5-disubstituted 1,3,4-oxadiazole derivatives was synthesized through active substructure splicing by using kresoxim-methyl as the lead compound. The structure of the title compound was confirmed via structural characterization, and the preliminary assessment of the fungicidal activities revealed that compounds 6b, 6k, 6m, 6n, and 6o are active against Pyricularia oryzae Cav. to a comparable degree to kresoxim-methyl (50 mg/L). Further, control experiments revealed that 6o exhibited in vitro fungicidal activity against P. oryzae Cav., having a median effective concentration (EC50) of 10.03 mg/L, slightly higher than that of kresoxim-methyl (14.21 mg/L). Therefore, 6o is a promising lead compound that warrants further investigation.