

HETEROCYCLES
An International Journal for Reviews and Communications in Heterocyclic ChemistryWeb Edition ISSN: 1881-0942
Published online by The Japan Institute of Heterocyclic Chemistry
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Published online: 25th May, 2023
Paper | Regular issue | Prepress■ Design, Synthesis, and Biological Evaluation of Novel 6,8-Disubstituted Imidazo[1,2-a]pyridine Derivatives as a Cdk2 Inhibitors
Bhargav Bhimani, Ashish Patel,* Umang Shah, Afzal Nagani, Vruti Parikh, Harnisha Patel, Hirak Shah, Drashti Shah, Bhavna Patel, and Nilesh Pandey
*Ramanbhai Patel College of Pharmacy, Charotar University of Science and Technology, CHARUSAT Campus, Changa-388421, India
Abstract
Imidazo[1,2-a]pyridine exerts a notable pharmacological efficiency and has emerged as an integral backbone for the treatment of various cancer. Inhibition of cyclin-dependent kinases has emerged as a potential therapeutic strategy for a variety of cancers. Here, we discuss the synthesis of imidazo[1,2-a]pyridine derivatives modified at positions 6 and 8 prepared using Suzuki-Miyaura cross-coupling, Buchwald reaction, and peptide coupling as the main synthetic methods. All synthesized compounds were characterized by spectroscopy techniques after purification and screened for their anti-cancer activity by in vitro MTT assays against MCF-T cell line and CDK2 inhibition by kinase inhibition assay. The in vitro and kinase inhibition assay revealed that compounds 11ii, 11iii, 11xxi, 11vi, and 11viii show potent anti-cancer activity for the treatment of breast cancer. This study demonstrates that substituted imidazo[1,2-a]pyridine can be exploited for future cyclin-dependent kinase (CDK2) inhibitor development.
Published online: 24th May, 2023
Review | Regular issue | Prepress■ 1,3,5-Triazine-Cored Star-Shaped (D-π)3-A Molecules Based on 2,4,6-Tris(5-Arylthiophen-2-Yl)-1,3,5-Triazine
Hiroki Muraoka* and Satoshi Ogawa
*Department of Chemistry and Bioengineering, Faculty of Engineering, Iwate University, 4-3-5 Ueda, Morioka, Iwate 020-8551, Japan
Abstract
Star-shaped (D–π)3–A molecules consist of three parts: an electron-accepting core (A), π-conjugated bridges (π), and electron-donating terminals (D). These molecules are commonly designed using a π (thiophene)3–A (1,3,5-triazine) segment composed of 2,4,6-tri(thiophen-2-yl)-1,3,5-triazine (TTT), which offers geometric and electronic structural advantages. By structurally and electronically modifying TTT with different types of electron-donating aryl terminals, we systematically construct TTT-based star-shaped (D–π)3–A molecules with controlled molecular properties attributed to a special structure in which the star-shaped and D–π–A structures are hybridized. This review summarizes our researches on the synthesis, optical and electronic characterization, and application of a series of 2,4,6-tris(5-arylthiophen-2-yl)-1,3,5-triazines based on our concept.
Published online: 23rd May, 2023
Short Paper | Regular issue | Prepress■ Cysteine Catalyzed Water Mediated Eco-Friendly Approach for the Synthesis of 5-Substituted 1H-Tetrazole and Its Derivatives
Vikas V. Borge, Ramchandra G. Thorat, Arun K. Kadu, Vikas M. Bangade, Parag S. Panse, Gangadhar A. Meshram, and Bhushan B. Popatkar*
*Department of Chemistry, University of Mumbai, Vidyanagari, Kalina, Santacruz (E), Mumbai, Maharashtra 400 098, India
Abstract
Cysteine catalyzed, water mediated, one-pot multi-component protocol for the synthesis of 5-substituted 1H-tetrazole and its functional derivatives has been developed. The reaction between various aldehydes, hydroxylamine hydrochloride and sodium azide under the optimized reaction condition affords desired product(s). The utilization of water as a green solvent for the synthesis of the titled compounds is an important feature of this process. The moderate to high yield of the product, reaction at room temperature, exclusion of volatile toxic organic solvent and an operational simplicity are some of the advantages of this methodology.
Published online: 19th May, 2023
Short Paper | Regular issue | Prepress■ Synthesis of Arylidenisoxazol-5-ones Catalyzed by Sodium Cyclamate
Ziba Daroughezadeh and Hamzeh Kiyani*
*School of Chemistry, Damghan University, 36719-41167 Damghan, Iran
Abstract
The three-component reactions using aryl aldehydes, hydroxylamine hydrochloride, and β-ketoesters (ethyl acetoacetate, ethyl 4-chloro-3-oxobutanoate, and ethyl 3-oxohexanoate) as available precursors were performed to synthesize arylideneisoxazol-5-ones. The experiments have been catalyzed using sodium cyclamate and high yields of products were obtained under green conditions at room temperature. Relatively shorter reaction time, free from the use of organic reaction medium, the simplicity of the method, the formation of pure products without using chromatographic methods, and inexpensive are among the advantages of this method. Heating and the use of other devices for energy supply are not required. Also, in this three-component process, using water as a reaction medium is in line with the principles of green chemistry.
Published online: 17th May, 2023
Paper | Regular issue | Prepress■ Construction of Supramolecular Frameworks Comprised of Fully-Substituted Cyclopentanocucurbit[6]uril and Two Phenolic Acids
Naqin Yang, Yue Ma, Jun Zheng, Xinan Yang, and Peihua Ma*
*Key Laboratory of Macrocyclic and Supramolecular Chemistry of Guizhou Province, Guizhou University, Guiyang 550025, People’s Republic of China
Abstract
In this paper, fully substituted cyclopentanocucurbit[6]uril (CyP6Q[6]) and calcium ions were coordinated in the presence of cadmium chloride in hydrochloric acid solution, followed by the addition of p-hydroxybenzoic acid (G1) and 2,5-dihydroxybenzoic acid (G2) to construct two supramolecular frameworks, respectively. Their structures and interactions were characterized using single-crystal X-ray diffraction, X-ray powder diffraction. The results showed that calcium ions coordinate with the carbonyl-fringed portals of CyP6Q[6], G1 and G2 act on the outer surface of CyP6Q[6] via C-H....π interactions, and [CdCl4]2– participates in ion-dipole interactions with CyP6Q[6] to form a framework structure consisting of pores and layers.
Published online: 17th May, 2023
Paper | Regular issue | Prepress■ Functionalization of Phenothiazine Derivatives by Ammonium Bridge
Hideki Hayashi,* Tadashi Ogawa, Hiroshi Seno, and Take-aki Koizumi
*Nagoya Municipal Industrial Research Institute, 3-4-41, Rokuban, Atsuta-ku, Nagoya 456-0058
Abstract
Ammonium-bridged bis(promazine) type compounds (BA-PF6: [Y-N+Me2-CH2-R-CH2-N+Me2-Y]2+[PF6-]2, Y = 3-(phenothiazin-10-yl)propyl, 3-(5-oxophenothiazin-10-yl)propyl, 3-(2-chlorophenothiazin-10-yl)propyl, and 3-(5-oxo-2-chlorophenothiazin-10-yl)propyl; R = octane-1,8-diyl, 1,4-phenylene, biphenylene-4,4’-diyl, and 2,2'-bipyridine-4,4’-diyl) were prepared and the effects of the central R unit and side Y unit were investigated. The products’ optical and electrochemical properties showed the effect of the central and side unit, suggesting that the products had two independent functional groups in one molecule. X-Ray crystallographic analyses indicated that the spatial placement of the compounds was controlled by the central R unit, which behaves as a spacer without changing the properties of the molecules.
Published online: 9th May, 2023
Review | Regular issue | Prepress■ Synthesis of Elastin Crosslinker Desmosines
Hiroaki Tanaka and Toyonobu Usuki*
*Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
Abstract
Desmosine (1) and isodesmosine (2) are 1,3,4,5- and 1,2,3,5-tetrasubstituted pyridiniums and exist only in the extracellular matrix protein elastin as major crosslinking amino acids. They are formed by the condensation and cyclization of one lysine and three allysines, generated from lysine by lysyl oxidase. Since the discovery of desmosines in 1964, there have been no reports on their chemical synthesis for decades. The first total synthesis of 1 was reported in 2012 and since then, isodesmosine (2), desmopyridine (3), isodesmopyridine (4), neodesmosine (5), and merodesmosine (6) have been synthesized. Isotopically labeled desmosines have also been synthesized for the precise analysis of desmosines using isotope-dilution LC–MS/MS analysis. Synthesis of conjugates with desmosines and carrier proteins was achieved for antibody production. This review summarizes a series of desmosine syntheses based on cross-coupling reactions and Chichibabin pyridinium synthesis as synthesis methodologies. The obtained results would help in the development of novel diagnostic and therapeutic methodologies for elastin-degradation-related diseases.
Published online: 9th May, 2023
Paper | Regular issue | Prepress■ Synthesis and Biological Assessment of Novel Heterocyclic Nucleoside Analogues Using Microwave-Assisted Hantzsch Reaction
Abdelaaziz Ouahrouch,* Jamal Krim, and Moha Taourirte
*Laboratory of Biotechnology, Materials and Environment, Faculty of Sciences, Ibn Zohr University, Agadir 80000, Morocco
Abstract
This paper reports a one-pot synthesis of 5-(1,4-dihydropyridyl) derivatives of 2’-deoxyuridines using Hantzsch condensation of 5-formyl-2’-deoxyuridine and NH4OAc with diverse β-dicarbonyl compounds under solvent-free microwave irradiation conditions. The synthesized compounds were evaluated for their antiviral activities against human rhinovirus (HRV) and hepatitis C virus (HCV), as well as antibacterial activities against a series of Gram-positive and Gram-negative bacteria. The products carrying an unsymmetrical 1,4-dihydropyridyl moiety showed excellent antiviral activity against HCV.
Published online: 8th May, 2023
Paper | Regular issue | Prepress■ An Efficient Ton Scale Process of Chlorfluazuron
Kai Yin,* Xin Yin, Hao Wu, Jiang Yu, Youlan He, Xin Yang, Minmin Gu, Wenliang Wu, Jiangyu Yang, and Yiwei Zhang*
*School of Chemistry and Chemical Engineering, Southeast University, SuYuan road No.79 in Nanjing 211189, China
Abstract
An efficient and novel synthetic route of chlorfluazuron (1) on a ton scale has been developed, from the commercially available chemicals 3,5-dichloronitrobenzene, 2,3-dichloro-5-(trifluoromethyl)pyridine, and 2,6-difluorobenzamide. The key intermediate, 4-amino-2,6-dichlorophenol (2), was synthesized in one step by 3,5-dichloronitrobenzene with 78.1% yield and 99.5% purity. At the same time, 3,5-dichloroaniline (15), a co-product with great market demand, was also obtained with 20.9% yield and 99.2% purity. Chlorfluazuron (1) was obtained from 4-amino-2,6-dichlorophenol (2) in 91.9% yield over two steps and 99.2% purity. Compared with the original process route, the new synthetic route has the advantages of fewer reaction steps, higher overall yield, less process safety hazard and environmental impact.
Published online: 26th April, 2023
Communication | Regular issue | Prepress■ New C19-Diterpeniod Alkaloids from Aconitum novoluridum
Peixin Deng, Yan Xiao, Mengyi Deng, Shuai Huang, Lin Chen, Jiang Xie, and Xianli Zhou*
*School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan, P.R. China
Abstract
Four new C19-diterpenoid alkaloids novolunines D–F (1–3) and 8-O-ethylbrevicanine C (4), were isolated from the root of Aconitum novoluridum. The structures of four new alkaloids were established on the basis of spectra data (HR-ESI-MS, 1D- and 2D-NMR). The anti-inflammatory activity of isolated alkaloids was also carried out.
Published online: 25th April, 2023
Short Paper | Regular issue | Prepress■ Design, Synthesis, and Molecular Docking Studies of Chroman-4-one Linked Thiosemicarbazide Derivatives as Inhibitors of KatG and Anti-Mycobacterium tuberculosis Agents
Lei Wang, Hong-Mei Dong, Xin Zhao, and Zai-Chang Yang*
*College of Pharmacy, Guizhou University, Guiyang 550025, PR China
Abstract
Twenty compounds were designed as ligands for molecular docking with Mtb KatG, and 13 compounds with high scoring values were selected for synthesis. In vitro antimicrobial susceptibility tests have shown that all the 13 compounds have anti-Mtb activity (MIC = 1-32 μg/mL). Among the 13 compounds, compound 4g showed the strongest anti-Mtb activity with an MIC of 1 μg/mL. Therefore, the mechanism of action of compound 4g was preliminarily investigated by molecular docking, enzyme inhibition test, ROS assay, and time-killing curve. The results indicated that the anti-Mycobacterium tuberculosis effect of compound 4g may be related to its inhibition of KatG enzyme. In summary, this study provides a new idea for the development of novel anti-Mtb drugs.
Published online: 17th April, 2023
Short Paper | Regular issue | Prepress■ Synthesis of 2-Anilino-2,4,4,6,6-pentachlorocyclotriphosphazenes (N3P3Cl5(NAr(R)))
Manabu Kuroboshi,* Ryota Takahashi, and Hideo Tanaka
*Graduate School of Natural Science and Technology, Okayama University, Tsushima-naka 3-1-1, Kita-ku, Okayama, Japan
Abstract
Hexachlorocyclotriphosphazene (HCCP, N3P3Cl6, 1) was treated with anilines in THF at 0 ºC to give a corresponding mono-substituted 2-anilino-2,4,4,6,6-pentachlorocyclotriphosphazenes (N3P3Cl5(NAr(R)), 2) in good to moderate yield. Multi-substituted products N3P3Cl6-n(NAr(R))n (n ≥ 2)) were not detected in 31P NMR spectra of the reaction mixture.
Published online: 14th April, 2023
Review | Regular issue | Prepress■ Advances on Catalytic Approaches towards the Synthesis of Quinoline Derivatives Using Povarov Reaction
Kamal Kant, Sourav Banerjee, Chandresh K. Patel, Sangita Kalita, Reetu Reetu, Priyadarshini Naik, Nayyef Aljaar, and Chandi C. Malakar*
*Department of Chemistry, National Institute of Technology Manipur, Imphal-795004, India
Abstract
The aza-Diels-Alder reaction is a [4+2] cycloaddition, involving the insertion of nitrogen atom into dienes or dienophiles. A series of biologically and pharmaceutically active essential heterocycles have been developed as a result of this approach. This method witnessed as a powerful tool for the construction of a diverse range of biological active quinoline scaffolds and other nitrogen containing heterocyclic compounds due to its operational modesty, high atom economy, regio- and stereoselectivity. The present report focuses on the advancement of aza-Diels-Alder reaction for the synthesis of optically active and inactive quinoline derivatives.
Published online: 12th April, 2023
Short Paper | Regular issue | Prepress■ N-Alkylation of Azoles with Enones Assisted by P(III) or Fe2O3-Nanoparticles as Recyclable Catalyst
Elangbam Pinky Devi, Saibabu Polina, Kamal Kant, Arup K. Kabi, Nabil Al-Zaqri, Nayyef Aljaar, and Chandi C. Malakar*
*Department of Chemistry, National Institute of Technology Manipur, Langol, Imphal-795004, Manipur, India
Abstract
Hexamethylphosphorous triamide (HMPT)-assisted and Fe2O3-nanoparticles (NPs) catalysed approaches towards the formation of C-N bond is described by the reaction between azoles and enone-compounds. The transformations were accomplished under mild conditions at temperatures 25 °C and 50 °C respectively. The efficacy and robustness of the reaction conditions can be envisioned by regioselective construction of N-heterocyclic scaffolds embedded with cycloalkyl residue. The established reaction conditions were found competent over a series of enones and azole derivatives to furnish the desired molecules in high yields ranging from 52-86% under P(III)-mediated conditions and 67-86% under the influences of Fe2O3-NPs as recyclable catalyst. It was observed that the catalyst can be recycled up to six times with good yields of the product.