HETEROCYCLES

■ Contents

■ Diverse and Important Contributions by Medicinal Chemists to the Development of Pharmaceuticals: An Example of Active Vitamin D3 Analog, Eldecalcitol

Noboru Kubodera*

*International Institute of Active Vitamin D Analogs, 35-6, Sankeidai, Mishima, Shizuoka 411-0017, Japan

Abstract

Presented herein are diverse and important contributions by medicinal chemists to different stages of pharmaceutical development. The conceptual elements reviewed, which are intended for young chemists who engage in drug discovery research, draw upon the author’s experience in developing eldecalcitol, an active vitamin D3 analog used to treat osteoporosis. The review covers exploratory research for a lead candidate compound; process development for practical manufacturing; and synthesis of other compounds relevant to the program, such as tritiated compounds, postulated metabolites, and miscellaneous analogs for mode of action studies.

■ 1-Methylimidazolium Trifluoroacetate Efficiently Catalyzed Three Component Synthesis of Diazaspiro[5.5]undecane-1,5,9-trione Derivatives under Solvent-Free Conditions

Zhaohui Xu,* Houfu Zhang, Chunhua Lin, and Deyong Liu

*College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330027, China

Abstract

A simple, green and efficient method for the synthesis of 2,4-dioxa- 8,10-diazaspiro[5.5]undecane-1,5,9-trione derivatives has been developed by the reaction of aromatic aldehydes with urea and 1,3-dioxane-4,6-dione catalyzed by 1-methylimidazolium trifluoroacetate under solvent-free conditions.

■ A Biomimetic Approach to the Synthesis of Terpene-Amino Acid Conjugates. The Ugi Reaction in the Hypothetical Biosynthesis of Marine Natural Products

Yoshiyasu Ichikawa,* Kenta Saito, Rika Mimura, Ayumi Kitamori, Akihito Matsukawa, Akifumi Ikeda, Toshiya Masuda, Hiyoshizo Kotsuki, and Keiji Nakano

*Faculty of Science, Kochi University, 2-5-1, Akebono-cho, Kochi 780-8520, Japan

Abstract

A unique pathway for the biosynthesis of the marine sponge terpenes, exigurin and boneratamides A–C, is proposed. Based on this proposal, a biomimetic strategy on key Ugi coupling reactions between terpene isocyanides and amino acids was developed for construction of the core structures of exigurin and boneratamides A–C.

■ An Efficient Route for Synthesis and Reactions of Seleno-[2, 3-c]coumarin

Shams H. Abdel-Hafez,* Ahmed Elkhateeb, Adel A. Gobouri, Islam H. El Azab, and Gilbert Kirsch

*Department of Chemistry, Faculty of Science, Taif University, Taif-Al-Haweiah 888/21974, Saudi Arabia

Abstract

Synthesis of new selenium-containing coumarin moiety via the reaction of 4-chloro-2-oxo-2H-chromene-3-carbonitrile with selenium and sodium borohydride gave 3-Cyano-4-coumarinselenol which reacted with different halo-acids, such as chloroacetonitrile, ethyl chloroacetate and chloroacetamide to give the corresponding 3-amino-4-oxo-4H-seleno[3,2-c]chromene-2- derivatives. Hydrazonolysis of the obtained new ethyl 3-amino-4-oxo-4H-seleno[3,2-c] chromene-2-carboxylate afforded the corresponding hydrazino compound. The hydrazino compound was used as a versatile precursor for synthesis of new other heterocyclic compounds containing selenocoumarin moiety. The newly synthesized compounds were characterized using the spectroscopic tools (IR, 1H NMR, 13C NMR and mass spectroscopy) as well as microanalysis.

■ Synthesis of 1-Aroyl-1,2-dihydro-3H-indol-3-ones via Cyclization of N-[2-(2-Chloroacetyl)phenyl]benzamides with Triethylamine in the Presence of Di-tert-butyl Dicarbonate

Kazuhiro Kobayashi,* Daiki Kado, and Kohei Nishikawa

*Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan

Abstract

1-Aroyl-1,2-dihydro-3H-indol-3-ones can now be conveniently obtained from 2-aryl-4-(Z)-(chloromethylidene)-4H-3,1-benzoxazines using an easy operated three-step sequence under mild conditions. Thus, the starting materials are hydrolyzed with dilute hydrochloric acid at 0 ˚C to N-[2-(2-chloroacetyl)phenyl]benzamides, of which treatment with triethylamine in the presence of di-tert-butyl dicarbonate at room temperature, followed by deprotection with trifluoroacetic acid at room temperature, provides the desired products.

■ Synthesis and Antimicrobial Evaluations of Novel Spiro Cyclic 2-Oxindole Derivatives of N-(1H-Pyrazol-5-Yl)-Hexahydroquinoline Derivatives

Said Ahmed Soliman Ghozlan, Muhammed Ali Ramadan, Amr Mohamed Abdelmoniem,* and Ismail Abdelshafy Abdelhamid*

*Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt

Abstract

A novel series of interesting spiro cyclic 2-oxindole derivatives of N-(1H-pyrazol-5-yl)hexahydroquinoline derivatives were prepared via the versatile readily accessible cyclic β-enaminones incorporating pyrazole. Antimicrobial evaluations were performed on the prepared compounds. Most of these compounds exhibited high to moderate antimicrobial activity.

■ Selective Synthesis of Monosubstituted p-tert-Butylthiacalix[4]arene under Phase Transfer Catalysis

Omran A. Omran*

*Medical laboratory department, College of Science, Majmaah University, Zulfi, 1712, 11932, Saudi Arabia
Chemistry Department, Faculty of Science, Sohag University, Sohag, 82524, Egypt

Abstract

Phase transfer catalysis (PTC) technique for lower rim alkylation of p-tert-butylthiacalix[4]arene (TCA) with diethyl bromomalonate, phenacyl bromide, N,N-diethylchloroacetamide, ethyl bromoacetate and chloroacetonitrile using K2CO3, CsOH or Na2CO3 as a base and tetraethylammonium bromide (TEAB) as catalyst in benzene has been employed. Selective synthesis of monosubstituted p-tert-butylthiacalixarene using K2CO3 or CsOH as base has been elaborated. Unprecedented alkylation cyclization as well as arene oxidation by using of Na2CO3 as a base for alkylation of p-tert-butylthiacalix[4]arene under PTC conditions led to the synthesis of two new p-tert-butylthiacalix[4]arene derivatives with heterocyclic bridging rings. The structures of the newly synthesized compounds were characterized by different spectroscopy methods IR, 1H NMR, 13C NMR, and single crystal X-ray diffraction.

■ Furan-2-carboxylic Acids from the Leaves of Nicotiana tabacum and Their Anti-Tobacco Mosaic Virus Activities

Chun-Bo Liu, Xin-Meng Xu, Qin-Peng Shen, Wei Zhang, Xiao-Feng Shen, Ye-Kun Yang, Feng-Mei Zhang, Pei He, Xiao-Xi Si, Ya-Dong Guo, Jian-Jun Xia,* and Guang-Yu Yang*

*Key Laboratory of Tobacco Chemistry of Yunnan Province, China Tobacco Yunnan Industry Company, Hongjin Road 181#, Kunming, 650231, China

Abstract

Three new furan-2-carboxylic acids, 5-(4-hydroxy-2-methoxy-6-methyl- phenyl)-3-methylfuran-2-carboxylic acid (1), methyl 5-(4-hydroxy-2-methoxy-6- methylphenyl)-3-methylfuran-2-carboxylate (2), and 5-(3-hydroxy-4-methoxy-5- methylphenyl)-3-methylfuran-2-carboxylic acid (3), together with two known furan-2-carboxylic acids (4 and 5) were isolated from the leaves of Nicotiana tabacum. Their structures were determined by means of HRESIMS and extensive 1D and 2D NMR spectroscopic studies. Compounds 1-5 were tested for their anti-TMV activities. The results showed that compounds 3 and 4 exhibited high anti-TMV activities with inhibition rates of 29.8 and 30.3%. These rates are close to that of positive control. The other compounds also showed potential activities with inhibition rates in the range of 22.8%~25.4%, respectively.

■ Concise Synthesis and Biological Evaluation of Chalcone Derivatives Bearing N-Heterocyclic Moieties

Zewei Mao, Xi Zheng, Yuping Lin, Yan Qi, Chunyan Hu, Chunping Wan,* and Gaoxiong Rao*

*Central laboratory, The NO.1 Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, 650021, China

Abstract

In this study, we designed and synthesized a series of chalcone derivatives bearing N- heterocyclic moieties, and screened in vitro anti- inflammatory in lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages and anticancer activity against a panel of human tumor cell lines. The results indicated that compound 9 not only had inhibitory effect on the generation of NO (IC50=8.11μM) and significantly inhibited the production of TNF-α, but also showed better anticancer activity against Hela and SGC7901 (IC50=1.05μM and 6.47μM, respectively), which was identified as the most potent anti-inflammatory and anticancer agent.

■ Synthesis and Antibacterial Evaluation of Some New 5-Substituted Hydantoins and Novel Twin-Drug Type Derivatives

Makoto Furutachi, Fumiko Fujisaki, Reika Tsuru, Ayumi Ejima, Toshiaki Gondo, Saho Goto, Miki Ito, Maki Nakamura, Hatsumi Aki, Nobuhiro Kashige, Fumio Miake, and Kunihiro Sumoto*

*Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan

Abstract

We report the preparation of new oxygen analogues 2 of twin-drug type bivalent mid-size lead molecule 1 and related single-drug type hydantoin derivatives 3. The new twin-drug type oxygen analogues (2a and 2b) also showed significant antibacterial activity against a Gram-positive strain (S. aureus). A comparison of the two types of twin-drug type mid-size compounds 1 and 2 showed that the original lead 1 had a higher level of antibacterial activity against a Gram-positive strain (S. aureus) than those of the compounds (2a and 2b). We also report the results of antibacterial evaluation of prepared compounds and the investigated structure-activity relationships of these molecules.

■ Synthesis and Antileukemic Activity of New Fluorinated 5-Aza-9-deazapurines

Felicia Phei Lin Lim, Koon Kee Kow, Eng Hwa Yeo, Sek Chuen Chow, and Anton V. Dolzhenko*

*School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Subang Jaya, Selangor 47500, Malaysia

Abstract

Novel fluorinated 4-benzylamino-7-phenylpyrazolo[1,5-a]- [1,3,5]triazin-2-amines were prepared using an efficient and practical approach. The chemoselectivity of condensation of pyrazolylguanidine and trichloroacetonitrile was found to be solvent-dependent and, when conducted in toluene, this reaction afforded 7-phenyl-4-trichloromethylpyrazolo[1,5-a]- [1,3,5]triazin-2-amine as the main product. This key intermediate underwent nucleophilic replacement of the trichloromethyl group with fluorinated benzylamines providing a series of the target compounds. Antiproliferative activity of the prepared compounds against Jurkat T cells was explored using MTS assay. Morphological changes observed in cells treated by the most potent compounds of this series, suggested that these compounds induced apoptosis in cells.

■ A One-Pot Synthesis of Phaitanthrin E Through Intermolecular Condensation/Intramolecular Aryl C-H Amination Cascade

Tomoki Itoh, Takumi Abe, Tominari Choshi, Takashi Nishiyama, and Minoru Ishikura*

*School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan

Abstract

A one-pot synthesis of phaitanthrin E starting from methyl indole-3-carboxylate and isatoic anhydride through intermolecular condensation/intramolecular aryl C-H amination cascade was developed.