HETEROCYCLES

■ Contents

■ Chemical Syntheses and Biological Studies of Agelastatin A, a Bioactive Marine Heterocycle Gifted from Nature

Takehiko Yoshimitsu*

*Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan

Abstract

Agelastatin A, an alkaloid originally isolated from the marine sponge Agelas dendromorpha, has long been an attractive target of chemical synthesis due to its significant biological activity and unique chemical structure. The synthetic approaches to the agelastatin alkaloid have demonstrated the advances of new methodologies and strategies for accessing a highly functionalized polycyclic nitrogen heterocycle. The present article reviews synthetic endeavors on agelastatin A that have been made by various synthetic chemists as well as biological studies on the natural product and its analogues aimed at the development of medicinal resources.

■ Synthesis of 4,7-Dibromobenzo[b]thiophene Derivatives via 2-(1-Adamantylsulfanyl)-1,4-dibromo-3-(ethynyl)benzenes and Their Reactions

Kozo Toyota,* Shinichi Mikami, Hiroki Tanaka, Shuhei Yoshida, Kazuma Iwai, Kenta Takahashi, Hiroki Kishi, Yota Kikuchi, Koya Saito, Homa Yamaguchi, and Hirotaka Mutoh

*Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan

Abstract

Mild Corey-Fuchs reaction conditions using dimethyl sulfoxide - aqueous KOH solution at room temperature were applied to preparation of 2-(1-adamantylsulfanyl)-1,4-dibromo-3-(ethynyl)benzene. Various substituents were introduced to the terminal alkyne moiety of the (ethynyl)(sulfanyl)benzene, either by substitution reaction or by Sonogashira cross coupling. The alkynes thus obtained were converted to the corresponding 4,7-dibromobenzo[b]thiophene derivatives by the ‘silica gel-assisted cyclization’ method. Reactions of 4,7-dibromobenzo[b]thiophene and 2,4,7-tribromobenzo[b]thiophene were also investigated.

■ Synthesis of Novel (Thiazol-5-yl)pyrazoles and Their Antimicrobial Evaluation

Sanjay U. Deshmukh,* Raghunath B. Toche,* Sushama J. Takate, Supriya P. Salve, and Ram W. Sabnis

*Department of Chemistry, KRT Arts, BH Commerce & AM Science College, Nashik 422002, India.

Abstract

A series of novel (thiazol-5-yl)pyrazoles were designed and synthesized. All the synthesized compounds were characterized by spectroscopic analysis and were evaluated for their antimicrobial activity in vitro against Gram-positive bacteria, Bacillus subtilis and Staphylococcus aureus, Gram-negative bacteria, Salmonella abony and Escherichia coli and fungi, Aspergillus flavus and Fusarium oxysporum.

■ Synthesis and Evaluation of β-Galactosidase-Targeting Spin-Label Probe: 5-O-β-D-Galactosyl-5-hydroxy-1,1,3,3-tetramethylisoindoline-2-oxyl

Koya Sugawara, Hiroyuki Konno, Tomohiro Ito, and Shingo Sato*

*Graduate School of Science and Engineering, Yamagata University, Jonan 4-3-16, Yonezawa-shi, Yamagata 992-8510, Japan

Abstract

In this study, 3-hydroxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and 5-hydroxy-1,1,3,3-tetramethylisoindoline-2-oxyl O-galactosides (PG, TG, and IG) were synthesized. Moreover, their reduction reactivity (RR) for ascorbic acid and hydrolysis reactivity (HR) for β-galactosidase were measured via electron paramagnetic resonance (EPR) spectroscopy and high-performance liquid chromatography (HPLC), respectively. The both rate constants for these two reactions were found to exhibit the following order: RR: TG > IG > PG, and HR: IG > PG > TG. Based on the results of the in vitro assay, IG was selected as the candidate for the bioassay. The bioassay of IG by HeLa cells (cancer cells) and PC12 cells (normal cells) indicated that after 20 min of IG addition, more nitroxide radicals were located in the cancer cells than in the normal cells, while their EPR intensity was low.

■ Facile Preparation of 5-Alkyl-1-aryltetrazoles with Arenes, Acyl Chlorides, Hydroxylamine, and Diphenylphosphoryl Azide

Kaho Shibasaki and Hideo Togo*

*Graduate School of Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

Successive treatment of arenes with acyl chlorides and AlCl3, the addition of water and removal of solvent, the reaction with NH2OH•HCl and K2CO3, and the reaction with diphenylphosphoryl azide and DBU under warming conditions gave the corresponding 5-alkyl-1-aryltetrazoles efficiently in good to moderate yields. The present method is one-pot transformation of arenes into 5-alkyl-1-aryltetrazoles using the Friedel-Crafts acylation and the Beckmann rearrangement under transition-metal-free conditions.

■ Efficient Synthesis and Anticancer Activities of Some Novel Functionalized (4-Oxo-4H-chromen-3-yl)-2-selenoxo-1,2-dihydropyrimidines

Tarik E. Ali,* Mohammed A. Assiri, Mamdouh M. Ali, Abeer E. M. Ali, Ibrahim S. Yahia, and Heba. Y. Zahran

*Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia

Abstract

Some novel functionalized 2-selenoxo-1,2-dihydropyrimidines bearing a chromone ring 2a-h were synthesized in excellent yields via a simple one-pot reaction. The simple method depended on one-pot three-component the reaction of 3-formylchromone (1) and selenourea with some active methylene compounds in the presence of sodium benzoate as a basic catalyst in a mixture of ethanol and water. The reactions were completed in 1.5–2.5 h in 88-94% yields. Structures of the synthesized compounds were based on elemental analysis, IR, 1H- and 13C-NMR and mass spectrometry. The anticancer properties of the synthesized compounds were evaluated against five cancer cell lines. Compounds 2a-d displayed the most potent anticancer activities against A549, MCF-7 and HepG2 cell lines in comparison with doxorubicin as the standard drug.

■ Synthesis and Evaluation of Biological Properties of 2-(2-(Phenoxy)pyridin-3-yl)quinazolin-4(3H)-one Derivatives

Li-qiong Zhang, Jia-min Liu, Yi-yuan Gan, Li-hui Shao, Yi-hong Fu, Zhen-chao Wang,* and Gui-ping Ouyang*

*College of Pharmacy, Guizhou University, Huaxi St., Guiyang 550025, China

Abstract

A series of novel 2-(2-(phenoxy)pyridin-3-yl)quinazolin-4(3H)-one derivatives were designed, synthesized as antitumor agents. The antitumor activities of target compounds were evaluated and compared with positive drug Gefitinib employing standard MTT assay against A549 (human lung adenocarcinoma cell), PC-3 (prostate cancer cells), K562 (human chronic myeloid leukemia cells), HepG2 (human liver cancer cell) cancer cell lines in vitro. The pharmacological screening results revealed that many compounds exhibited moderate levels of antitumor activities against four cancer cell lines, especially 6-chloro-2-(2-(3,5-dimethylphenoxy)pyridin-3-yl)-3,8-dimethylquinazolin-4(3H)-one (z8) displayed promising activities against A549 (IC50 = 12.47±2.86 μM) than Gefitinib (IC50 = 17.37±6.01 μM). The mechanism and the apoptosis inducing effect of z8 against A549 cell line were studied. The results showed that z8 could inhibit migration and motility of cancer cells, induce cell apoptosis and exhibit the typical apoptotic morphology.

■ Synthesis and Reactivity of Dimethoxy Activated Benzothiazoles

Mahiuddin Alamgir, Hao Jiang, Mohan Bhadbhade, Naresh Kumar, and David StC. Black*

*School of Chemistry, The University of New South Wales, Sydney 2052, Australia

Abstract

A range of 2-substituted-5,7-dimethoxybenzothiazoles and 2-substituted-4,6-dimethoxybenzothiazoles have been synthesized by oxidative cyclization of the corresponding thioamides. These activated benzothiazoles display nucleophilic reactivity at C4 and C7 respectively and undergo formylation, acetylation and related reactions. Some 5,7-dimethoxybenzothiazoles with functionalization in a 2-aryl substituent are also reported as potential precursors for so far unsuccessful formation of macrocycles containing two benzothiazoles and two benzimidazoles.

■ Synthesis and Antibacterial Survey of Some New Pyridine-Based Heterocycles

Ebrahim Abdel-Galil, Moged A. Berghot, Alshimaa I. Zaki, and Ehab Abdel-Latif*

*Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt

Abstract

Treatment of ethyl 2-((3-cyano-4,6-dimethylpyridin-2-yl)thio)acetate (4) with hydrazine hydrate furnished 2-((3-cyano-4,6-dimethylpyridin-2-yl)thio)-acetohydrazide (5) which underwent condensation with five benzaldehydes to afford the corresponding N'-arylidene-2-((3-cyano-4,6-dimethylpyridin-2-yl)thio)-acetohydrazides 6a-e. The reaction of hydrazide 5 with ethyl acetoacetate yielded the expected 2-((2-(3-methyl-5-oxo-pyrazolyl)-2-oxoethyl)thio)nicotinonitrile derivative 7 which diazo-coupled with different diazonium chlorides to furnish the corresponding 2-(4-(2-arylhydrazono)pyrazolyl)-2-oxoethyl)thio)nicotinonitriles 8a-c. In addition, the nucleophilic substitution of chlorine from 2-chloroacetamide derivative 16 by various types of nucleophiles (salicylaldehyde, ethyl thioglycolate, 2-mercaptobenzoxazole, ammonium thiocyanate and/or malononitrile) was investigated. In general, all synthesized pyridine scaffolds revealed better activity against the Gram-positive bacterium (Bacillus subtilis) rather than the Gram-negative bacterium (Escherichia coli).

■ Synthesis of Some Novel Antimicrobial and Antioxidant Agents of Functionalized Pyrazolo[4',3':5,6]pyrano[3,2-d]- [1,2]azaphospholes and Pyrazolo[4',3':5,6]pyrano[2,3-d][1,3,2]diazaphosphinines

Noha M. Hassanin,* Tarik E. Ali, Hafez M. El-Shaaer, Somaia M. Abdel-Kariem, Somaya M. El-Edfawy, and Wafaa R. Abdel-Monem

*Department of Chemistry, Faculty of Education, Ain Shams University, Roxy 11757, Cairo, Egypt

Abstract

We have demonstrated facile synthetic approach for some novel functionalized pyrazolo[4',3':5,6]pyrano[3,2-d]-[1,2]azaphospholes and pyrazolo[4',3':5,6]pyrano[2,3-d][1,3,2]diazaphosphinines via treatment of 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile with some phosphorus halides. The structure of the products was characterized by elemental analysis and spectral tools. The antimicrobial and antioxidant activities of the products were also evaluated.

■ Four-Component Domino Reaction for the Synthesis of Novel 8-Methyl-9-substituted-2,10-diaryl-2,3-dihydro-10H-pyrano[3,2-e][1,2,4,3]triazaphospholo[1,5-c]pyrimidines

Dina A. Bakhotmah and Tarik E. Ali*

*Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia

Abstract

A novel four-component domino reaction for the synthesis of 8-methyl-9-substituted-2,10-diaryl-2,3-dihydro-10H-pyrano[3,2-e]-[1,2,4,3]triazaphospholo[1,5-c]pyrimidines has been established. The reaction was performed in THF using readily available 5-substituted-2-amino-6-methyl-4-phenyl-4H-pyran-3-carbonitrile, dimethyl-formamide dimethyl acetal, hydrazine hydrate and aryldichlorophosphine. The simple and efficient one-pot four-component approach, catalyst free and mild reaction conditions made the present methodology a good synthetic procedure.