HETEROCYCLES

■ Contents

■ A Comprehensive Study of Pyrimidine and Its Medicinal Applications

Vikas Vilas Borge* and Juilee Vaze

*Department of Chemistry, University of Mumbai, Vidyanagari, Kalina, Mumbai-400098, India

Abstract

Pyrimidine is a heterocyclic aromatic organic compound which is versatile lead compound for designing potent therapeutic agents. Different pyrimidine derivatives have been synthesized by various conventional methods and also from green methods. The pyrimidine moiety widely occurs in biologically occurring compounds, such as nucleic acids components, folic acid and vitamin B1 etc. This compound has various biological activities like anticancer, antitubercular, antimicrobial, antifungal, antibacterial, antioxidant, anticonvulsant, analgesic, CNS depressant, anti-inflammatory, anti-HIV, antihelmentic and herbicidal activity. Available data represents pyrimidine being heterocyclic six membered ring systems has various pharmacological actions and synthesis of pyrimidine and their derivatives are discussed.

■ Novel Pyrazolines and Benzothiazepines as Tubulin Polymerization Inhibitors: Synthesis, Biological Evaluation, and Molecular Docking

Alaadin E. Sarhan,* Ashraf A. Sediek, Nagy M. Khalifa, and Essam E. Hasan

*Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Institute, National Research Centre, Dokki, Cairo, 12622 Egypt

Abstract

Synthesis, biological evaluation, and molecular docking of pyrazoline-linked benzenesulfonamides and diaryl 1,5-benzothiazepines prepared from new chalcones are described and elucidated. Novel compounds were studied for their in vitro anticancer profiles on HepG2, HEK-293, MCF-7, and MDA-MB-231 cancer cell lines, where, compounds IIb, III, and IVe demonstrated high to moderate cell proliferation inhibition activity. Compound IIb was further assessed for tubulin polymerization inhibition effects due to its high potency, which showed superior suppression compared to the reference drug. It induced cell cycle cessation at the G2/M phase and accumulation of cells in the pre-G1 phase, preventing its mitotic cycle. In addition, compound IIb activated caspase-7, mediating apoptosis of HepG2 cells. These findings, along with molecular docking and pharmacophore constructed models, provide a new scaffold of cytotoxic agents targeting tubulin.

■ An Unprecedented Synthesis of 8b-Hydroxy-3a-(1H-pyrrol-2-yl)/(1H-indol-3-yl)-3a,8b-dihydroindeno[1,2-b]pyrrol-4(1H)-one Derivatives from Pyrrole/Indole with Ninhydrin and β‑Enaminocarbonyls

Mozhgan Masoudi*

*Department of chemistry, Rafsanjan Branch, Islamic Azad University, Rafsanjan, Iran

Abstract

Heterocyclic systems containing (1H-pyrrol-2-yl) or (1H-indol-3-yl)-dihydroindenopyrrole moieties were synthesized using heterocyclization of pyrrole or indole with ninhydrin and β‑enaminocarbonyls in water under reflux conditions. An efficient, facile, and environmentally friendly protocol was found for the production of new heterocyclic compounds. This reaction was used to gain access to a wide range of pyrrole/indole derivatives. Plate chromatography was utilized to isolate the products whose structures were established from their spectroscopic data.

■ Chemical Reactivity of 1H-Benzimidazol-2-ylacetonitrile and Dimedone toward Simple Condensates Derived from 3-Formylchromone

Magdy A. Ibrahim*

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

Abstract

The chemical reactivity of 1H-benzimidazol-2-ylacetonitrile and dimedone was investigated towards some simple condensates (1a-d and 2a-c) obtained from condensation reaction of 3-formylchromone with some active methylene compounds. Mainly, the used nucleophiles undergo nucleophilic addition at the olefinic carbon with concomitant cycloaddition or cyclocondensation. Chromonylacrylonitrile 1a reacted with 1H-benzimidazol-2-ylacetonitrile through γ-pyrone ring opening followed by cyclocondensation giving pyrido[1,2-a]benzimidazole derivative 5. The simple condensates 2b and 2c showed similar behavior towards 1H-benzimidazol-2-ylacetonitrile and dimedone leading to the same products which are identical with those obtained from 3-formylchromone with the same reagents. Structures of the new synthesized products were established based on elemental analysis and spectral data.

■ A New C,C-Linked Functionalized Bipyrazole: Synthesis, Crystal Structure, Spectroscopies and DFT Studies. Evaluation of the Antibacterial Activity and Catalytic Properties

Ibrahim Bouabdallah, Tarik Harit,* Yahya Rokni, Mahmoud Rahal, Monique Tillard, Driss Eddike, Abdeslam Asehraou, and Fouad Malek*

*Laboratory of Applied Chemistry and Environment, Faculty of Sciences, Mohammed First University Bd Mohamed VI, 60 000 Oujda, Morocco

Abstract

The synthesis of new C,C-linked functionalized bipyrazole is reported. Its molecular structure has been confirmed by spectroscopic and spectrometric methods and its single crystal structure determined by X-ray analysis. The ligand 2 has been subjected to DFT and TD-DFT theoretical calculations and results are consistent with the experimental chemical analyses. The compound possesses no antibacterial activity up to 256 g/mL. However, its complexes with copper(II) salts are found to be good catalysts for the oxidation of 3,5-di-tert-butylcatechol (DTBC) into 3,5-di-tert-butylquinone (DTBQ) with a rate varying from 9.58 μmol• L-1• min-1 for the 2-[Cu(MeCO2)2] complex to 5.27 μmol• L-1• min-1 for the 2-[Cu(BF4)2] complex.

■ Design, Synthesis and Insecticidal Activity of 3-Arylisoxazoline-N-alkylpyrazole-5-carboxamide Derivatives against Tetranychus urticae Koch

Shuhao Qu,* Lifei Zhu, Qiang Wang, and Xiaoli Wang

*School of Veterinary Medicine, Henan University of Animal Husbandry and Economy, Zhengzhou 450046, China.

Abstract

Starting from ethyl 5,5-dimethoxy-2,4-dioxopentanoate 2, 3-arylisoxazoline-N-alkylpyrazole-5-carboxamide derivatives 1a-1d were designed and synthesized with the key steps of 1,3-dipolar cycloaddition and EDCl coupling. Their insecticidal activity against Tetranychus urticae Koch was further evaluated and the results indicated that, compared with Fluralaner, all 1a-1d showed moderate and less activity at 500 mg/L and 250 mg/L, respectively. This study complements the structure-activity relationship of N-alkylpyrazole-5-carboxamides to Fluralaner, giving further guidance in Fluralaner-based pesticide drug design and discovery.

■ Development of a Scalable Synthesis of SIRT1 Modulator Macrocycles

János Tatai, Márk Molnár, Maud Villeneuve, Laure Haberkorn, and Miklós Nyerges*

*Servier Research Institute of Medicinal Chemistry, 7 Záhony utca, 1031, Budapest, Hungary

Abstract

An improved multigram route to key intermediate 26 for macrocyclic SIRT1 modulators has been developed. The increasing demand for this key intermediate caused the rerouting of the initial discovery route resulted in increase of overall yield to 8.3% over 8 steps, with the elimination of some tedious chromatographic purifications, and the substitution of critical reaction steps, which hindered a feasible scale-up. The key modification was the introduction of the microwave assisted intramolecular Suzuki reaction for the macrocyclization step, which provided in a reliable and reproducible manner of the targeted product 40. This newly developed synthetic access to this first described macrocyclic ring system was capable of ensuring the supply of our medicinal chemistry program.

■ Functionalization of Meldrum’s Acid by Diels‒Alder Approach

Sambasivarao Kotha* and Vidyasagar Gaikwad

*Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai - 400076, India

Abstract

We have synthesized several Meldrum’s acid derivatives using Diels‒Alder reaction as a key step. Here, the key sultine derivative is prepared by rongalite and the sultine derivative is useful as a latent diene.

■ A New Iridoid Glycoside from Santisukia pagetii

Poolsak Sahakitpichan, Nitirat Chimnoi, Chutima Srinroch, Chaleaw Petchthong, Somsak Ruchirawat, and Tripetch Kanchanapoom*

*Chulabhorn Research Institute, Kamphaeng Phet 6, Talat Bang Khen, Lak Si, Bangkok 10210, Thailand

Abstract

A new iridoid glycoside, 6-O-[(2E,6R)-8-hydroxy-2,6-dimethyl-2-octenoyl]-catalpol (kanchanikoside, 1) was isolated from the leaves and twigs of Santisukia pagetii. In addition to the new compound, the 17 known glycosides were isolated: nemoroside, 6"(Z)-nemoroside, ambiguuside, specioside, verminoside, 6-trans-feruloylcatalpol, 6,6'-di-O-caffeoylcatalpol, amphicoside, 6-O-veratroylcatalpol, citrusin B, (7R,8S)-balanophonin 4-O-β-D-glucopyranoside, (7R,8S)-dehydrodiconiferyl-O-β-D-glucopyranoside, martynoside, benzyl O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside, benzyl O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside, icariside D1 and (6S,9R)-roseoside. Their structures were determined based on the spectroscopic evidence including 1D and 2D NMR, and HR-ESI-TOF-MS experiments.

■ Development of 5-Trifluoromethylpyrimidine Derivatives as Dual Inhibitors of EGFR and Src for Cancer Therapy

Qin Wang, Nian Rao, Li Liu,* Yi Le, and Longjia Yan*

*School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China

Abstract

In this paper, we reported a new series of 5-trifluoromethylpyrimidine derivatives (4a-4f, 6a-6j) for cancer therapy. They were tested for antitumor activity in vitro on four human cancer cell lines including A549, K562, HepG2, MCF-7 and two kinase including wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and c-Src. The results suggested that some of the compounds (4a, 4b, 4c, 4e, 6b, 6d, 6e, 6f, 6g, 6h) performed well activities. Especially 2-((2-((4-((2-(cyclohexylamino)-3,4-dioxocyclobut-1-en-1-yl)aminophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide (6g) showed high antitumor activities against four cancer cell lines with 1.08 μM, 2.06 μM, 1.24 μM and 2.57 μM, respectively. Furthermore, compound 6g inhibited EGFRwt and Src at the values of 0.75 μM and 0.15 μM.

■ Synthesis of Trifluoromethyl Derivatives of Quinoline and Isoquinoline

Aki Fujisaka, Daiki Aomatsu, Yoichiro Kakutani, Ryuya Terai, Kumiko Sakaguchi, Masahiro Ikejiri, and Kazuyuki Miyashita*

*Faculty of Pharmacy, Osaka Ohtani University, Nishikiori-Kita 3-11-1, Tondabayashi, Osaka 584-8540, Japan

Abstract

Trifluoromethyl derivatives of quinoline and isoquinoline were synthesized using phosphonium salts with a trifluoroacetamide group in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene. The quinoline skeleton was formed from a phenethylphosphonium salt with a trifluoroacetamide NH proton, whereas the isoquinoline formation required masking of the amide proton of trifluoroacetamide in the benzylphosphonium structure.

■ One-Pot Synthesis of Fully Substituted Oxazol-2-amines via Staudinger/Aza-Wittig/Isomerization Reaction

Hai Xie,* Qing-Qing Hu, Xiu-Ting Qin, Jia-Min Liang, Lu- Li, Ya-Li Zhang, and Zhen Lu

*College of Chemistry and Chemical Engineering, Shanxi Datong University, Datong, 037009, People’s Republic of China

Abstract

Readily available vinyl azide alcohols reacted with triphenylphosphine and aromatic isocyanates via sequential Staudinger reaction and intramolecular aza-Wittig reaction to afford the corresponding isoxazole intermediates, which can isomerize into aromatic oxazol-2-amines in situ without addition of catalyst under 115 ℃. This methodology provided a new and efficient one-pot approach for fully substituted oxazol-2-amines.