Synthesis and Cytotoxicity of Quinazolin-4(3 H )-one Based Peptides
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ynthesis and Cytotoxicity of Quinazolin-4(3H)-one Based Peptides P. Shankaraiaha,b, A. K. D. Bhavania,*, A. Kishore Kumarb, and K. Ramakrishnaa a Department
of Chemistry, University College of Science, Osmania University, Hyderabad, 500007 India of Humanities and Sciences, Vardhaman College of Engineering, Shamshabad, Hyderabad, Telangana, 501218 India *e-mail: [email protected]
b Department
Received February 12, 2020; revised March 18, 2020; accepted March 21, 2020
Abstract—A novel series of quinazolin-4(3H)-one derivatives has been synthesized in high yields using the multicomponent Ugi reaction and characterized by IR, NMR and mass spectral data. The products have been tested for their cytotoxic activity against HeLa cells. Two tested compounds have shown potent activity compared to standard drug Doxorubicin. The in silico docking studies of the compounds against quinone reductase-2 (4ZVM) enzyme have also supported their activity. Keywords: quinazolin-4(3H)-one, Ugi multicomponent reaction, cytotoxic, isocyanide
DOI: 10.1134/S1070363220040246 INTRODUCTION Quinazolin-4(3H)-one is a building block of naturally occurring alkaloids and utilized as a drug like scaffolds in some natural products such as trypanthrin, rutaecarpine and luotonin A. Quinazolin-4(3H)-one and its derivatives demonstrate a wide range of biological activities including anti-tumor [1], anti-inflammatory [2], analgesic [3], and antimicrobial [4]. In the current study we have designed and synthesized quinazolin-4(3H)-one based peptides utilizing the Ugi multi-component reaction, and tested cytotoxicity of the products against cancer cell line (HeLa cells). RESULTS AND DISCUSSION 6-Amino quinazolinone (5) was chosen as a precursor in development of a multifunctional aliphatic chain at the position-6 of quinazolin-4(3H)-one via the Ugi reaction [5]. The compound 5 was synthesized from isatin as presented in Scheme 1 [6–9]. A reaction of 6-amino quinazolin-4(3H)-one (5) with benzaldehyde (6a), benzoic acid (7a) and tert-butyl isocyanide (8a) in methanol gave the corresponding N-[2-(tertbutylamino)-2-oxo-1-phenylethyl]-N-(3-methyl-4-oxo3,4-dihydroquinazolin-6-yl)benzamide (9a) in 76% yield. This multicomponent reaction was extended to different substituted aromatic aldehydes 6b–6e, aromatic acids 7b, 7c and isocyanide 8b that gave the corresponding
quinazolin-4(3H)-one derivatives (9b–9l) (Scheme 1). The structure of products was confirmed by IR, NMR and mass spectral data. IR spectra of the products 9a–9l demonstrated the characteristic bands for three different C=O groups in the range of 1740–1605 cm–1. Formation of the amido groups was also confirmed by three characteristic signals in the range of 157.2–171.1 ppm of their 13C NMR spectra. In 1H NMR spectrum the benzylic proton signals were recorded between 6.15 and 6.65. Cytotoxicity of the synthesized compounds. The in vitro cytotoxic activity of the newly synthesized quinazolin-4(3H)-one derivatives 9a–9l was tested against human cervical carcinoma (HeLa) cells by using the MTT assay [10
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