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Issue 14, 2019, Issue in Progress
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A methanol and protic ionic liquid Ugi multicomponent reaction path to cytotoxic α-phenylacetamido amides

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Abstract

The Ugi four component reaction of an aldehyde, amine, isocyanide and an ethanoic acid was effected smoothly in protic ionic liquids ethylammonium nitrate (EAN) and propylammonium nitrate (PAN) to afford analogues of α-phenylacetamido amides in good to excellent isolated yields. The corresponding reactions in [BMIM][PF6] and the protic ionic liquid ethanolammonium nitrate (ETAN) failed. Microwave irradiation in EAN facilitated rapid access to three focused libraries, based on the parent isocyanide: cyclohexyl isocyanide, benzyl isocyanide and ethyl isocyanoacetate. Analysis of the structure activity relationship data suggested the presence of a bulky moiety originating from the isocyanide (cyclohexyl and benzyl) enhanced cytotoxicity. Removal of the acetylenic H-atom from the ethanoic acid moiety was detrimental to cytotoxicity. The most active analogues produced, N-(2-cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl-N-(3,5-dimethoxyphenyl)propiolamide, returned average GI50 values of ≤1 μM across the cancer cell lines evaluated. Combined, these data suggest that analogues of this nature are interesting potential anti-cancer development leads.

Graphical abstract: A methanol and protic ionic liquid Ugi multicomponent reaction path to cytotoxic α-phenylacetamido amides

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Article information


Submitted
06 Jan 2019
Accepted
04 Feb 2019
First published
08 Mar 2019

This article is Open Access

RSC Adv., 2019,9, 7652-7663
Article type
Paper

A methanol and protic ionic liquid Ugi multicomponent reaction path to cytotoxic α-phenylacetamido amides

A. Al Otaibi, F. M. Deane, C. C. Russell, L. Hizartzidis, S. N. McCluskey, J. A. Sakoff and A. McCluskey, RSC Adv., 2019, 9, 7652
DOI: 10.1039/C9RA00118B

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