CC BY 4.0 · SynOpen 2023; 07(03): 401-407
DOI: 10.1055/a-2148-9518
letter

Synthesis of Squaric Acid Monoamides as Building Blocks for Drug Discovery

Nathan Long
a   School of Life Sciences, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK
,
Adam Le Gresley
a   School of Life Sciences, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK
,
Arran Solomonsz
b   Asynt Ltd., Hall Barn Road Industrial Estate, Hall Barn Rd, Isleham, Ely, CB7 5RJ, UK
,
Antony Wozniak
b   Asynt Ltd., Hall Barn Road Industrial Estate, Hall Barn Rd, Isleham, Ely, CB7 5RJ, UK
,
Steve Brough
c   Key Organics Ltd., Highfield Road Insutrial Estate Camelford, Cornwall, PL32 9RA, UK
,
a   School of Life Sciences, Pharmacy and Chemistry, Faculty of Health, Science, Social Care and Education, Kingston University, Penrhyn Road, Kingston upon Thames, KT1 2EE, UK
› Author Affiliations


The Wren Group would like to dedicate this article to Tory May Wren who sadly passed away on the 28th October 2022. She is a constant source of inspiration for her dad (Stephen P. Wren).

Abstract

Herein, we present a synthetic compound library comprising of 28 anilino and benzylamino monosquarate-amide derivatives. Members of this library were designed as bioisosteric replacements for groups such as the ubiquitous carboxylic acid moiety. Further to their synthesis, we have shown the potential of these chemical building blocks for the generation of additional novel compounds. This work forms part of our efforts aimed at the assembly of 96-well plates loaded with bioisosteric analogues that may be used to enrich drug discovery programs. The research presented in this work focuses on the chemistry of 3,4-dihydroxycyclobut-3-ene-1,2-dione, a known carboxylic acid bioisostere.

Supporting Information



Publication History

Received: 03 July 2023

Accepted after revision: 03 August 2023

Accepted Manuscript online:
04 August 2023

Article published online:
29 August 2023

© 2023. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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  • 31 Experimental procedures are detailed in the Supporting Information. Two example syntheses are given here.Compound 26To 3,4-diethoxycyclobut-3-ene-1,2-dione (500 mg, 0.43 mL, 2.94 mmol, 1 equiv) dissolved in EtOH (15 mL) at 0 °C was added 4-hydroxyaniline (321 mg, 2.94 mmol, 1 equiv) in EtOH (10 mL). The reaction was allowed to warm to r.t. and stirred for 12 h before being concentrated under reduced pressure and purified via column chromatography (5% MeOH in DCM). The desired compound was obtained as a tan solid (311 mg, 45%); mp 208–213 °C. FTIR: νmax = 3695 (NH), 3212 (OH stretch), 2982 (CH aromatic), 1807 (CH alkyl), 1728 (C=O) cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 10.56 (s, 1 H), 9.42 (s, 1 H), 7.14 (s, 2 H), 6.75–6.69 (m, 2 H), 4.72 (q, J = 7.1 Hz, 2 H), 1.44–1.32 (m, 3 H). 13C NMR (101 MHz, acetone-d 6): δ = 155.6, 131.2, 122.5, 116.5, 70.3, 16.1. HRMS (ESI): m/z [M + Na]+ calcd for C12H11NO4Na: 256.0580; found: 256.0603.Compound 41To 3,4-diethoxycyclobut-3-ene-1,2-dione (500 mg, 0.43 mL, 2.94 mmol, 1 equiv) dissolved in EtOH (7 mL) was added 1-(4-bromophenyl)-N-methylmethanamine (588 mg, 0.59 mL, 2.94 mmol, 1 equiv) dropwise. The reaction was then stirred at r.t. for 24 h before being concentrated under reduced pressure and purified via column chromatography (55% EtOAc–hexane). The product was obtained as a white solid (870 mg, 91%); mp 110–114 °C. FTIR: νmax = 2988 (NH), 2928 (CH aromatic), 1802 (CH alkyl), 1703 (C=O), 1591 (CO) cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 7.59 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 4.75 (s, 1 H), 4.67 (p, J = 6.8 Hz, 2 H), 4.52 (s, 1 H), 3.05 (d, J = 63.5 Hz, 3 H), 1.35 (q, J = 7.3 Hz, 3 H). 13C NMR (151 MHz, DMSO-d 6): δ = 188.8, 181.6, 176.5, 171.4, 134.9, 131.7, 130.3, 130.2, 121.2, 69.2, 53.0, 36.0, 15.5. HRMS (ESI): m/z [M + H]+ calcd for C14H15 81BrNO3: 326.02298; found: 326.0203.