One-Pot Phosphate-Mediated Synthesis of Novel 1,3,5-Trisubstituted Pyridinium Salts: A New Family of S. aureus Inhibitors.

Thomas Pesnot,Markus C Gershater,Martin Edwards,Helen C Hailes,John M Ward

doi:10.3390/molecules22040626

Thomas Pesnot, Markus C Gershater + Show 3 more

Open Access

https://doi.org/10.3390/molecules22040626

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Abstract

Polysubstituted pyridinium salts are valuable pharmacophores found in many biologically active molecules. Their synthesis typically involves the use of multistep procedures or harsh reaction conditions. Here, we report water-based phosphate mediated reaction conditions that promote the condensation of arylacetaldehydes with amines to give 1,3,5-pyridinium salts. The reaction, carried out at pH 6, provides conditions suitable for the use of less stable aldehydes and amines in this Chichibabin pyridine condensation. The evaluation of selected 1,3,5-trisubstituted pyridinium salts highlighted that they can inhibit the growth of S. aureus in the low μg/mL range. The synthetic accessibility of these compounds and preliminary growth inhibition data may pave the way towards the discovery of new anti-bacterials based on the 1,3,5-trisubstituted pyridinium scaffold.

Highlights

Polysubstituted pyridine and pyridinium salts such as the coenzymes NAD+ and NADP+ [1]are involved in many essential biochemical processes
Tcohnedceonnsdaetinosnatoiofnthoifs tphhisenpehtehnyeltahmyilname fionre efoxramexpalme pwleithwaitnh aalndeahldyedheysduecshuacsh pahs epnhyelnaycelataceldtaelhdyedheyd4ae 4ina pinotpaostsaisusmiumphpohsposhpahteat(eK(PKi)Pib)ubfufeffregragvaevethteheTTHHIAIA55(S(Scchheemmee22))..CChhiicchhiibbaabbiinnaanndd Pictet-Spengler condensations both involve amine and aldehyde components, imine formation and activation, and by analogy with the Pictet-Spengler reaction it was anticipated that the Chichibabin reaction could be pprroommootted bbyypphhoosspphhaatteess
This hhypothesis was iinnvveesstigated by rreeaaccttiinng pphheennyyllaacetaldehyde 4a with ttyyrrammine ((44--hhyydroxyphenethylamine) 6a in a 1.2:1 ratio in KKPPii bbuuffffeerr ((ppHH 66)), aatt 6600 ◦°C ffoor 1122 hh

Summary

Introduction

Polysubstituted pyridine and pyridinium salts such as the coenzymes NAD+ and NADP+ [1]. Are involved in many essential biochemical processes. They are part of other biologically active natural products such as juliprosine [2], the antibacterial alkaloid ficuseptine [3,4,5], and the neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+) [6,7] (Figure 1). The reaction involves the condensation of aldehydes with an amine to yield pyridiniums in a single synthetic step. The reaction required elevated temperatures and pressure, or acid catalysis [12,13,14,15,16,17], but the intrinsic instability of aldehydes under these forcing conditions often resulted in product yields that were at best mediocre

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