Quinoline and cyanine dyes—putative anti-MRSA drugs

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Abstract

One way in which drug-resistant bacteria may be attacked is to screen new series of candidate compounds. Quaternary quinoline compounds and dyes were studied by Carl Browning (1887–1972) and Julius Cohen (1859–1935). A remarkable part of Browning and Cohen's work was the early development of structure–activity relationships for their series of compounds. Thus cationic species were found generally to be more effective antibacterials than neutrals or anionics, and the testing of partial or deconstructed active molecules was also carried out. Much of this work underpinned the fuller understanding of e.g. aminoacridine action developed by Adrien Albert (1907–1989), himself also a collaborator of Browning. Analysis of the activity of a range of compounds developed by Browning and Cohen suggests that these might again be examined as topical antimicrobials in the fight against methicillin-resistant S. aureus (MRSA) and other resistant bacteria.

Introduction

At the turn of the 20th century, the concept of synthetic drugs, facilitated by the contemporary upsurge in organic chemical knowledge, was gaining increasing acceptance due to the work of medical scientists such as Paul Ehrlich. Carl Browning (1887–1972) studied the microbicidal action of synthetic dyes under Ehrlich and this led to the introduction of the flavines as wound antimicrobials during World War 1. Julius Cohen (1859–1935) was Professor of Organic Chemistry at the University of Leeds, and with H.D. Dakin (1880–1952) developed chlorinated antiseptics such as chloramine [1], [2].

The work carried out by Browning in the immediate post-war period represented a continuation of his two main interests: antibacterials and trypanocidal agents. The aftermath of the war brought into focus the considerable achievement of Browning and others in introducing into the clinical milieu the synthetic antiseptics acriflavine and proflavine (Fig. 1), which were far more effective than the German-produced hydrocuprein derivatives [3], [4]. This encouraged further exploration of synthetic dye-based compounds and the availability of extended series of compounds (foreshadowing modern compound libraries) facilitated some idea of the structure–activity relationships arising. Expansion of the range of chromophores employed in the research also provided a foundation for future chemotherapeutic drug design, particularly in the field of acridine and phenanthridine trypanocidal agents. The promising antibacterial results shown by many of the candidate compounds produced during Browning and Cohen's collaboration did not lead to further investigation and development, mainly because of the perceived all-encompassing superiority of penicillin from the 1940s onwards, and the fact that sulphonamides were also readily available and, apparently, effective [5]. The simple aminoacridines, including proflavine, were employed quite widely before penicillin became readily available to the allied armed forces in World War II, but the exigencies of the conflict quite rightly did not allow for speculative research into ‘new’ antibacterials when those available were adequate and drug-resistant microbes were not a significant cause for concern.

Section snippets

Antibacterial development

One requirement for activity in early acridine compounds was recognised to be the inclusion of amino groups; this explained, for example, the difference in antibacterial efficacy between the parent molecule and proflavine [6]. Initially, the presence of the amino group was thought to be essential for activity. However, acridines without amino groups, such as sinflavin (3,6-dimethoxy-10-methylacridinium chloride, Fig. 1) were later shown to be highly active, at least against Gram-positive

Quinoline derivatives

A large series of quinoline derivatives was produced by Cohen, based on the reaction of quaternised quinaldine species (N-alkylated 2-methylquinolinium salts), either with aromatic aldehydes or nitrosoanilines, in both cases coloured compounds resulted; these were styryl or imino (anil) compounds, respectively, in order to maintain the structural features seen in the acriflavine molecule [13], [14].

While the series of quinoline compounds contained varying chemical groups, the number,

The Leeds trial

Perhaps unsurprisingly, the single example from the series which was allowed entry into a clinical trial was an imino compound (No. 48). However, this had by no means exhibited the optimum activity in vitro, and was selected for the trial when better-performing candidates from the in vitro work proved too insoluble in normal saline for use in either animals or humans [16]. Indeed, the clinical work was finally carried out using a sulfonated version of the chosen compound on the grounds of

Quinoline compounds—mode of action

In his landmark study of the antibacterial action of the aminoacridines, Adrien Albert reported the activities of a huge number of heterocyclic compounds, including several examples from the quinoline series. Albert's hypothesis was that the aminoacridines were only active if highly ionised as cations at physiological pH, and that this was due to their interaction with bacterial DNA. In order to prove a steric requirement for the interaction Albert cited the inactivity of both the

Alternative chromophores

Given the obvious high activity of the quinoline series, it is perhaps unsurprising that Browning and Cohen, in the main, confined their investigations to compounds containing this nucleus. However, several series of dyes based on other chromophoric types were produced for screening, including the closely analogous benzo[f]quinolines [26]. Benzothiazole-based cyanine dyes were also examined, although advances in the photographic industry may have encouraged this part of the work [27]. While the

Modern cyanine antimicrobials

Although little use was made of the quinoline compounds described above, research continued to provide useful agents. For example, pyrvinium salts (Fig. 1) are related to the styrylquinoline derivatives, having a pyrrolic moiety in place of phenyl. This compound is in current use (as the pamoate salt) as an antihelminthic rather than an antimicrobial. The considerable utility of styryl and cyanine dyes in cellular research is outside the scope of the current review.

With the advances in the

Further work

In the face of the current burgeoning of drug-resistant bacteria, particularly of Gram-positive type, e.g. MRSA, the requirement for new chromophores is particularly urgent. The activities of the quinoline derivatives discussed here are unknown against such species as MRSA, but there are several examples (e.g. nos. 18 and 30, Table 2) having activities against S. aureus comparable with those of crystal violet (Table 1), a compound employed successfully in the recent past by healthcare concerns

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