MW5487 Wainwright

Journal of Antimicrobial Chemotherapy (2001) 47, 1–13 JAC Review Acridine—a neglected antibacterial chromophore Mark Wainwright* Centre for Forensic Science, University of Central Lancashire, Preston PR1 2HE, UK The use of acridines as antimicrobial agents was first proposed by Ehrlich and Benda in 1912, and the first clinical use of these agents occurred in 1917. Many compounds containing the acridine chromophore were synthesized and tested, and the aminoacridines found wide use, both as antibacterial agents and as antimalarials, during World War II. The emergence of the penicillins eclipsed the acridines in antisepsis due to the greater therapeutic efficacies of the former. However, with the current massive increases in drug-resistant bacterial infection, new acridine derivatives may be of use. In addition, the topical utilization of aminoacridines in conjunction with directed low-power light offers bactericidal action at much lower doses. Introduction A student of Ehrlich’s, Browning was instrumental in the introduction of proflavine and acriflavine as wound anti- Of the many advances in medical science in the twentieth septics in base hospitals serving the Western Front. In the century, few have been as pervasive as those made in the post-war era Browning worked with the then Professor of field of antimicrobial chemotherapy. Although the early Organic Chemistry at the University of Leeds, J. B. Cohen, breakthroughs made by Ehrlich using arsenicals may have on the early structure–activity relationships pertaining to been associated with considerable morbidity, they intro- the antimicrobial action of a variety of dye-derived cationic duced the idea of synthetic chemotherapy. Compounds heterocyclics, both in the antibacterial and trypanocidal such as Salvarsan were products of the systematic screening fields.3 These cationics included cyanine and styryl deriva- of available series of chemicals, most of which were pro- tives of several classes of heterocycle, such as quinoline duced as dyestuffs. However, there was a considerable and phenazine, as well as the established acridine chromo- antibacterial gap between Salvarsan and the widespread phore. availability of penicillins (1944). From the latter part of Similarly, in Germany, workers at the chemical giant I. G. World War I to the early-mid part of World War II this was Farben were following antimicrobial research programmes filled by mercury salts, therapeutic dyes and dye derivatives broadly based on biologically active dyestuffs. At this time such as the sulphonamides (1935). In addition, the consid- the use of the phenothiazinium dye methylene blue as a erable progress made in the treatment of protozoal tropical lead compound resulted in the development of the anti- diseases such as trypanosomiasis and malaria was based malarials primaquine and pamaquine, both based on the squarely on acridine, phenothiazine and quinoline deriva- 8-aminoquinoline chromophore, and of chloroquine, based tives. The genesis of the alkylamino side chain, so common on 4-aminoquinoline. The analogous acridine-based anti- in modern drugs, can be traced to this period.1 malarial Mepacrin (Atebrin, Quinacrine; Figure 1) was to The use of heteroaromatic dyes as antibacterial agents find widespread use by the Allies in eastern theatres of evolved directly from the experimentation of Ehrlich in World War II, in the absence of quinine from Japanese-held the late nineteenth century. The trypanocidal activity of Java.4 10-methyl-3,6-diaminoacridinium chloride (Trypaflavin, The second key figure in acridine antibacterial develop- acriflavine; Table) was reported in 1912 by Ehrlich and ment was Adrien Albert. An Australian chemist, Albert Benda, and the antibacterial activity of the same compound was interested in the idea of structure–activity relation- and the neutral (non-methylated) acridine proflavine ships, and it was his work on acridines that ultimately led to (Table) in the following year by Carl Browning, a major the understanding of their mode of action.5 figure in the development of acridine-based chemotherapy.2 Having synthesized and tested many different acridines, *E-mail: [email protected] 1 © 2001 The British Society for Antimicrobial Chemotherapy M. Wainwright Albert rationalized the following parameters as being This unifying hypothesis explained the activity against necessary for antibacterial activity: bacteria of many fused aromatic compounds. For example, the presence of the acridine nucleus per se is not required, ● cationic ionization; e.g. isomeric aminobenzoquinolines and phenanthridines ● у high levels of ionization at neutral pH (i.e. pKa 8); are also active. In fact, a heteroaromatic nucleus is not ● planar molecular surface area у38 Å2. essential—2-guanidinoanthracene is antibacterial.6 Albert Table. Clinically used acridines, 1917–1946 R2 R3 R4 R6 R9 R10 Reference no. Proflavine H NH2 HNH2 HH 8 a Euflavine HNH2 HNH2 HCH3 9 Diflavine NH2 HHNH2 HH 10 Sinflavin H CH3OH CH3OH CH3 11 Flavicid CH3 NH2 H (CH3)2NH CH3 12 Ethacridine CH3CH2OH H NH2 NH2 H13 Aminacrine H H H H NH2 H14 Salacrin H H CH3 HNH2 H15 aAs a component of acriflavine, Gonoflavin, Trypaflavin, etc. Figure 1. Acridine structures: (a) Mepacrine; (b) Azacrine; (c) m-AMSA; (d) dercetin; (e) heterocyclic styrylacridine; and (f) Nitro- akridin 3582. 2 Acridine—a neglected antibacterial chromophore merases) rather than DNA itself, damage being caused by the stabilization of the enzyme–DNA cleavage complex.22 DNA intercalation has also formed the main foundation for opposition to the widespread use of acridines as main- stream antibacterials in modern clinical practice, the nucleic acid site of action resulting in positive mutagenicity Figure 2. Numbering of the acridine chromophore. testing in vitro. In terms of modern chromophoric alternatives, a range concentrated on the aminoacridine derivatives since these of naturally occurring ring-fused acridines have been dis- had been known since Browning to be active and of covered of the pyrido-/thiazolo-fused variety, e.g. dercetin low toxicity. Within the series, Albert showed that those (Figure 1). The site of action of these natural products is aminoacridines having electronic conjugation between the again reported to be DNA, in agreement with the above.23 ring nitrogen and the amino group were the most active, However, the most abundant acridine-containing natural due to the high ionization of such compounds. In this products are the acridine alkaloids present in plants of the respect, the important positions in the acridine chromo- family Rutaceae.24,25 An observation that might be made phore are 3, 6 and 9 (Figure 2), and many derivatives based concerning acridine-based natural products is that they are on these structures are effective antibacterial agents.7 In usually tested for anticancer properties exclusively. That terms of clinically useful materials, the Table gives the this is so is probably due to the in vitro mutagenicity found structures of acridines that were employed as antibacterial with some aminoacridines, alluded to above. Unfortun- agents in the period up to the end of World War II. The ately, this may mean that promising antimicrobials have introduction of the derivatives Aminacrine and Salacrin been overlooked. A rare exception to this is the work of into clinical usage should be accredited to Albert himself, Queener concerning the activity of Rutaceae acridones although the useful lifetime of these agents was shortened against Pneumocystis carinii.26 considerably by the advent of the -lactam agents that became available in quantity towards the end of World War II. With the acceptance of the activity of aminoacridines as Clinical use antibacterials, and the widespread use of the Allies’ altern- Systemic administration ative antimalarial preparation, Mepacrine, research into the medicinal properties of the acridine chromophore Although acriflavine (as Gonoflavin, I. G. Farben, Ger- reached its zenith in the immediate post-war period. At this many) was given iv for the treatment of gonorrhoea (0.1 g time chromophoric analogues such as the pyridoquinolines three times per week27 or 10 doses of 40–80 mg at 2–3 day (‘azacridines’, e.g. Azacrine, Figure 1) were also examined intervals28), the use of simple aminoacridines in the clinical as antimicrobials, although mainly in the domain of anti- treatment of blood-borne infection, e.g. staphylococcal malarial research,16,17 reflecting the focus of contemporary septicaemia, has never been a realistic option owing to the antibacterial research (and clinical reliance) on -lactam short half-life of drugs such as acriflavine or proflavine in drugs. In the 1950s and early 1960s, the work of Steck on the bloodstream. For example, iv treatment of septicaemia anti-rickettsial acridines,18 based on a nitroaminoacridine with Argoflavin (I. G. Farben, Germany), a mixture of system (previously Nitroakridin 3582, Figure 1), and of euflavine lactate and silver lactate, was not usually success- Elslager on acridine N-oxides19 are noteworthy as being ful.29 This is unsurprising, since the concentration in the the last major research efforts in systemic acridine antibac- blood of iv-administered acriflavine (200 mg) was found to terials. Tabern’s ‘Phenacridane’ series20 was intended as a have decreased by 90% over 5 min and to be undetectable topical anti-infective and this has been the major area of at 30 min.30 Aminacrine and rivanol exhibited similar acridine-based antibacterial treatment since that time, pharmacokinetics.13,31 mainly

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