The trypanocidal action of certain phenanthridinium compounds

The powerful trypanocidal activity of certain phenanthridinium compounds was first demonstrated by Browning and his collaborators in 1938 (Browning, Morgan, Robb, and Walls, 1938;Walls, 1947a; Browning, 1949). This activity is highly specific against African bovine trypanosomiasis caused by T. congolense and T. vivax. A single dose is usually effective and, in spite of local irritant action and the occasional late toxic effects observed in some districts, several million doses have been given. The drugs have thus gained a place in the treatment of a disease for which radical cure was previously difficult to achieve.At the time the work described in this paper started it had been demonstrated (Walls, 1947b) that high trypanocidal activity in the phenanthridinium series is a property of quaternary salts containing a primary amino-group in the 7-and a phenyl group in the 9-position; the activity is much enhanced by the presence of a second primary amino-group, 2: 7-diamino-9-phenyl-10-methylphenanthridinium bromide (dimidium bromide) being particularly effective. Compounds with the amino-group in the 3-position are less active. Our work was designed to test these conclusions further, and if possible to extend them. The investigations fall into five main groups:(a) To establish whether the 7-position represents the optimum location for the first primary amino-group.(b) To determine the effect of variation of the 9-substituent and, in particular, whether the high activity of the 2: 7-diamino-compounds is associated with other 9-substituents than phenyl.(c) To determine the effect of modifying the primary amino-groups.(d) To determine the effect of alkoxyl groups. (e) To consider the relation between trypanocidal and antibacterial activity.

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confidence: 99%

The Chemotherapeutic Action of Phenanthridine Compounds

Brownlee

Goss

Goodwin

et al. 1950

British Journal of Pharmacology and Chemotherapy

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“…The very approximate therapeutic index (MTD / MCD) obtained from these values was about 2 for the most active of the impure preparations tested. Bearing in mind that the impurity formed only a part of the preparation tested, this figure suggested a high degree of activity in the hypothetical impurity, because the therapeutic indices obtained in the same way for presumably pure specimens of the two most active of the phenanthridinium compounds known at that time, dimidium bromide and " phenidium " chloride (Browning et al, 1938) (Keneford et al, 1948 (1938,1939), the complex structure of (i) was the naturally occurring cyclopentenophenanthrene configuration; and the mono-and bis-compounds of stages (ii) and (iii) were those shown in formulae V and VI.…”

Section: Theoretical and Early Experimental Backgroundmentioning

confidence: 99%

“…This species is relatively resistant to the arsenicals, diamidines and suramin, which are so useful against T. gambiense, the cause of the most common form of the disease in man. It was therefore not until compounds of the phenanthridinium group were introduced by Browning, Morgan, Robb, and Walls (1938) that the chemotherapy of T. congolense infections began to assume a favourable aspect. Of this chemical group " dimidium " bromide, 2: 7-diamino-9-phenyl-10-methylphenanthridinium bromide (see formula I), first used in cattle by Carmichael and Bell (1944), has achieved considerable success in field practice; and another member of the group, 2: 7-diamino-9-p-aminophenyl-10-methylphenanthridinium chloride, has recently been claimed by Brownlee, Goss, Goodwin, Woodbine, and Walls (1950) as an improvement on dimidium bromide in T. congolense infections in mice.…”

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A CINNOLINE COMPOUND (“528”) FOR THE TREATMENT OF TRYPANOSOMA CONGOLENSE INFECTIONS

Lourie

Morley

Simpson

et al. 1951

British Journal of Pharmacology and Chemotherapy

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The most common pathogenic trypanosome of cattle throughout tropical Africa is Trypanosoma congolense. This species is relatively resistant to the arsenicals, diamidines and suramin, which are so useful against T. gambiense, the cause of the most common form of the disease in man. It was therefore not until compounds of the phenanthridinium group were introduced by Browning, Morgan, Robb, and Walls (1938) that the chemotherapy of T. congolense infections began to assume a favourable aspect. Of this chemical group " dimidium " bromide, 2: 7-diamino-9-phenyl-10-methylphenanthridinium bromide (see formula I), first used in cattle by Carmichael and Bell (1944), has achieved considerable success in field practice; and another member of the group, 2: 7-diamino-9-p-aminophenyl-10-methylphenanthridinium chloride, has recently been claimed by Brownlee, Goss, Goodwin, Woodbine, and Walls (1950) as an improvement on dimidium bromide in T. congolense infections in mice.The first type of compound to be successful against T. congolense infections on a wide scale was therefore one in which the he.ero-N is quaternized. This is interesting because no such type has found a place in the chemotherapy of human trypanosomiasis. It is a development that was foreshadowed many years earlier by the limited success of another group of quaternary ammonium compounds, viz., the styryl-quinolinium substances of Browning, Cohen, Ellingworth, and Gulbransen (1926). Quaternary nitrogen, this time at two points on the molecule, is again a feature of the most recent compound to be used successfully against T. congolense on a wide scale, namely "antrycide" (Curd andDavey, 1949, 1950), a salt of substituted quinaldinium-pyrimidinium residues connected by an imino linkage (see formula II). THEORETICAL AND EARLY EXPERIMENTAL BACKGROUNDA preliminary note on the initial work which eventually led to " 528 " has already appeared (Keneford et al., 1948

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“…Certain phenanthridine compounds, originally synthesized by Morgan and Walls (1938), were found by Browning, Morgan, Robb, and Walls (1938) to possess trypanocidal properties. This discovery led Walls and his colleagues (1945, 1947, 1948, 1950a, b, c, d, 1952a, b) to synthesize a large number of phenanthridine derivatives, some of which have been used with success against T. congolense infections of cattle.…”

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confidence: 99%