Structure and Antipneumococcic Activity in the Cinchona Series.

Abstract

The present survey gives particular emphasis to recent studies of the antipneumococcic action of some cinchona derivatives. A brief historical survey is presented and reference is made to speculations concerning the mode of action of cinchonas in the animal body. Antipneumococcic action is analyzed with regard to isomeric and structural modifications of the cinchona molecule. A summary of recent data on bacteriostasis, toxicity, animal protection, pharmacologic testing, and clinical studies is given. Synthetic analogs are discussed in relation to significant structural factors.Cinchona alkaloids have been used as antimalarials since 1630, but evidence of the specific antipneumococcic action of these compounds dates only from 1911. RIorgenroth's (84) study of cinchonas as antipneumococcic agents has been described as "the first striking instance of the successful application of a chemical to the treatment of a bacterial infection in a laboratory animal" (53). Because Morgenroth had been studying quinine in relation to trypanosome infections in animals and was acquainted with the capsule-formation characteristic of trypanosomes, spirilla, and the pneumococcus, he was led to investigate the action of the alkaloid in pneumococcic septicemia in mice. There followed an extensive study of hydrocupreine ethers with the synthesis of the well-known optochin, vuein, and eucupin. Between 1919 and 1924 Heidelberger and Jacobs (42, 54) a t the Rockefeller Institute and Giemsa (32, 33) in Germany published the results of further studies in the hydrocupreine series. These results have been reviewed by von Oettingen (111) and by Houben (50), and the clinical findings have been discussed by Moore and Chesney (87), by Kolmer (63), and by Solis-Cohen (107).The remarkable antipneumococcic action of optochin has been a spur to reinvestigation of this field. In again studying cinchona derivatives the search was not so much for a compound of greater power but rather for a compound free from deleterious side-effects. The last decade has brought extensive synthesis in the field of apocinchonas. In the early 1930's methylapocupreinel [or 1 At the time the term apocupreine (8) was suggested, its use was based firstly on the similarities of apocupreine (formula 11) and cupreine (formula I), which differ chemically only in the 3-substituent of ethylidene or vinyl, respectively, and secondly on the established usage of Leger (59, 66) in applying the terms apocinchonine and apocinchonidine (characterized by the ethylidene side chain) to the corresponding substances derived from cinchonine and cinchonidine. In the case of quinine, demethylation is accomplished by boiling with 60 per cent sulfuric acid; a shift of the double bond also occurs. The product, called apoquinine by Hesse (49), consists of substances of different toxicities and antipneumococcic powers and these give derivatives of various biological properties. The name 49

Antimalarial Efficacy of Hydroxyethylapoquinine (SN-119) and Its Derivatives

“…These results suggest that isomerization of the vinyl group did not decrease this cardiac potassium channel inhibition, whereas the hydroxyethyl substituent may slightly decrease parasite activity while also importantly decreasing the hERG potassium channel inhibition. Cretcher and Renfrew previously commented on the effect of the resulting modifications on antipneumococcal activity, stating that "greater antipneumococcic action appears to be associated with the ethylidene group," and they observed an increased dosage of drug required to obtain the same toxic effects of quinine (33). While we did not observe increased potency with the ethylidene or isomerized vinyl group, we did observe a decrease in hERG channel inhibition associated with the hydroxyethyl substitution, suggesting that this modification and not isomerization of the vinyl group can be credited for the great reduction in overall cardiac disturbances for these compounds seen in historic manuscripts in the 1930s and 1940s.…”

A Cinchona Alkaloid Antibiotic That Appears To Target ATP Synthase in Streptococcus pneumoniae

“…The antibiotic optochin 1 (Figure A), a cinchona alkaloid derivative, possesses highly selective pneumococcal activity and was also shown to effectively treat septicemia in animals and humans. − However, development of optochin was discontinued because of toxicity observed in humans with incidence of optical disturbances in up to 5% of patients given ∼25 mg/kg/day and moderate activity in treating lobar pneumonia, the most prevalent infection caused by S. pneumoniae .…”

The Blood Distribution and Toxicity of Several Cinchona Alkaloid Derivatives

“…Hogan Bracken, and their co-workers at Mercy Hospital, Pittsburgh, for cinchona derivatives useful in the treatment of pneumonia. For reviews of this work see Redrew and Cretcher (6). and Maclachlan, Johnston, Bracken, and Pierce (7).…”