Cinchona Alkaloids in Pneumonia. VIII. Some Sulfur Derivatives of Apocupreicine Ethers and Aminoquinolines

Renfrew, Alice G.; Butler, C. L.

doi:10.1021/ja01869a009

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confidence: 61%

“…(The numbering introduced by Rabe (97) has been adopted in most publications, although it is not in strict conformity with the rules established by the International Commission (94)). C» has a levo rotation, as observed by Solomon (108a) in methylapocupreicine and in other apocupreicine ethers (99), and the combined rotational value of carbon atoms 3 and 4, in the naturally occurring cinchona alkaloids, indicates a dextro configuration For the typical cinchona structure, the levorotatory quinine derivatives are more effective than the dextro isomers against both the malarial parasite and the pneumococcus, as evidenced by dihydroquinine and optochin in contrast with the dextro forms. The comparative antimalarial values of the dextro and levo series of different types of ethers have been presented by Buttle (14).…”

Section: )mentioning

confidence: 78%

“…Attempts to combine the sulfanilamide molecule and an aminoquinoline have not been productive (88,99) in the simple derivatives, but in the testing of N4-alkylaminoacetylsulfanilamidoquinolines Juneja (58) has cIaimed results "comparing favorably with sulfapyridine." Synthetic derivatives of 6-methoxyquinoline in which a pyrryl (60) or a piperidyl (1) nucleus or a 0-dialkylaminomethyl group (61) has been substituted for the quinuclidine portion of the cinchonas have shown action on paramecia or antimalarial power, but no study of the antipneumococcic action has been reported.…”

Section: A Simple Substituted Quinolinesmentioning

confidence: 99%

“…(99). Keither reduction of the keto group to give an asymmetric secondary alcohol (42e), nor restoration of a tertiary character to the nitrogen by replacement of the hydrogen of the piperidyl KH group with an alkyl group (42d, 42e) produces active compounds.…”

Section: Ch2 Conhrimentioning

confidence: 99%

“…Keither reduction of the keto group to give an asymmetric secondary alcohol (42e), nor restoration of a tertiary character to the nitrogen by replacement of the hydrogen of the piperidyl KH group with an alkyl group (42d, 42e) produces active compounds. The introduction of the sulfanilyl radical on the piperidine nitrogen gave compounds without value against the pneumococcus (99). 6 In considering the significance of the 1 ,&fission with regard to the correlation of structure and antipneumococcic action, it is important to remember that conversion of the quinuclidine to a piperidine ring is not invariably dystherapeutic, as shown by the antimalarial effectiveness of niquine and niquidine (31, 108b) and of 4'-(6'-methoxyquinolyl)-2-piperidylcarbinol (synthesized by Ainley and King (1)).…”

Section: Ch2 Conhrimentioning

confidence: 99%

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Structure and Antipneumococcic Activity in the Cinchona Series.

Renfrew¹,

Cretcher²

1942

Chem. Rev.

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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

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confidence: 78%