Antimalarial activity and structure-activity relationships of protoberberine alkaloids

Kinuko Iwasa, Hye-Sook Kim, Yusuke Wataya, Dong Ung Lee

Research output: Contribution to journalArticle

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Abstract

The thirty-nine protoberberine derivatives including berberine 1 and palmatine 2 were tested for antimalarial activity in vitro against Plasmodium falciparum and structure-activity relationships are proposed. The activity of the protoberberine alkaloids was influenced by the type of the quaternary nitrogen atom, the nature and the size of the substituents at the C-13 position, and the type of O-alkyl substituents on rings A and D. The activity of the quaternary protoberberinium salts with an aromatic ring C such as berberine was higher than that of the quaternary salts such as the N-metho salts or the N-oxides of tetrahydro and dihydro derivatives as well as tertiary tetrahydroprotoberberines. Of the 13-alkyl derivatives of 1 and 2, the activity did not always increase as the length of the aliphatic chain rose in the order methyl, ethyl, propyl, butyl, and hexyl group. 13- Butylberberine (1Bu) and 13-propylpalmatine (2Pr) were the most active compounds among the 13-alkylberberines and 13-alkylpalmatines, respectively. 13-Hydroxyberberine 3 possessed the same level of activity as 1. Of 1 and 2 with different substituents types on Ring A, the activity of 1 was significantly higher than that of 2. Among berberrubines 4 and 5 and their C- 9-O-alkyl derivatives 6 and 7, the activity of 9-O-ethylberberrubine 6 was the highest. Of the potent protoberberinium salts, the activity decreased in the order: 1, 3 > 2Pr > 6 > 1Bu. A positive effect on the activity might be exerted by the introduction of a more hydrophilic function into the C-13 position of the protoberberinium salts.

Original languageEnglish
Pages (from-to)65-69
Number of pages5
JournalEuropean Journal of Medicinal Chemistry
Volume33
Issue number1
DOIs
Publication statusPublished - Jan 1998

Fingerprint

Antimalarials
Structure-Activity Relationship
Alkaloids
Salts
Berberine
Derivatives
Plasmodium falciparum
Oxides
Nitrogen
protoberberine
Atoms

Keywords

  • In vitro antimalarial activity
  • Protoberberinium salts
  • Structure-activity relationships

ASJC Scopus subject areas

  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

Cite this

Antimalarial activity and structure-activity relationships of protoberberine alkaloids. / Iwasa, Kinuko; Kim, Hye-Sook; Wataya, Yusuke; Lee, Dong Ung.

In: European Journal of Medicinal Chemistry, Vol. 33, No. 1, 01.1998, p. 65-69.

Research output: Contribution to journalArticle

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abstract = "The thirty-nine protoberberine derivatives including berberine 1 and palmatine 2 were tested for antimalarial activity in vitro against Plasmodium falciparum and structure-activity relationships are proposed. The activity of the protoberberine alkaloids was influenced by the type of the quaternary nitrogen atom, the nature and the size of the substituents at the C-13 position, and the type of O-alkyl substituents on rings A and D. The activity of the quaternary protoberberinium salts with an aromatic ring C such as berberine was higher than that of the quaternary salts such as the N-metho salts or the N-oxides of tetrahydro and dihydro derivatives as well as tertiary tetrahydroprotoberberines. Of the 13-alkyl derivatives of 1 and 2, the activity did not always increase as the length of the aliphatic chain rose in the order methyl, ethyl, propyl, butyl, and hexyl group. 13- Butylberberine (1Bu) and 13-propylpalmatine (2Pr) were the most active compounds among the 13-alkylberberines and 13-alkylpalmatines, respectively. 13-Hydroxyberberine 3 possessed the same level of activity as 1. Of 1 and 2 with different substituents types on Ring A, the activity of 1 was significantly higher than that of 2. Among berberrubines 4 and 5 and their C- 9-O-alkyl derivatives 6 and 7, the activity of 9-O-ethylberberrubine 6 was the highest. Of the potent protoberberinium salts, the activity decreased in the order: 1, 3 > 2Pr > 6 > 1Bu. A positive effect on the activity might be exerted by the introduction of a more hydrophilic function into the C-13 position of the protoberberinium salts.",
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AB - The thirty-nine protoberberine derivatives including berberine 1 and palmatine 2 were tested for antimalarial activity in vitro against Plasmodium falciparum and structure-activity relationships are proposed. The activity of the protoberberine alkaloids was influenced by the type of the quaternary nitrogen atom, the nature and the size of the substituents at the C-13 position, and the type of O-alkyl substituents on rings A and D. The activity of the quaternary protoberberinium salts with an aromatic ring C such as berberine was higher than that of the quaternary salts such as the N-metho salts or the N-oxides of tetrahydro and dihydro derivatives as well as tertiary tetrahydroprotoberberines. Of the 13-alkyl derivatives of 1 and 2, the activity did not always increase as the length of the aliphatic chain rose in the order methyl, ethyl, propyl, butyl, and hexyl group. 13- Butylberberine (1Bu) and 13-propylpalmatine (2Pr) were the most active compounds among the 13-alkylberberines and 13-alkylpalmatines, respectively. 13-Hydroxyberberine 3 possessed the same level of activity as 1. Of 1 and 2 with different substituents types on Ring A, the activity of 1 was significantly higher than that of 2. Among berberrubines 4 and 5 and their C- 9-O-alkyl derivatives 6 and 7, the activity of 9-O-ethylberberrubine 6 was the highest. Of the potent protoberberinium salts, the activity decreased in the order: 1, 3 > 2Pr > 6 > 1Bu. A positive effect on the activity might be exerted by the introduction of a more hydrophilic function into the C-13 position of the protoberberinium salts.

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