Studies on the Chemotherapy of the Human Malarias. Iii. The Physiological Disposition and Antimalarial Activity of the Cinchona Alkaloids 123

Taggart, John V.; Earle, David P.; Berliner, Robert W.; Zubrod, C. Gordon; Welch, William J.; Wise, Nancy Bowman; Schroeder, Edmond F.; London, Irving M.; Shannon, James A.

doi:10.1172/jci101977

Cited by 50 publications

(28 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4B). This relationship is mirrored in their relative potencies, with quinidine possessing more antimalarial potency than quinine both in vitro and in vivo (1,4,15,18,23,25,26), and in certain strains in vitro, (ϩ)-mefloquine is more potent than (Ϫ)-mefloquine (16). Stereoselectivity plays a role in human mefloquine pharmacokinetics.…”

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

Karle

2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The absolute configuration of (؊)-mefloquine has been established as 11R,12S by X-ray crystallography of the hydrochloride salt, thus allowing comparison of the configuration of mefloquine's optical isomers to those of quinine and quinidine. (؊)-Mefloquine has the same stereochemistry as quinine, and (؉)-mefloquine has the same stereochemistry as quinidine. Since (؉)-mefloquine is more potent than (؊)-mefloquine in vitro against the D6 and W2 strains of Plasmodium falciparum and quinidine is more potent than quinine, a common stereochemical component for antimalarial activity is implicated. The crystal of (؊)-mefloquine hydrochloride contained four different conformations which mainly differ in a small rotation of the piperidine ring. These conformations are essentially the same as the crystalline conformations of racemic mefloquine methylsulfonate monohydrate, mefloquine hydrochloride, and mefloquine free base. Quinine and quinidine (Fig. 1), antimalarial agents isolated from the bark of the Cinchona tree, are diastereomers, but they mirror each other at carbons C-8 and C-9. In vitro quinidine is more potent than quinine against many strains of Plasmodium falciparum. Specifically, quinidine is 2.3 and 2.8 times more potent than quinine against the chloroquine-sensitive Sierra Leone D-6 clone and the chloroquine-resistant Indochina W-2 clone, respectively (15). Quinidine is 2.5 times more potent than quinine and cinchonine (the demethoxy analog of quinidine) is 2.8 times more potent than cinchonidine (the demethoxy analog of quinine) in vitro against Papua New Guinea FCQ-27/PNG P. falciparum (25). Similarly, quinidine was 2.2 and 3.2 times more potent than quinine against Cameroon chloroquine-resistant FCM 29 and Ivory Coast chloroquine-sensitive L-3 strains, respectively (1). Against clinical isolates from Liberia, quinidine was on average 3 times more potent than quinine (4). Clinical differences in the antimalarial activities of quinine and quinidine have also been reported. Compared to quinine, quinidine was twice as effective against induced McClendon P. falciparum infections (23) and more potent clinically against Thai P. falciparum (18,26).Mefloquine, a synthetic analog of quinine and quinidine, is marketed in racemic form under the trade name Lariam. Mefloquine is basically a structurally simpler form of quinine and quinidine. Mefloquine differs from the cinchona alkaloids in that it has a different substitution on the quinoline ring, a piperidine ring rather than the bicyclo quinuclidine ring, and no vinyl group (see Fig. 1). However, the C-8 and C-9 chiral centers of the cinchona alkaloids are preserved in the mefloquine molecule (numbered C-12 and C-11, respectively). Thus, one enantiomer of mefloquine will share the same stereochemistry as quinine and the other enantiomer of mefloquine will share the same stereochemistry as quinidine at the equivalent chiral centers.Since quinine and quinidine possess different antimalarial activities, the (ϩ) and (Ϫ) isomers of mefloquine were tested against P. falc...

show abstract

Section: Discussionmentioning

confidence: 97%

“…Clinical differences in the antimalarial activities of quinine and quinidine have also been reported. Compared to quinine, quinidine was twice as effective against induced McClendon P. falciparum infections (23) and more potent clinically against Thai P. falciparum (18,26).…”

mentioning

confidence: 95%

Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

Karle

2002

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…EQN (weakly dextrorotatory) and EQD (dextrorotatory) are comparatively ineffective; a previous study noted lower efficacies of approximately 100-fold compared to QN and QD (37). Observations of stereospecificity extend to in vivo studies on QN and QD efficacy against P. falciparum, where the latter is the more potent clinically (62,69).…”

mentioning

confidence: 91%

Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

Griffin

Hoke

Samarakoon

et al. 2012

Antimicrob Agents Chemother

View full text Add to dashboard Cite

eThe Cinchona alkaloids are quinoline aminoalcohols that occur as diastereomer pairs, typified by (؊)-quinine and (؉)-quinidine. The potency of (؉)-isomers is greater than the (؊)-isomers in vitro and in vivo against Plasmodium falciparum malaria parasites. They may act by the inhibition of heme crystallization within the parasite digestive vacuole in a manner similar to chloroquine. Earlier studies showed that a K76I mutation in the digestive vacuole-associated protein, PfCRT (P. falciparum chloroquine resistance transporter), reversed the normal potency order of quinine and quinidine toward P. falciparum. To further explore PfCRT-alkaloid interactions in the malaria parasite, we measured the in vitro susceptibility of eight clonal lines of P. falciparum derived from the 106/1 strain, each containing a unique pfcrt allele, to four Cinchona stereoisomer pairs: quinine and quinidine; cinchonidine and cinchonine; hydroquinine and hydroquinidine; 9-epiquinine and 9-epiquinidine. Stereospecific potency of the Cinchona alkaloids was associated with changes in charge and hydrophobicity of mutable PfCRT amino acids. In isogenic chloroquine-resistant lines, the IC 50 ratio of (؊)/(؉) CA pairs correlated with side chain hydrophobicity of the position 76 residue. Second-site PfCRT mutations negated the K76I stereospecific effects: charge-change mutations C72R or Q352K/R restored potency patterns similar to the parent K76 line, while V369F increased susceptibility to the alkaloids and nullified stereospecific differences between alkaloid pairs. Interactions between key residues of the PfCRT channel/transporter with (؊) and (؉) alkaloids are stereospecifically determined, suggesting that PfCRT binding plays an important role in the antimalarial activity of quinine and other Cinchona alkaloids.A lkaloids from the Cinchona tree, exemplified by quinine (QN) and quinidine (QD), have proven to be an important source of antimalarial therapies, especially after resistance to chloroquine (CQ) emerged. QN remains a first-line drug in the treatment of severe malaria in many parts of the world, even with increased use of artemisinin-based combination therapies (70). The Cinchona alkaloids (CA) are aryl amino alcohols where the aryl group is a quinoline (quinoline aminoalcohols). They have four chiral centers, two of which, C-8 and C-9, can have different configurations (66) (Fig. 1). Among the pharmacologically active 8,9-erythro isomers, QN, hydroquinine (HQN), and cinchonidine (CD) all present the S configuration around C-8 and the R configuration at C-9 and are levorotatory (rotate plane polarized light in an anticlockwise [Ϫ] direction). The reverse ordering, R at C-8 and S at C-9, occurs in the respective dextrorotatory (rotate plane polarized light in a clockwise [ϩ] direction) diastereomers, QD, hydroquinidine (HQD), and cinchonine (CN). The 8,9-threo diastereomers 9-epiquinine (EQN) and 9-epiquinidine (EQD) are 8S, 9S, and 8R, 9R, respectively.Against Plasmodium falciparum, the CA diastereomer pairs have a well-established in ...

show abstract

“…26 In rats bearing resistant tumors, cinchonine is more efficient than quinine in increasing the efficacy of anticancer drugs. 25 Although cinchonine has been used previously in the clinic, either alone or in combination with quinine and/or quinidine for the treatment of malaria, its pharmacokinetics remained incompletely studied, 27,28 its tolerance in humans had not been widely investigated and its combination with cytotoxic drugs remained to be tested.…”

Section: Introductionmentioning

confidence: 99%

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

Solary

Mannone²,

Moreau³

et al. 2000

Leukemia

View full text Add to dashboard Cite

show abstract

Studies on the Chemotherapy of the Human Malarias. Iii. The Physiological Disposition and Antimalarial Activity of the Cinchona Alkaloids 123

Cited by 50 publications

References 8 publications

Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

Crystal Structure of (−)-Mefloquine Hydrochloride Reveals Consistency of Configuration with Biological Activity

Mutation in the Plasmodium falciparum CRT Protein Determines the Stereospecific Activity of Antimalarial Cinchona Alkaloids

Phase I study of cinchonine, a multidrug resistance reversing agent, combined with the CHVP regimen in relapsed and refractory lymphoproliferative syndromes

Contact Info

Product

Resources

About