Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: Charting a workable structure-activity relationship using simple prototypes

Yuxiang Dong, Jacques Chollet, Hugues Matile, Susan A. Charman, Francis C.K. Chiu, William N. Charman, Bernard Scorneaux, Heinrich Urwyler, Josefina Santo Tomas, Christian Scheurer, Christopher Snyder, Arnulf Dorn, Xiaofang Wang, Jean M. Karle, Yuanqing Tang, Sergio Wittlin, Reto Brun, Jonathan L. Vennerstrom

Research output: Contribution to journalArticle

90 Citations (Scopus)

Abstract

This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.

Original languageEnglish (US)
Pages (from-to)4953-4961
Number of pages9
JournalJournal of Medicinal Chemistry
Volume48
Issue number15
DOIs
StatePublished - Jul 28 2005

Fingerprint

Lead compounds
Plasma stability
Pharmacokinetics
Peroxides
Antimalarials
Structure-Activity Relationship
Toxicology
Suspensions
Plasmas
Biological Availability
Experiments
formal glycol
artesunate
Lead

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides : Charting a workable structure-activity relationship using simple prototypes. / Dong, Yuxiang; Chollet, Jacques; Matile, Hugues; Charman, Susan A.; Chiu, Francis C.K.; Charman, William N.; Scorneaux, Bernard; Urwyler, Heinrich; Santo Tomas, Josefina; Scheurer, Christian; Snyder, Christopher; Dorn, Arnulf; Wang, Xiaofang; Karle, Jean M.; Tang, Yuanqing; Wittlin, Sergio; Brun, Reto; Vennerstrom, Jonathan L.

In: Journal of Medicinal Chemistry, Vol. 48, No. 15, 28.07.2005, p. 4953-4961.

Research output: Contribution to journalArticle

Dong, Y, Chollet, J, Matile, H, Charman, SA, Chiu, FCK, Charman, WN, Scorneaux, B, Urwyler, H, Santo Tomas, J, Scheurer, C, Snyder, C, Dorn, A, Wang, X, Karle, JM, Tang, Y, Wittlin, S, Brun, R & Vennerstrom, JL 2005, 'Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: Charting a workable structure-activity relationship using simple prototypes', Journal of Medicinal Chemistry, vol. 48, no. 15, pp. 4953-4961. https://doi.org/10.1021/jm049040u
Dong, Yuxiang ; Chollet, Jacques ; Matile, Hugues ; Charman, Susan A. ; Chiu, Francis C.K. ; Charman, William N. ; Scorneaux, Bernard ; Urwyler, Heinrich ; Santo Tomas, Josefina ; Scheurer, Christian ; Snyder, Christopher ; Dorn, Arnulf ; Wang, Xiaofang ; Karle, Jean M. ; Tang, Yuanqing ; Wittlin, Sergio ; Brun, Reto ; Vennerstrom, Jonathan L. / Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides : Charting a workable structure-activity relationship using simple prototypes. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 15. pp. 4953-4961.
@article{78a64b86b66c41b186b2bd90547afbed,
title = "Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides: Charting a workable structure-activity relationship using simple prototypes",
abstract = "This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.",
author = "Yuxiang Dong and Jacques Chollet and Hugues Matile and Charman, {Susan A.} and Chiu, {Francis C.K.} and Charman, {William N.} and Bernard Scorneaux and Heinrich Urwyler and {Santo Tomas}, Josefina and Christian Scheurer and Christopher Snyder and Arnulf Dorn and Xiaofang Wang and Karle, {Jean M.} and Yuanqing Tang and Sergio Wittlin and Reto Brun and Vennerstrom, {Jonathan L.}",
year = "2005",
month = "7",
day = "28",
doi = "10.1021/jm049040u",
language = "English (US)",
volume = "48",
pages = "4953--4961",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "15",

}

TY - JOUR

T1 - Spiro and dispiro-1,2,4-trioxolanes as antimalarial peroxides

T2 - Charting a workable structure-activity relationship using simple prototypes

AU - Dong, Yuxiang

AU - Chollet, Jacques

AU - Matile, Hugues

AU - Charman, Susan A.

AU - Chiu, Francis C.K.

AU - Charman, William N.

AU - Scorneaux, Bernard

AU - Urwyler, Heinrich

AU - Santo Tomas, Josefina

AU - Scheurer, Christian

AU - Snyder, Christopher

AU - Dorn, Arnulf

AU - Wang, Xiaofang

AU - Karle, Jean M.

AU - Tang, Yuanqing

AU - Wittlin, Sergio

AU - Brun, Reto

AU - Vennerstrom, Jonathan L.

PY - 2005/7/28

Y1 - 2005/7/28

N2 - This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.

AB - This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we established a workable structure-activity relationship in the context of physicochemical, biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes without the spiroadamantane. The trioxolanes were substantially less effective in a standard oral suspension formulation compared to a solubilizing formulation and were more active when administered subcutaneously than orally, both of which suggest substantial biopharmaceutical liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes generally had better oral activity than their more polar counterparts. In pharmacokinetic experiments, four trioxolanes had high plasma clearance values, suggesting a potential metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of artesunate.

UR - http://www.scopus.com/inward/record.url?scp=22744432838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=22744432838&partnerID=8YFLogxK

U2 - 10.1021/jm049040u

DO - 10.1021/jm049040u

M3 - Article

C2 - 16033274

AN - SCOPUS:22744432838

VL - 48

SP - 4953

EP - 4961

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 15

ER -