Synthetic peroxides as antimalarizals

Research output: Contribution to journalReview article

217 Citations (Scopus)

Abstract

The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable "drug-like" physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.

Original languageEnglish (US)
Pages (from-to)425-448
Number of pages24
JournalMedicinal Research Reviews
Volume24
Issue number4
DOIs
StatePublished - Jul 1 2004

Fingerprint

Peroxides
Antimalarials
Artemisinins
Stereochemistry
Chemotherapy
Pharmaceutical Preparations
Animals
Animal Models
Derivatives
Recurrence
Drug Therapy
Atoms

Keywords

  • Antimalarials
  • Artemisinin
  • SAR
  • Synthetic peroxides

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Synthetic peroxides as antimalarizals. / Tang, Yuanqing; Dong, Yuxiang; Vennerstrom, Jonathan L.

In: Medicinal Research Reviews, Vol. 24, No. 4, 01.07.2004, p. 425-448.

Research output: Contribution to journalReview article

@article{58e0910f763d4bceb75a7ced2816af08,
title = "Synthetic peroxides as antimalarizals",
abstract = "The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable {"}drug-like{"} physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.",
keywords = "Antimalarials, Artemisinin, SAR, Synthetic peroxides",
author = "Yuanqing Tang and Yuxiang Dong and Vennerstrom, {Jonathan L.}",
year = "2004",
month = "7",
day = "1",
doi = "10.1002/med.10066",
language = "English (US)",
volume = "24",
pages = "425--448",
journal = "Medicinal Research Reviews",
issn = "0198-6325",
publisher = "John Wiley and Sons Inc.",
number = "4",

}

TY - JOUR

T1 - Synthetic peroxides as antimalarizals

AU - Tang, Yuanqing

AU - Dong, Yuxiang

AU - Vennerstrom, Jonathan L.

PY - 2004/7/1

Y1 - 2004/7/1

N2 - The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable "drug-like" physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.

AB - The discovery of artemisinin in 1971 initiated a new era in antimalarial chemotherapy. Although the clinically useful semisynthetic artemisinin derivatives are rapid acting and potent antimalarial drugs, they have short half-lives and must be administered over a period of 5-7 days, leading to noncompliance and recrudescence. With this in view, many synthetic antimalarial peroxides have been prepared. Yet, identification of orally active synthetic peroxide drug development candidates that are easily synthesized, inexpensive, and with good biopharmaceutical properties has been surprisingly difficult. In this review, we document the pitfalls and progress made in this endeavor. For each of 15 synthetic peroxide structural classes, we note highlights of the synthetic routes, product stereochemistry, and origin of the peroxide O atoms. Both in vitro and in vivo antimalarial data are then discussed and any SAR noted. Available data indicates that several synthetic 1,2,4-trioxanes are only marginally less effective than the semisynthetic artemisinins. Within a given peroxide chemical family, the more lipophilic members are more potent and possess better oral antimalarial activity in animal models than their more polar counterparts. This poses a challenge to identify peroxide structures with suitable "drug-like" physicochemical properties. Nonetheless, substantial progress has been made in the identification of a new generation of synthetic antimalarial peroxides.

KW - Antimalarials

KW - Artemisinin

KW - SAR

KW - Synthetic peroxides

UR - http://www.scopus.com/inward/record.url?scp=3042613588&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3042613588&partnerID=8YFLogxK

U2 - 10.1002/med.10066

DO - 10.1002/med.10066

M3 - Review article

C2 - 15170591

AN - SCOPUS:3042613588

VL - 24

SP - 425

EP - 448

JO - Medicinal Research Reviews

JF - Medicinal Research Reviews

SN - 0198-6325

IS - 4

ER -