Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis

Alan H. Fairlamb (Lead / Corresponding author), Stephen Patterson

Research output: Contribution to journalReview article

3 Citations (Scopus)
96 Downloads (Pure)

Abstract

Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.

Original languageEnglish
Pages (from-to)4454-4475
Number of pages22
JournalCurrent Medicinal Chemistry
Volume26
Issue number23
Early online date26 Apr 2018
DOIs
Publication statusPublished - 2019

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Nitro Compounds
Leishmaniasis
Trypanosomiasis
Parasites
Nifurtimox
Chemical activation
Nitroreductases
Pharmacodynamics
African Trypanosomiasis
Pharmacokinetics
Visceral Leishmaniasis
Chagas Disease
Prodrugs
Structure-Activity Relationship
Pharmaceutical Preparations
Communicable Diseases
Toxicity
2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo(2,1-b)(1,3)oxazine
OPC-67683
benzonidazole

Keywords

  • Chagas' disease
  • Human African trypanosomiasis
  • benznidazole
  • delamanid
  • fexinidazole
  • nifurtimox
  • nitro-drugs
  • pretomanid
  • visceral leishmaniasis.

Cite this

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title = "Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis",
abstract = "Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.",
keywords = "Chagas' disease, Human African trypanosomiasis, benznidazole, delamanid, fexinidazole, nifurtimox, nitro-drugs, pretomanid, visceral leishmaniasis.",
author = "Fairlamb, {Alan H.} and Stephen Patterson",
note = "This work was funded by the Wellcome Trust (079838)",
year = "2019",
doi = "10.2174/0929867325666180426164352",
language = "English",
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TY - JOUR

T1 - Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis

AU - Fairlamb, Alan H.

AU - Patterson, Stephen

N1 - This work was funded by the Wellcome Trust (079838)

PY - 2019

Y1 - 2019

N2 - Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.

AB - Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds.

KW - Chagas' disease

KW - Human African trypanosomiasis

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KW - delamanid

KW - fexinidazole

KW - nifurtimox

KW - nitro-drugs

KW - pretomanid

KW - visceral leishmaniasis.

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U2 - 10.2174/0929867325666180426164352

DO - 10.2174/0929867325666180426164352

M3 - Review article

C2 - 29701144

VL - 26

SP - 4454

EP - 4475

JO - Current Medicinal Chemistry

JF - Current Medicinal Chemistry

SN - 0929-8673

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ER -