Minor groove binders for DNA as antitypanosomal agents: the veterinary context

Colin J. Suckling, Fraser Scott, Abedawn Khalaf, Kirsten Gillingwater, Liam Morrison, Harry de Koning, Michael Barrett, Federica Giordani

Research output: Contribution to conferencePaper

Abstract

Animal African trypanosomiasis (or nagana) is a wasting livestock disease found in sub-Saharan Africa and caused by protozoan parasites Trypanosoma congolense, T. vivax and T. brucei. Chemotherapy (mostly with the diamidine diminazene aceturate) and chemoprophylaxis (mostly with the phenanthridine isometamidium chloride) are essential for disease control. However, as current treatments lose efficacy due to increased drug resistance, the need for new veterinary trypanocides becomes a high-priority. Trypanosoma spp. are one of the genera of parasites that are susceptible to DNA minor groove binder drugs synthesised at the University of Strathclyde (S-MGBs). All three of the above African species are susceptible to S-MGBs and in addition, the South American species, T. cruzi has been shown to be similarly susceptible. One of the principal challenges to obtaining compounds useful in the field is to achieve activity across the range of infectious species so that characterisation of the infection is not required at diagnosis. Over 100 S-MGBs have been evaluated at the University of Glasgow and the Swiss Tropical Health Institute, Basel, and compounds with development potential have been identified. As an example, S-MGB 234 has been shown to be curative in in vivo models of trypanosome infection in mice. Importantly S-MGB 234 does not show cross resistance with other antitrypanosomal drugs such as diminazine, isometamidium, or ethidium bromide, which is consistent with a different route into the parasite’s cell. S-MGBs that contain alkene links, such as in S-MGB 234, are the most active sub-class of S-MGB and point the way towards structural optimisation.

Conference

Conference3rd International Electronic Conference on Medicinal Chemistry
Period1/11/1730/11/17
Internet address

Fingerprint

isometamidium
African Trypanosomiasis
Binders
Parasites
parasites
DNA
Phenanthridines
Trypanocidal Agents
Trypanosoma congolense
trypanocides
African trypanosomiasis
bovine trypanosomiasis
Pharmaceutical Preparations
diminazene
Disease control
Wasting Syndrome
Pentamidine
Trypanosoma
livestock diseases
drugs

Keywords

  • livestock disease
  • disease control
  • minor groove binders
  • DNA

Cite this

Suckling, C. J., Scott, F., Khalaf, A., Gillingwater, K., Morrison, L., de Koning, H., ... Giordani, F. (2017). Minor groove binders for DNA as antitypanosomal agents: the veterinary context. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, . https://doi.org/10.3390/ecmc-3-04647
Suckling, Colin J. ; Scott, Fraser ; Khalaf, Abedawn ; Gillingwater, Kirsten ; Morrison, Liam ; de Koning, Harry ; Barrett, Michael ; Giordani, Federica. / Minor groove binders for DNA as antitypanosomal agents : the veterinary context. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, .19 p.
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abstract = "Animal African trypanosomiasis (or nagana) is a wasting livestock disease found in sub-Saharan Africa and caused by protozoan parasites Trypanosoma congolense, T. vivax and T. brucei. Chemotherapy (mostly with the diamidine diminazene aceturate) and chemoprophylaxis (mostly with the phenanthridine isometamidium chloride) are essential for disease control. However, as current treatments lose efficacy due to increased drug resistance, the need for new veterinary trypanocides becomes a high-priority. Trypanosoma spp. are one of the genera of parasites that are susceptible to DNA minor groove binder drugs synthesised at the University of Strathclyde (S-MGBs). All three of the above African species are susceptible to S-MGBs and in addition, the South American species, T. cruzi has been shown to be similarly susceptible. One of the principal challenges to obtaining compounds useful in the field is to achieve activity across the range of infectious species so that characterisation of the infection is not required at diagnosis. Over 100 S-MGBs have been evaluated at the University of Glasgow and the Swiss Tropical Health Institute, Basel, and compounds with development potential have been identified. As an example, S-MGB 234 has been shown to be curative in in vivo models of trypanosome infection in mice. Importantly S-MGB 234 does not show cross resistance with other antitrypanosomal drugs such as diminazine, isometamidium, or ethidium bromide, which is consistent with a different route into the parasite’s cell. S-MGBs that contain alkene links, such as in S-MGB 234, are the most active sub-class of S-MGB and point the way towards structural optimisation.",
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Suckling, CJ, Scott, F, Khalaf, A, Gillingwater, K, Morrison, L, de Koning, H, Barrett, M & Giordani, F 2017, 'Minor groove binders for DNA as antitypanosomal agents: the veterinary context' Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, 1/11/17 - 30/11/17, . https://doi.org/10.3390/ecmc-3-04647

Minor groove binders for DNA as antitypanosomal agents : the veterinary context. / Suckling, Colin J.; Scott, Fraser; Khalaf, Abedawn; Gillingwater, Kirsten; Morrison, Liam; de Koning, Harry; Barrett, Michael; Giordani, Federica.

2017. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, .

Research output: Contribution to conferencePaper

TY - CONF

T1 - Minor groove binders for DNA as antitypanosomal agents

T2 - the veterinary context

AU - Suckling, Colin J.

AU - Scott, Fraser

AU - Khalaf, Abedawn

AU - Gillingwater, Kirsten

AU - Morrison, Liam

AU - de Koning, Harry

AU - Barrett, Michael

AU - Giordani, Federica

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Animal African trypanosomiasis (or nagana) is a wasting livestock disease found in sub-Saharan Africa and caused by protozoan parasites Trypanosoma congolense, T. vivax and T. brucei. Chemotherapy (mostly with the diamidine diminazene aceturate) and chemoprophylaxis (mostly with the phenanthridine isometamidium chloride) are essential for disease control. However, as current treatments lose efficacy due to increased drug resistance, the need for new veterinary trypanocides becomes a high-priority. Trypanosoma spp. are one of the genera of parasites that are susceptible to DNA minor groove binder drugs synthesised at the University of Strathclyde (S-MGBs). All three of the above African species are susceptible to S-MGBs and in addition, the South American species, T. cruzi has been shown to be similarly susceptible. One of the principal challenges to obtaining compounds useful in the field is to achieve activity across the range of infectious species so that characterisation of the infection is not required at diagnosis. Over 100 S-MGBs have been evaluated at the University of Glasgow and the Swiss Tropical Health Institute, Basel, and compounds with development potential have been identified. As an example, S-MGB 234 has been shown to be curative in in vivo models of trypanosome infection in mice. Importantly S-MGB 234 does not show cross resistance with other antitrypanosomal drugs such as diminazine, isometamidium, or ethidium bromide, which is consistent with a different route into the parasite’s cell. S-MGBs that contain alkene links, such as in S-MGB 234, are the most active sub-class of S-MGB and point the way towards structural optimisation.

AB - Animal African trypanosomiasis (or nagana) is a wasting livestock disease found in sub-Saharan Africa and caused by protozoan parasites Trypanosoma congolense, T. vivax and T. brucei. Chemotherapy (mostly with the diamidine diminazene aceturate) and chemoprophylaxis (mostly with the phenanthridine isometamidium chloride) are essential for disease control. However, as current treatments lose efficacy due to increased drug resistance, the need for new veterinary trypanocides becomes a high-priority. Trypanosoma spp. are one of the genera of parasites that are susceptible to DNA minor groove binder drugs synthesised at the University of Strathclyde (S-MGBs). All three of the above African species are susceptible to S-MGBs and in addition, the South American species, T. cruzi has been shown to be similarly susceptible. One of the principal challenges to obtaining compounds useful in the field is to achieve activity across the range of infectious species so that characterisation of the infection is not required at diagnosis. Over 100 S-MGBs have been evaluated at the University of Glasgow and the Swiss Tropical Health Institute, Basel, and compounds with development potential have been identified. As an example, S-MGB 234 has been shown to be curative in in vivo models of trypanosome infection in mice. Importantly S-MGB 234 does not show cross resistance with other antitrypanosomal drugs such as diminazine, isometamidium, or ethidium bromide, which is consistent with a different route into the parasite’s cell. S-MGBs that contain alkene links, such as in S-MGB 234, are the most active sub-class of S-MGB and point the way towards structural optimisation.

KW - livestock disease

KW - disease control

KW - minor groove binders

KW - DNA

U2 - 10.3390/ecmc-3-04647

DO - 10.3390/ecmc-3-04647

M3 - Paper

ER -

Suckling CJ, Scott F, Khalaf A, Gillingwater K, Morrison L, de Koning H et al. Minor groove binders for DNA as antitypanosomal agents: the veterinary context. 2017. Paper presented at 3rd International Electronic Conference on Medicinal Chemistry, . https://doi.org/10.3390/ecmc-3-04647