Simon M Jones

Publications (3)10.3 Total impact

• Article: Thiolactomycin analogues as potential anti-Toxoplasma gondii agents.

  Erica S Martins-Duarte, Simon M Jones, Ian H Gilbert, Georgia C Atella, Wanderley de Souza, Rossiane C Vommaro
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  ABSTRACT: The discovery of new compounds active against Toxoplasma gondii is extremely important due to the severe disease caused by this pathogen in immunocompromised hosts and to congenital infection. Type II fatty acid biosynthesis has shown to be a promising target for drug intervention in toxoplasmosis. Here we describe the inhibitory effect of 8 thiolactomycin (TLM) analogues against tachyzoite-infected LLC-MK(2) cells. The TLM analogues demonstrated anti-T. gondii activity, arresting tachyzoite proliferation with IC(50) values in the micromolar level after 24 h and 48 h of treatment. Metabolic labelling of extracellular parasites treated with TLM analogues using [(3)H]acetate demonstrated that these drugs affected acylglycerol synthesis. The rapid reduction of parasite load suggests that these compounds have selective cytotoxic effects against T. gondii. Transmission electron microscopy demonstrated that TLM analogues interfered with membrane-bounded organelles and parasite division and this in turn affected parasite development and survival.
  Parasitology International 09/2009; 58(4):411-5. · 2.13 Impact Factor
• Source

  Available from: unca.edu

  Article: Analogues of thiolactomycin as potential antimalarial agents.

  Simon M Jones, Jonathan E Urch, Marcel Kaiser, Reto Brun, John L Harwood, Colin Berry, Ian H Gilbert
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  ABSTRACT: Analogues of the natural antibiotic thiolactomycin (TLM), an inhibitor of the condensing reactions of type II fatty acid synthase, were synthesized and evaluated for their ability to inhibit the growth of the malaria parasite Plasmodium falciparum. Alkylation of the C4 hydroxyl group led to the most significant increase in growth inhibition (over a 100-fold increase in activity compared to TLM). To investigate the mode of action, the P. falciparum KASIII enzyme was produced for inhibitor assay. A number of TLM derivatives were identified that showed improved inhibition of this enzyme compared to TLM. Structure-activity relationships for enzyme inhibition were identified for some series of TLM analogues, and these also showed weak correlation with inhibition of parasite growth, but this did not hold for other series. On the basis of the lack of a clear correlation between inhibition of pfKASIII activity and parasite growth, we conclude that pfKASIII is not the primary target of TLM analogues. Some of the analogues also inhibited the growth of the parasitic protozoa Trypanosoma cruzi, T. brucei, and Leishmania donovani.
  Journal of Medicinal Chemistry 10/2005; 48(19):5932-41. · 5.25 Impact Factor
• Article: Analogues of thiolactomycin as potential anti-malarial and anti-trypanosomal agents.

  Simon M Jones, Jonathan E Urch, Reto Brun, John L Harwood, Colin Berry, Ian H Gilbert
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  ABSTRACT: A series of analogues of the naturally occurring antibiotic thiolactomycin (TLM) have been synthesised and evaluated for their ability to inhibit the growth of the malaria parasite, Plasmodium falciparum. Thiolactomycin is an inhibitor of Type II fatty acid synthase which is found in plants and most prokaryotes, but not an inhibitor of Type I fatty acid synthase in mammals. A number of the analogues showed inhibition equal to or greater than TLM. The introduction of hydrophobic alkyl groups at the C3 and C5 positions of the thiolactone ring lead to increased inhibition, the best showing a fourteenfold increase in activity over TLM. In addition, some of the analogues showed activity when assayed against the parasitic protozoa, Trypanosoma cruzi and Trypanosoma brucei.
  Bioorganic & Medicinal Chemistry 03/2004; 12(4):683-92. · 2.92 Impact Factor