title: Synthesis and biological activity of nitro heterocycles analogous to megazol, a trypanocidal lead.
abstract: As part of our efforts to develop new compounds aimed at the therapy of parasitic infections, we synthesized and assayed analogues of a lead compound megazol, 5-(1-methyl-5-nitro-1H-2-imidazolyl)-1,3,4-thiadiazol-2-amine, CAS no. 19622-55-0), in vitro. We first developed a new route for the synthesis of megazol. Subsequently several structural changes were introduced, including substitutions on the two rings of the basic nucleus, replacement of the thiadiazole by an oxadiazole, replacement of the nitroimidazole part by a nitrofurane or a nitrothiophene, and substitutions on the exocyclic nitrogen atom for evaluation of an improved import by the glucose or the purine transporters. Assays of the series of compounds on the protozoan parasites Trypanosoma brucei, Trypanosoma cruzi, and Leishmania donovani, as either extracellular cells or infected macrophages, indicated that megazol was more active than the derivatives. Megazol was then evaluated on primates infected with Trypanosoma brucei gambiense, including late-stage central nervous system infections in combination with suramin. Full recovery was observed in five monkeys in the study with no relapse of parasitemia within a 2 year follow-up. Because there is a lack of efficacious treatments for sleeping sickness in Africa and Chagas disease in South America, megazol is proposed as a potential alternative. The mutagenicity of this compound is at present being reevaluated, and metabolism is also under investigation prior to possible further developments.
authors.affiliation: Groupe de Chimie Organique Biologique, Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique, Université Paul Sabatier, UMR CNRS 5068, 31062 Toulouse, France. chauvier@cict.fr
authors.forename: Gérard
authors.initials: G
authors.lastname: Chauvière
authors.forename: Bernard
authors.initials: B
authors.lastname: Bouteille
authors.forename: Bertin
authors.initials: B
authors.lastname: Enanga
authors.forename: Cristina
authors.initials: C
authors.lastname: de Albuquerque
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Michel
authors.initials: M
authors.lastname: Dumas
authors.forename: Jacques
authors.initials: J
authors.lastname: Périé
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D066298:In Vitro Techniques; D007891:Leishmania / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D009574:Nitro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014347:Trypanosoma brucei gambiense; D014349:Trypanosoma cruzi / Q000187:drug effects; D014352:Trypanosomiasis / Q000188:drug therapy / Q000469:parasitology
chemical_list: D009574:Nitro Compounds; D010069:Oxadiazoles; D013830:Thiadiazoles; D014344:Trypanocidal Agents; C013378:megazol