The leishmanicidal activity of four batches of meglumine antimoniate, produced in Farmanguinhos-Fiocruz, Brazil (TAMs), was assessed and compared to Glucantime®-Aventis Pharma Ltda. Using the amastigote-like in vitro model, the active concentrations of Sb v varied from 10µg/ml to 300 µg/ml for L. (L.) chagasi and from 50µg/ml to 300µg/ml for L. (L.) amazonensis, with no statistically significant differences among the four batches of TAMs and Glucantime®. The inhibitory concentrations (IC50) determined by the amastigote-infected macrophage model for TAM01/03 and Glucantime® were, respectively: 26.3µg/ml and 127.6µg/ml for L. chagasi, 15.4µg /ml and 22.9µg/ml for L. amazonensis, and 12.1µg/ml and 24.2µg/ml for L. (V.) braziliensis. The activities of the four batches of TAMs were confirmed in an in vivo model by assessing, during eight weeks skin lesions caused by L. braziliensis in hamster that were treated with 20mg Sb v/Kg/day for 30 consecutive days. The meglumine antimoniate produced by Farmanguinhos was as effective as the reference drug, Glucantime®-Aventis, against three species of Leishmania that are of medical importance in Brazil.

Este trabalho descreve a versatilidade sintética dos derivados N-Acil-3,3-diflúor-2-oxoindóis, obtidos a partir da reação de N-acilisatinas com dietilaminotrifluoreto de enxofre (DAST) que, através da reação com diferentes nucleófilos, promovem a abertura do anel heterocíclico, levando à formação de vários produtos. A reação de N-Acil-3,3-diflúor-2-oxoindóis com água fornece os ácidos 2-(2-N-acilfenil)-2,2-difluoracéticos e com álcoóis fornece os ésteres correspondentes. Reações com aminas e glicina levam à formação das correspondentes amidas 2-(2-N-acilfenil)-2,2-difluoracetamidas. Na reação com tiossemicarbazidas os derivados difluortiossemicarbazidas são obtidos. Estes últimos sofrem uma ciclização catalisada por ácido para fornecer N-(2-((5-aminoaril-1,3,4-tiadiazol-2-il)difluormetil)-4-(R)-fenil)acetamida. A estrutura de N-(2-((5-amino-1,3,4-tiadiazol-2-il)difluormetil)-4-metilfenil)acetamida foi determinada por raio-X.

This paper describes the versatility of N-Acyl-3,3-difluoro-2-oxoindoles, obtained from the the reaction of N-acylisatins with (diethylamino)sulphur trifluoride (DAST) which, on opening of the heterocyclic ring by reactions with nucleophiles, lead to the formation of a variety of products: reaction with water yields 2-(2-amidoacyl)-2,2-difluoroacetic acids, with alcohols yields alkyl 2-(2-amidoacyl)-2,2-difluoroacetates, with amines and glycine yields 2-(2-amidoacyl)-2,2-difluoroacetamides and with thiosemicarbazides yields difluorothiosemicarbazide derivatives. The latter undergo acid-catalysed cyclizations to yield N-(2-((5-aminoaryl-1,3,4-thiadiazol-2-yl)difluoromethyl)-4-(R)-phenyl)acetamide. The X-ray structure of N-(2-((5-amino-1,3,4-thiadiazol-2-yl)difluoromethyl)-4-methylphenyl)acetamide has been determined.