Evaluation of Genotoxic Effects of New Molecules with Possible Trypanocidal Activity for Chagas Disease Treatment

• Published in: TheScientificWorld 2013-01, Vol.2013 (2013), p.1-8
• Main Authors: Felzenszwalb, Israel, Alessandra Fortes Aiub, Claudia, Boechat, Nubia, Bastos, Mônica M., Carvalho, Alcione S., Mello, Francisco V. C.
• Format: Article
• Language: English
• Subjects: Ames test; Analogs; Animals; Antimicrobial agents; Cell Line; Chagas disease; Chagas Disease - drug therapy; Chagas Disease - metabolism; Chemotherapy; Cytotoxicity; Design modifications; Disease; DNA Damage; Drug development; Drug resistance; Experiments; Genotoxicity; Health risks; Humans; Macrophages; Medical treatment; Metabolic activation; Metabolic rate; Metabolism; Micronuclei, Chromosome-Defective - chemically induced; Mutagenesis - drug effects; Mutagenicity; Mutation; Nitroimidazole; Parasites; Pharmaceutical sciences; Protozoa; Pyrazole; Rats; Salmonella; Salmonella enterica; Salmonella enterica - genetics; Salmonella enterica - metabolism; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Toxicity; Triazoles; Triazoles - chemistry; Triazoles - pharmacology; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma cruzi - genetics; Trypanosoma cruzi - metabolism; Variance analysis; Vector-borne diseases
• ISSN: 2356-6140; 1537-744X
• DOI: 10.1155/2013/287319

Chagas disease is responsible for a large number of human infections and many are also at risk of infection. There is no effective drug for Chagas disease treatment. The Institute of Pharmaceutical Technology at Fiocruz, Brazil, has designed three nitro analogs of the nitroimidazole-thiadiazole, megazol: two triazole analogs PTAL 05-02 and PAMT 09 and a pyrazole analog PTAL 04-09. A set of Salmonella enterica serovar Typhimurium strains were used in the bacterial reverse mutation test (Ames test) to determine the mutagenicity and cytotoxicity of megazol and its nitro analogs. Megazol presented positive mutagenic activity at very low concentration, either with or without metabolic activation S9 mix. The mutagenic response of the analogs was detected at higher concentration than the lowest megazol concentration to yield mutagenic activity showing that new advances can be made to develop new analogs. The micronucleus test with rat macrophage cells was used in the genotoxic evaluation. The analogs were capable of inducing micronucleus formation and showed cytotoxic effects. PTAL 04-09 structural modifications might be better suitable for the design of promising new drugs candidate for Chagas’ disease treatment.