25º Congresso Brasileiro de Microbiologia

25º Congresso Brasileiro de Microbiologia

ResumoID:2005-2

Área: Micobacteriologa ( Divisão C )

ANTI-TUBERCULOSIS ACTIVITY AND TOXICOLOGICAL STUDIES OF TWO NEW ISONIAZID-DERIVED INORGANIC COMPOUNDS

Valnês da Silva Rodrigues-junior (INCT-TB,CPBMF,PUC-RS); Christopher Zandoná Schneider (INCT-TB,CPBMF,PUC-RS); André Avelino dos Santos-junior (INCT-TB,CPBMF,PUC-RS); Anderson Jader Brizola dos Santos (INCT-TB,CPBMF,PUC-RS); André Arigony Souto (INCT-TB,CPBMF,PUC-RS); João Batista Calixto (INCT-TB,CPBMF,PUC-RS); Luiz Augusto Basso (INCT-TB,CPBMF,PUC-RS); Maria Martha Campos (INCT-TB,CPBMF,PUC-RS); Diógenes Santiago Santos (INCT-TB,CPBMF,PUC-RS)

Resumo

Tuberculosis (TB) continues to be one of the deadliest diseases in the world. The emergence of multi-drug-resistant strains of M. tuberculosis, the unbearable side effects of the available drugs and the frequent patient non-compliance in completing the therapy have increased the need for development of new effective agents to treat TB. Isoniazid (INH) is the most prescribed drug for active TB and prophylaxis, and requires activation by the enzyme KatG. The product of the M. tuberculosis inhA structural gene (InhA; enoyl-ACP reductase) has been shown to be the primary target for INH. Our group has recently published the rational design and synthesis of new isoniazid-derived compounds with possible anti-TB activity. Importantly, it was proved that these new compounds do not require activation by KatG or other enzyme to bind to its molecular target, the M. tuberculosis InhA. In addition, it was demonstrated that these INH analogs are able to inhibit in vitro the activity of wild-type and INH-resistant M. tuberculosis enoyl reductases. This work describes the in vitro activity of two pentacyano(isoniazid)ferrateII complexes (named IQG-607 and IQG-639) in cultures of M. tuberculosis H37Rv and INH-resistant clinical isolates. We have determined the MIC of each compound by using the microplate Alamar Blue assay. The MICs for IQG-607 are 0.25 µg/mL against M. tuberculosis H37Rv laboratorial strain, and 1.00 and 4.00 µg/mL for the resistant clinical isolates S94A and C15T, respectively. The MICs for IQG-639 are 0.50 µg/mL for the H37Rv strain, and 2.00 and 4.00 µg/mL for the resistant isolates S94A and C15T, respectively. Furthermore, we have performed toxicological assays to investigate the security profile of these two compounds in mice. We have determined the acute toxicity after administration of a single p.o. administration in groups of 10 male and 10 female mice. We have evaluated the doses of 250, 500, 1000 and 2000 mg/kg of IQG607, and 500, 1000 and 2000 mg/kg of IQG639. The LD₅₀ for the IQG607 is approximately of 1000 mg/kg, and for the IQG639 is up to 2000 mg/kg. No death was observed when animals received the 500 mg/kg dose of IQG607 or IQG639. No significant alterations were observed in the body weight neither of the animals, nor in their heart, lungs, kidneys, spleen and liver weights 15 days after the administration of 250 mg/kg of IQG607 or 500 mg/kg of IQG639, when compared to the control group. These are promising data revealing the security of these compounds in vivo. Experiments are being currently performed in our laboratory to determine the pharmacokinetic parameters of these compounds. In addition, we are now performing pre-clinical trials to confirm the in vivo effects of compounds, by using a TB model in mice. We believe that IQG607 and IQG639 may represent a new class of lead compounds to the development of anti-tubercular agents.

Palavras-chave: anti-tuberculosis drugs, Mycobacterium tuberculosis, toxicology

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