Published: July 21, 2011 r2011 American Chemical Society 5988 dx.doi.org/10.1021/jm2003624 | J. Med. Chem. 2011, 54, 5988–5999 ARTICLE pubs.acs.org/jmc Novel 1,2,3-Triazole Derivatives for Use against Mycobacterium tuberculosis H37Rv (ATCC 27294) Strain Nubia Boechat,* , † Vitor F. Ferreira, ‡ Sabrina B. Ferreira, ‡ Maria de Lourdes G. Ferreira, † Fernando de C. da Silva, ‡ Monica M. Bastos, † Marilia dos S. Costa, † Maria Cristina S. Lourenc -o, ‡ Angelo C. Pinto, || Antoniana U. Krettli, ^ Anna Caroline Aguiar, ^ Brunno M. Teixeira, ‡ Nathalia V. da Silva, ‡ Priscila R. C. Martins, ‡ Flavio Augusto F. M. Bezerra, § Ane Louise S. Camilo, † Gerson P. da Silva, †,|| and Carolina C. P. Costa † † Fundac - ~ ao Oswaldo Cruz, Instituto de Tecnologia em F armacos, Departamento de Síntese Org ^ anica, Manguinhos, 21041-250 Rio de Janeiro, RJ, Brazil ‡ Fundac - ~ ao Oswaldo Cruz, Instituto de Pesquisa Clínica Evandro Chagas-IPEC, Laborat orio de Bacteriologia e Bioensaios em Micobact  erias, 21045-900, Rio de Janeiro, RJ, Brazil § Fundac - ~ ao Oswaldo Cruz, Instituto de Pesquisa Clínica Evandro Chagas-IPEC, Laborat orio de Bacteriologia e Bioensaios em Micobact  erias, 21045-900 Rio de Janeiro, RJ, Brazil ) Universidade Federal do Rio de Janeiro, Instituto de Química, Departamento de Química Org ^ anica, Cidade Universit  aria, 21941-909 Rio de Janeiro, RJ, Brazil ^ Fundac - ~ ao Oswaldo Cruz, Laborat orio de Mal  aria, Centro de Pesquisas Ren e Rachou, 30190-002 Belo Horizonte, MG, Brazil ’ INTRODUCTION Tuberculosis (TB) is an infectious disease that has affected humanity for more than five millennia. 1 The etiologic agent of TB, Mycobacterium tuberculosis (or Koch bacillus), is suspected of causing a large number of deaths despite the availability of effective chemotherapy and the Bacille CalmetteGu  erin (BCG) vaccine. 2 It is estimated that 70% of the population in poor countries is infected with the Koch bacillus, and 7.5 million new cases and 2.8 million deaths are reported each year. The high rate of disease occurrence in these countries is closely related to the precarious living conditions encountered there. The two factors associated with the spread of TB are human immunodeficiency virus (HIV) infection and the emergence of M. tuberculosis strains that are resistant to one or more drugs (“multiple drug resistant” M. tuberculosis, MDR-TB). The ever-increasing number of MDR- TB cases has caused great concern because they contribute to an increase in deaths from TB and are often associated with HIV infection. It is estimated that one-third of the 42 million individuals infected with HIV are coinfected with M. tuberculosis; most people infected with HIV develop TB as the first manifesta- tion of acquired immunodeficiency syndrome (AIDS). The presence of MDR-TB reflects a weakness in TB control, but this weakness can be treated with extended chemotherapy (approximately two years). With an extended treatment period, however, patients have an increased risk of toxicity and the treatment costs are approximately 100 times higher than the typical treatment of TB (which is conducted for six to nine months). 3 INH is an active oral drug that exhibits bacteriostatic effects on bacillus and is highly active against Mycobacterium tuberculosis. 4 The MIC of INH is notably low (0.02 to 0.06 μg/mL), which contributes to its effectiveness. The concept of making structural analogues of INH became increasingly important in the 1990s after the discovery of its mechanism of action; INH interferes with the synthesis of mycolic acid, one of the chemical pathways responsible for the produc- tion of cell walls in M. tuberculosis. Thus, INH inhibits the bacteria from multiplying and causes bacterial death. INH is metabolized in the human liver and forms compounds, such as hydrazine, that are toxic to the organs and the central nervous system. 57 Because INH is a critical drug in the therapeutic arsenal 811 for TB treatment, efforts are being made to develop of new INH derivatives with greater activity, lower toxicity, and fewer side effects than INH. 1214 Received: March 18, 2011 ABSTRACT: The purpose of this study was to prepare various 4-substituted N-phenyl-1,2,3-triazole derivatives using click chemistry. The derivatives were screened in vitro for antimi- crobial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar Blue susceptibility test. The activity was expressed as the minimum inhibitory concentra- tion (MIC) in μg/mL (μM). Derivatives of isoniazid (INH), (E)-N 0 -[(1-aryl)-1H-1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, exhibited significant activity with MIC values ranging from 2.5 to 0.62 μg/mL. In addition, they displayed low cytotoxicity against liver cells (hepatoma HepG2) and kidney cells (BGM), thereby providing a high therapeutic index. The results demonstrated the potential and importance of developing new INH derivatives to treat mycobacterial infections.