Send Orders for Reprints to reprints@benthamscience.net 2850 Current Topics in Medicinal Chemistry, 2013, 13, 2850-2865 Recent Advances in the Synthesis of New Antimycobacterial Agents Based on the 1H-1,2,3-Triazoles Daniel Tadeu G. Gonzaga, David R. da Rocha, Fernando de C. da Silva and Vitor F. Ferreira * Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, 24020-150, Niterói, RJ, Brazil Abstract: The 1H-1,2,3-triazoles have been studied for many years as an important class of heterocyclic compounds and still attracting considerable attention due to their several application such as, organocatalyst, ionic liquid and broad range of biological activities, including several neglected diseases as tuberculosis. This review emphasizes the recent advances of these triazoles and their perspective in the development of new bioactive chemical entities against tuberculosis. Keywords: Antimycobacterial agents, inhibitors of glycosidases, 1H-1,2,3-triazoles, 1,4-1H-1,2,3-triazoles, 1,4,5-1H-1,2,3- triazoles, tuberculosis. INTRODUCTION This review includes articles published between 2009- 2012 and demonstrates that 1H-1,2,3-triazole compounds are excellent alternatives for producing compounds with differ- ent degrees of complexity and improved antitubercular activity. Tuberculosis (TB) is an infectious disease with a high degree of mortality and morbidity that has affected humans and animals for millennia. Currently, it remains a worldwide health threat. TB is caused by various bacteria of the Myco- bacterium genus, and Mycobacterium tuberculosis, also known as Koch’s bacillus, that is the etiological agent that primarily causes human tuberculosis. TB is a highly conta- gious disease that begins as a bacterial infection in the lungs and is spread through the air. Its symptoms include cough, chest pains, weakness, weight loss, fever and night sweats. TB can be asymptomatic in healthy individuals, whose im- mune systems are able to block the action of the bacteria [1]. It is estimated that 70% of the population in poor countries is infected with M. tuberculosis and that approximately 8.7 million new cases occur annually, leading to the death of 1.4 million people [2-5]. Although its incidence has been de- creasing since 2002 at an average rate of 1.3% per year [5], recent statistics have shown alarming numbers of new infec- tions. The high rate of occurrence of this disease in poor countries is closely related to poor living conditions and the spread of the HIV virus. Resistant strains of M. tuberculosis have been systemati- cally detected in countries that do not emphasize public health and fail to heed recommendations regarding the im- portance of treatment adherence. Drug resistance to existing TB drugs is growing, and as a result, there is an alarming weakness in the medical armamentarium. *Address correspondence to this author at the Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, 24020- 150, Niterói, RJ, Brazil; Tel: +55-21-26292345; Fax: +55-21-26292136; Email: cegvito@vm.uff.br The primary treatment for TB uses a combination of four drugs: isoniazid (1), pyrazinamide (2), ethambutol (3), and rifampicin (4) (Fig. 1). Using this combination of existing drugs is meant to increase patient adherence to the treatment and thus avoid the emergence of new resistant strains of bac- teria that utilize different mechanisms of action. Rifampicin (4) inhibits the biosynthesis of RNA polymerase, isoniazid (1) inhibits mycolic acid synthesis, pyrazinamide (2) inhibits cell membrane synthesis, and ethambutol (3) inhibits cell wall synthesis. However, these older drugs have severe side effects, and various strains of bacteria have developed resis- tance to them. Therefore, the development of new and more efficient drugs that act on other targets of M. tuberculosis is imperative [6-9]. The search for innovative medicines has become the fo- cus of several research programs, and many new inhibitors of M. tuberculosis have been reported. These new M. tuber- culosis growth inhibitors include compounds with unknown mechanisms of action and others whose mechanisms of ac- tion are known, such as the glycophospholids, which affect the biosynthesis of cell walls to weaken interactions with host cells [10]. Several reviews have been published describ- ing the development of novel synthetic and natural product against M. tuberculosis and the possible biological targets of these candidates. Several drugs have completed Phase I clinical trials and are being evaluated in Phase II trials in humans with TB to determine the safety, tolerability, efficacy, pharmacokinetics, and dosing. Fig. 2 shows the drug candidates that are in Phase II and III clinical trials [11-14]. Heterocyclic compounds are commonly used as drugs for the treatment of various diseases, and nitrogen-containing heterocyclic rings are present in the majority of these drugs. Several examples in Fig. 3 illustrate this fact, which is well known in medicinal chemistry. Some examples of drugs with nitrogen-containing heterocycles are the antifungal drugs itraconazole (9), fluconazole (10), and ketoconazole (11), the /13 $58.00+.00 © 2013 Bentham Science Publishers