The Medicinal Chemistry of 3-nitro-1,2,4-triazoles: Focus on Infectious Diseases

Infectious diseases are among the leading causes of death worldwide, especially in developing countries. The historical lack of interest of the pharmaceutical industry in developing new drugs against many of these diseases, such as tuberculosis, leishmaniasis, Chagas disease, sleeping sickness, and fungal infections, has left millions of individuals dependent on old treatments that are often ineffective and present different adverse effects. In this sense, new substances against these diseases must be identified. A class of substances that has stood out in the search for new drugs against these diseases is azole derivatives. Within this class, the 3-nitro-1,2,4-triazole nucleus has attracted increasing interest due to its potential, specifically when compared to the 1,2,4-triazole nucleus without the presence of the nitro group, and also in relation to the 2-nitroimidazole nucleus, showing greater potency and selectivity against different etiological agents. This is even more relevant considering that 3-nitro-1,2,4-triazolic substances can promote their activity through different mechanisms of action, such as the inhibition of ergosterol biosynthesis and also via activation by the nitroreductase enzyme, which can avoid the development of cross-resistance. Therefore, in this review, the medicinal chemistry of nitrotriazoles is discussed through the analysis of their potential in terms of biological activity against the etiological agents of several diseases, such as Chagas disease, sleeping sickness and leishmaniasis, caused by kinetoplastid parasites, tuberculosis, caused by the mycobacteria Mycobacterium tuberculosis, and against different species of pathogenic fungi. In addition, aspects related to enzymatic activities, molecular modeling and organic synthesis of these substances are also addressed.