Current Topics in Medicinal Chemistry - Volume 21, Issue 23, 2021

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.

Modulators of quorum sensing pathways in Pseudomonas aeruginosa (PA) gain attention due to their potential therapeutic applications. These chemical agents are viewed as anti-virulence agents capable of increasing the existing therapeutic agents’ efficacy against resistant clinical strains. Additionally, they can be utilized in developing anticancer therapeutics, whole-cell biosensors, and artificial biological systems. In this mini-review, we summarize recent (2015-2021) publications on PA's QS modulation.

The need to overcome ever-increasing cases of antifungal resistance and circumvent side effects and drug interactions related to currently available drugs has impelled the demand to expedite the drug discovery and the development of novel antifungals. 1,4-disubstituted 1,2,3-triazole has gained tremendous interest in the last two decades mainly because of its ease of synthesis via copper( I)-catalyzed azide-alkyne cycloaddition (CuAAC) and its broad spectrum of chemotherapeutic potential. 1,2,3-Triazole is an excellent pharmacophore that has been used as a bioisostere for obtaining libraries of new medicinally important scaffolds. The present review focuses on the recent advances (2016-2021) in 1,2,3-triazole derivatives obtained by CuAAC as potential antifungal agents that may facilitate the triazole-based antifungal development process.

Background: Dihydroorotate dehydrogenase (DHODH) has long been recognized as an important drug target for proliferative and parasitic diseases, including compounds that exhibit trypanocidal action and broad-spectrum antiviral activity. Despite numerous and successful efforts in structural and functional characterization of DHODHs, as well as in the development of inhibitors, DHODH hot spots remain largely unmapped and underexplored. Objective: This review describes the tools that are currently available for the identification and characterization of hot spots in protein structures and how freely available webservers can be exploited to predict DHODH hot spots. Moreover, it provides for the first time a review of the antiviral properties of DHODH inhibitors. Methods: X-ray structures from human (HsDHODH) and Trypanosoma cruzi DHODH (TcDHODH) had their hot spots predicted by both FTMap and Fragment Hotspot Maps web servers. Results: FTMap showed that hot spot occupancy in HsDHODH is correlated with the ligand efficiency (LE) of its known inhibitors, and Fragment Hotspot Maps pointed out the contribution of selected moieties to the overall LE. The conformational flexibility of the active site loop in TcDHODH was found to have a major impact on the druggability of the orotate binding site. In addition, both FTMap and Fragment Hotspot Maps servers predict a novel pocket in TcDHODH dimer interface (S6 site). Conclusion: This review reports how hot spots can be exploited during hit-to-lead steps, docking studies or even to improve inhibitor binding profile and by doing so using DHODH as a model, points to new drug development opportunities.