Leishmaniasis is a neglected tropical disease caused by Leishmania species. Available therapeutic options have several limitations. The drive to develop new, more potent, and selective antileishmanial agents is thus a major goal. Herein we report the synthesis and the biological activity evaluation against promastigote and amastigote forms of Leishmania amazonensis of nine 4,8-dimethoxynaphthalenyl chalcones. Compound ((E)-1-(4,8-dimethoxynaphthalen-1-yl)-3-(4-nitrophenyl)prop-2-en-1-one), 4f, was the most promising with an IC50 = 3.3 ± 0.34 μM (promastigotes), a low cytotoxicity profile (CC50 = 372.9 ± 0.04 μM), and a high selectivity index (SI = 112.6). Furthermore, 4f induced several morphological and ultrastructural changes in the free promastigote forms, loss of plasma membrane integrity, and increased reactive oxygen species (ROS). An in silico analysis of drug-likeness and ADME parameters suggested high oral bioavailability and intestinal absorption. Compound 4f reduced the number of infected macrophages and the number of amastigotes per macrophage, with an IC50 value of 18.5 ± 1.19 μM. Molecular docking studies with targets, ARG and TR, showed that compound 4f had more hydrogen bond interactions with the ARG enzyme, indicating a more stable protein-ligand binding. These results suggest that 4,8-dimethoxynaphthalenyl chalcones are worthy of further study as potential antileishmanial drugs.
CYP1B1 plays an essential role in cancer's pathogenesis since it activates procarcinogens. Significantly, this enzyme catalyzes the hydroxylation of 17β-estradiol, leading to carcinogenic metabolites involved in carcinogenesis and cancer progression. Therefore, the inhibition of CYP1B1 activity is considered a therapeutic target for chemotherapy. In addition, CYP1B1 is overexpressed in hormone-dependent cancer cells and could be related to resistance to anticancer drugs. However, the activity of CYP1B1 in the tumor microenvironment can metabolize and activate prodrugs in cancer cells, providing more selectivity and being useful for chemoprevention or chemotherapy strategies. Furthermore, due to its importance in anticancer drug design, recent studies have reported using computational methods to understand the intermolecular interactions between possible ligands and CYP1B1. Therefore, in this perspective, we highlight recent findings in developing CYP1B1 inhibitors (flavonoids, trans-stilbenes, estradiol derivatives, and carbazoles) and CYP1B1-activated prodrugs (a chalcone DMU-135 and an oxime DMAKO-20). Finally, we have analyzed their possible molecular interactions with this enzymatic target by molecular docking, which can help to design new active substances.
Leishmaniasis is a neglected tropical disease widely distributed worldwide, caused by parasitic protozoa of the genus Leishmania. Despite representing a significant public health problem, the therapeutic options are old, with several reported adverse effects, have high costs, with administration mainly by parenteral route, which makes treatment difficult, increasing dropout and, consequently, the emergence of resistant strains. Thus, the research and development of new antileishmanial therapies become necessary. In this field, inhibiting essential targets that affect the parasite’s growth, survival, and infectivity represents an attractive therapeutic strategy. With this in mind, this review addresses the main structural, functional characteristics and recent reports of the discovery of promising inhibitors of the enzymes arginase (ARG) and trypanothione synthase (TryS), which are involved in the biosynthesis of polyamines and trypanothione and trypanothione reductase (TR), responsible for the reduction of trypanothione thiol.
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