Monoamine oxidase (MAO) catalyzes the oxidative deamination of biogenic and exogenous amines and its inhibitors have therapeutic value for several conditions including affective disorders, stroke, neurodegenerative diseases and aging. The discovery of 2,3,6-trimethyl-1,4-naphthoquinone (TMN) as a nonselective and reversible inhibitor of MAO, has suggested 1,4-naphthoquinone (1,4-NQ) as a potential scaffold for designing new MAO inhibitors. Combining molecular modeling tools and biochemical assays we evaluate the kinetic and molecular details of the inhibition of human MAO by 1,4-NQ, comparing it with TMN and menadione. Menadione (2-methyl-1,4-naphthoquinone) is a multitarget drug that acts as a precursor of vitamin K and an inducer of mitochondrial permeability transition. Herein we show that MAO-B was inhibited competitively by 1,4-NQ (K(i)=1.4 μM) whereas MAO-A was inhibited by non-competitive mechanism (K(i)=7.7 μM). Contrasting with TMN and 1,4-NQ, menadione exhibited a 60-fold selectivity for MAO-B (K(i)=0.4 μM) in comparison with MAO-A (K(i)=26 μM), which makes it as selective as rasagiline. Fluorescence and molecular modeling data indicated that these inhibitors interact with the flavin moiety at the active site of the enzyme. Additionally, docking studies suggest the phenyl side groups of Tyr407 and Tyr444 (for MAO-A) or Tyr398 and Tyr435 (for MAO-B) play an important role in the interaction of the enzyme with 1,4-NQ scaffold through forces of dispersion as verified for menadione, TMN and 1,4-NQ. Taken together, our findings reveal the molecular details of MAO inhibition by 1,4-NQ scaffold and show for the first time that menadione acts as a competitive and reversible inhibitor of human MAO.

Background: A series of bi-triazoles conjugates 1,2,3 and 1,2,4 was synthesized with an aim to study the evaluation of the antimalarial profile of families of triazole derivatives. The study used the W2 strain of Plasmodium falciparum (Chloroquine-Resistant), to determine the inhibitory concentration of 50% of the parasites (IC50) and HepG2 cells to describe the cytotoxic concentration for 50% of the cells (CC50). Among the study classes, bi-triazoles stood out with IC50 values between 8.9 to 0.45 µM; highlighted the compound 14d (IC50 of 0.45 ± 0.02 µM) with the most promising result. Regarding the cytotoxic concentration, all compounds that presented IC50 values ≤ 100 µM were evaluated. Three compounds stood out as the highest selectivity index (SI) values, 14b (SI ˃111.1), 13d (SI ˃111.1) and 14d (SI ˃1.111). Such results expose the importance of working with classes of molecules that allow rapid synthesis and dispositions for structural changes. Highlighting the evolution of the IC50 values of the compounds, when adding the second triazole block. Thus, the results found in this study, have the possibility of choosing new molecules for the treatment of malaria. Objective: This work was to synthesize a series of bi-triazole conjugates 1,2,3 and 1,2,4-triazole moiety and evaluate their activities against Plasmodium falciparum. Methods: The bi-triazole was synthesized in a 3-step route in moderated yields, and their structures were confirmed by NMR spectral data analyses. For the in vitro antiplasmodial assays, the SYBR Green fluorimetric technique and the W2 strain were used, where an IC50 (Inhibitory Concentration) value was obtained for each compound. The compounds were also evaluated for their stage-specificity and speed of action (W2 strain). Safety tests were performed to determine the hemolytic and cytotoxic action of the evaluated compounds. In these tests, the cell lines HepG2 and VERO were used, and the cytotoxicity was evaluated by the MTT technique. This allowed the CC50 values to be obtained (Cytotoxic Concentration). Subsequently, the Selectivity Index (SI) was calculated for each compound. Results: The newly synthesized bi-triazole compounds could serve as potent leads for the development of novel antimalarial compounds. In general, the bi-triazoles with trifluoromethyl group present at 1,2,4-triazole moiety proved to be more potent regarding antiplasmodial activity. Conclusion: The synthesized bi-triazole compounds could serve as potent leads for the development of novel antimalarial agents.