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The problems with current strategies to control canine visceral Leishmaniasis (CVL), which include the euthanasia of infected animals, and also the toxicity of the drugs currently used in human treatments for CVL, add urgency to the search for new therapeutic agents. This study aimed to evaluate the activity against Leishmania (L.) infantum of 12 amides that are chemically inspired by gibbilimbol B, a bioactive natural product that was initially obtained from Piper malacophyllum . Three of these compounds- N -(2-ethylhexyl)-4-chlorobenzamide ( 9 ), N -(2-ethylhexyl)-4-nitrobenzamide ( 10 ), and N -(2-ethylhexyl)-4-( tert -butyl)benzamide ( 12 ) -demonstrated activity against the intracellular amastigotes without toxicity to mammalian host cells (CC 50 > 200 μM); compounds 9 , 10 , and 12 resulted in EC 50 values of 12.7, 12.2, and 5.1 μM, respectively. In silico drug-likeness studies predicted that these compounds would show high levels of gastrointestinal absorption, would be able to penetrate the blood-brain barrier, would show moderate solubility, and would not show unwanted molecular interactions. Due to their promising pharmacological profiles, compounds 9 and 10 were selected for mechanism of action studies (MoA). The MoA studies in L. (L.) infantum revealed that neither of the compounds affected the permeabilization of the plasma membrane. Nevertheless, compound 9 induced strong alkalinization of acidocalcisomes, which resulted in a significant and rapid increase in intracellular Ca 2+ levels, thereby causing the depolarization of the mitochondrial membrane potential and a reduction in the levels of reactive oxygen species (ROS). In contrast, compound 10 induced a gradual increase in intracellular Ca 2+ levels and a similarly gradual reduction in ROS levels, but it caused neither acidocalcisome alkalinization nor mitochondrial membrane potential depolarization. Finally, the MALDI-TOF/MS assessment of protein alterations in L. (L.) infantum treated separately with compounds 9 and 10 revealed changes in mass spectral profiles from both treatments. These results highlight the anti- L. (L.) infantum potential of these amides-especially for compounds 9 and 10 -and they suggest that these compounds could be promising candidates for future in vivo studies in VL-models., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Multitargeting ligands on enzymes and receptors may generate a profile for a potential treatment of cognitive impairment. Considering this, a set of 21 substituted aryl-alkyl-piperazines were designed, prepared and tested for their binding affinities at histamine H 3 and dopamine D 3 receptors (H 3 R and D 3 R, respectively) as well as acetyl- and butyrylcholinesterases (AChE/BChE) as potentially synergistic profile. Initial screening of the compounds at H 3 R and D 3 R was done at 1 or 10 µM and 100 µM at AChE and BChE assays. The most promising compounds were then evaluated in full concentration-response curves to estimate the K i and IC 50 values. Results showed that several compounds were ligands at H 3 R (n = 10), D 3 R (n = 6), AChE (n = 3), and BChE (n = 9). Compounds LINS05006 (K i H 3 R 2.8 µM; D 3 R 0.7 µM; IC 50 BChE 26.3 µM) and LINS05015 (K i H 3 R 1.1 µM; D 3 R 3.1 µM; IC 50 AChE 97.8 µM; BChE 43.7 µM) are highlighted since presented affinity in three different. These results suggest that methylpiperazine moiety led to balanced activity at all three classes of targets, and longer linker provided the best affinities. These compounds presented high ligand efficiency values (LE > 0.3) and may have adequate pharmacokinetic profile as suggested by calculated physicochemical properties., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The role of histamine and acetylcholine in cognitive functions suggests that compounds able to increase both histaminergic and cholinergic neurotransmissions in the brain should be considered as promising therapeutic options. For this purpose, dual inhibitors of histamine H 3 receptors (H 3 R) and cholinesterases (ChEs) have been designed and assessed. In this context, this paper reviews the strategies used to obtain dual H 3 R/ChEs ligands using multitarget design approaches. Hybrid compounds designed by linking tacrine or flavonoid motifs to H 3 R antagonists were obtained with high affinity for both targets, and compounds designed by merging the H 3 R antagonist pharmacophore with known anticholinesterase molecules were also reported. These reports strongly suggest that key modifications in the lipophilic region (including a second basic group) seem to be a strategy to reach novel compounds, allied with longer linker groups to a basic region. Some compounds have already demonstrated efficacy in memory models, although the pharmacokinetic and toxicity profile should be considered when designing further compounds. In conclusion, the key features to be considered when designing novel H 3 R/ChEs inhibitors with improved pharmacological profile were herein summarized., (© 2021 John Wiley & Sons A/S.)