Citation: de Santiago-Silva, K.M.; Bortoleti, B.T.d.S.; Oliveira, L.d.N.; Maia, F.L.d.A.; Castro, J.C.; Costa, I.C.; Lazarin, D.B.; Wardell, J.L.; Wardell, S.M.S.V.; Albuquerque, M.G.; et al. Antileishmanial Activity of 4,8-Dimethoxynaphthalenyl Chalcones on Leishmania amazonensis. Antibiotics 2022, 11, 1402. https:// doi.org/10.3390/antibiotics11101402 Academic Editors: Željko Petrovski and Luis Cobra Branco Received: 1 September 2022 Accepted: 3 October 2022 Published: 13 October 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). antibiotics Article Antileishmanial Activity of 4,8-Dimethoxynaphthalenyl Chalcones on Leishmania amazonensis Kaio Maciel de Santiago-Silva 1 , Bruna Taciane da Silva Bortoleti 2,3 , Laudicéa do Nascimento Oliveira 4 , Fernanda Lima de Azevedo Maia 4 , Joyce Cristina Castro 4 , Ivete Conchon Costa 2 , Danielle Bidóia Lazarin 2 , James L. Wardell 5 , Solange M. S. V. Wardell 6 , Magaly Girão Albuquerque 4 , Camilo Henrique da Silva Lima 4 , Wander Rogério Pavanelli 2 , Marcelle de Lima Ferreira Bispo 1, * and Raoni Schroeder B. Gonçalves 4, * 1 Laboratório de Síntese de Moléculas Medicinais (LaSMMed), Departamento de Química, Centro de Ciências Exatas, Universidade Estadual de Londrina, Londrina 86057-970, PR, Brazil 2 Laboratório de Imunoparasitologia das Doenças Negligenciadas e Câncer (LIDNC), Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Londrina 86057-970, PR, Brazil 3 Programa de Pós-Graduação em Biociências e Biotecnologia, Instituto Carlos Chagas (ICC), Fiocruz, Curitiba 81350-010, PR, Brazil 4 Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil 5 Department of Chemistry, University of Aberdeen, Meston Walk, Old Aberdeen, Aberdeen AB24 3UE, Scotland, UK 6 CHEMSOL, 1 Harcourt Road, Aberdeen AB15 5NY, Scotland, UK * Correspondence: mlfbispo@uel.br (M.d.L.F.B.); raoni.schroeder@iq.ufrj.br (R.S.B.G.); Tel.: +55-43-33714810 (M.d.L.F.B.) Abstract: Leishmaniasis is a neglected tropical disease caused by Leishmania species. Available therapeutic options have several limitations. The drive to develop new, more potent, and selec- tive antileishmanial agents is thus a major goal. Herein we report the synthesis and the biolog- ical 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 IC 50 = 3.3 ± 0.34 μM (promastig- otes), a low cytotoxicity profile (CC 50 = 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 intesti- nal absorption. Compound 4f reduced the number of infected macrophages and the number of amastigotes per macrophage, with an IC 50 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. Keywords: 4,8-dimethoxynaphthalenyl; arginase; leishmaniasis; neglected diseases; trypanosomatids; trypanothione reductase 1. Introduction The leishmaniases are a group of neglected diseases widely distributed among tropical and subtropical countries. Leishmaniases are caused by the protozoan parasite of the genus Leishmania and transmitted to humans by the bite of infected female phlebotomine sandflies. This parasitic disease presents mainly four clinical manifestations: visceral leishmaniasis (VL, also known as kala-azar), cutaneous leishmaniasis (CL), diffuse cutaneous leishma- niasis (DCL), and mucocutaneous leishmaniasis (MCL). According to the World Health Organization (WHO), 700,000 to 1 million new cases and 26,000 to 65,000 deaths occur yearly, constituting a major global public health problem [1,2]. Antibiotics 2022, 11, 1402. https://doi.org/10.3390/antibiotics11101402 https://www.mdpi.com/journal/antibiotics