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Leishmaniasis is a public health concern, especially in Brazil and India. The drugs available for therapy are old, cause toxicity and have reports of resistance. Therefore, this paper aimed to carry out initial structure-activity relationships (applying molecular docking and dynamic simulations) of arylindole scaffolds against the pteridine reductase (PTR1), which is essential target for the survival of the parasite. Thus, we used a series of 43 arylindole derivatives as a privileged skeleton, which have been evaluated previously for different biological actions. Compound 7 stood out among its analogues presenting the best results of average number of interactions with binding site (2.00) and catalytic triad (1.00). Additionally, the same compound presented the best binding free energy (−32.33 kcal/mol) in dynamic simulations. Furthermore, with computational studies, it was possible to comprehend and discuss the influences of the substituent sizes, positions of substitutions in the aromatic ring and electronic influences. Therefore, this study can be a starting point for the structural improvements needed to obtain a good leishmanicidal drug. [ABSTRACT FROM AUTHOR]

• The leishmanicidal activity of a triazole-phthalimide derivative (PT4) was evaluated. • PT4 decrease the growth and survival of promastigote and amastigotes. • PT4 showed inhibitory potential over the CYP51 enzyme of Leishmania spp. • PT4 induced an increase in ROS and depolarization of the mitochondrial membrane. • Our results pointed PT4 as a promissory agent against Cutaneous Leishmaniasis. Organic compounds obtained by click chemistry reactions have demonstrated a broad spectrum of biological activities being widely applied for the development of molecules against pathogens of medical and veterinary importance. Cutaneous leishmaniasis (CL), caused by intracellular protozoa parasite of genus Leishmania , comprises a complex of clinical manifestations that affect the skin and mucous membranes. The available drugs for the treatment are toxic and costly, with long periods of treatment, and the emergence of resistant strains has been reported. In this study we investigated the in vitro effects of a phthalimide-1,2,3-triazole derivative, the 4-Phenyl-1-[2-(phthalimido-2-yl)ethyl]-1H-1,2,3-triazole (PT4) obtained by click chemistry , on mammalian cells and on L. amazonensis and L. braziliensis , the causative agents of CL in Brazil. In silico ADMET evaluation of PT4 showed that this molecule has good pharmacokinetic properties with no violation of Lipinski's rules. The in vitro assays showed that PT4 was more selective for both Leishmania species than to mammalian cells. This compound also presented low cytotoxicity to mammalian cells with CC 50 > 500 μM. Treatment of promastigote forms with different concentrations of PT4 resulted in ultrastructural alterations, such as plasma membrane wrinkling, shortening of cell body, increased cell volume and cell rupture. The molecular dynamic simulations showed that PT4 interacts with Lanosterol 14 α-demethylase from Leishmania, an essential enzyme of lipid synthesis pathway in this parasite. Our results demonstrated PT4 was effective against both species of Leishmania. PT4 caused a decrease of mitochondrial membrane potential and increased production of reactive oxygen species, which may lead to parasite death. Taken together, our results pointed PT4 as promissing therapeutic agent against CL. [ABSTRACT FROM AUTHOR]