RESUMEN
This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho-quinone methide intermediates (o-QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron-rich dienophiles in inverse-electron demand hetero-Diels-Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.
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Indolquinonas , Técnicas de Química Sintética , Reacción de Cicloadición , Indolquinonas/químicaRESUMEN
The triazole heterocycle is a privileged scaffold in medicinal chemistry, since its structure is present in a large number of biologically active molecules, including several drugs currently in the market. Due to their vast applications, a wide variety of methods are described for their preparation, such as the 1,3-dipolar cycloaddition and processes involving diazo compounds and diazo transfer reactions. Considering the significant number of contributions from our research group to this chemistry in recent decades, in this account we discuss both the development of new methods for the synthesis of 1,2,3-triazoles and the preparation of new triazole-functionalized biologically active molecules using classical approaches.
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Triazoles , Reacción de CicloadiciónRESUMEN
In December 2019, a new variant of SARS-CoV emerged, the so-called acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus causes the new coronavirus disease (COVID-19) and has been plaguing the world owing to its unprecedented spread efficiency, which has resulted in a huge death toll. In this sense, the repositioning of approved drugs is the fastest way to an effective response to a pandemic outbreak of this scale. Considering these facts, in this review we provide a comprehensive and critical discussion on the chemical aspects surrounding the drugs currently being studied as candidates for COVID-19 therapy. We intend to provide the general chemical community with an overview on the synthetic/biosynthetic pathways related to such molecules, as well as their mechanisms of action against the evaluated viruses and some insights on the pharmacological interactions involved in each case. Overall, the review aims to present the chemical aspects of the main bioactive molecules being considered to be repositioned for effective treatment of COVID-19 in all phases, from the mildest to the most severe.
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Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Reposicionamiento de Medicamentos , Animales , Antivirales/síntesis química , Antivirales/farmacología , COVID-19/epidemiología , Línea Celular Tumoral , Ensayos Clínicos como Asunto , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Pandemias , SARS-CoV-2/efectos de los fármacosRESUMEN
HSV disease is distributed worldwide. Anti-herpesvirus drugs are a problem in clinical settings, particularly in immunocompromised individuals undergoing herpes simplex virus type 1 infection. In this work, 4-substituted-1,2,3-1H-1,2,3-triazole linked nitroxyl radical derived from TEMPOL were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. The nitroxide derivatives were characterized by infrared spectroscopy and elemental analysis, and three of them had their crystal structures determined by single-crystal X-ray diffraction. Four hybrid molecules showed important anti-HSV-1 activity with IC50 values ranged from 0.80 to 1.32 µM. In particular, one of the nitroxide derivatives was more active than Acyclovir (IC50 = 0.99 µM). All compounds tested were more selective inhibitors than the reference antiviral drug. Among them, two compounds were 4.5 (IC50 0.80 µM; selectivity index CC50/IC50 3886) and 7.7 times (IC50 1.10 µM; selectivity index CC50/IC50 6698) more selective than acyclovir (IC50 0.99 µM; selectivity index CC50/IC50: 869). These nitroxide derivatives may be elected as leading compounds due to their antiherpetic activities and good selectivity.
Asunto(s)
Herpesvirus Humano 1RESUMEN
Tempol, a superoxide dismutase-mimetic drug, has been shown to attenuate radical-induced damage, exerting beneficial effects in the animal models of oxidative stress and hypertension. This study evaluated the effect of Tempol on renal structural and functional alterations in two-Kidney, one-Clip hypertensive rats. In this study, young male Wistar rats had the left kidney clipped (2K1C), and sham-operated animals (Sham) were used as controls. Animals received Tempol (1mmol/L in drinking water) or vehicle for 5 weeks. Systolic blood pressure was evaluated once a week. At the end of the experimental protocol, the animals were placed in metabolic cages to collect urine (24h) and then anesthetized with thiopental (70mg/kg i.p.) to collect blood by puncturing the descending aorta for biochemical analysis, and the clipped kidney for morphological and immunohistochemical analyses. The vasodilator effect of Tempol was evaluated in mesenteric arterial bed (MAB) isolated from adult Wistar rats. The chronic treatment with Tempol prevented the development of hypertension and the increased plasma levels of urea, creatinine, and 8-isoprostane in 2K1C animals. Tempol also improved both glomeruli number and kidney volume to normal levels in the 2K1C+Tempol group. In addition, the treatment prevented the increased collagen deposition and immunostaining for renin, caspase-3, and 8-isoprostane in the stenotic kidney of 2K1C animals. Moreover, Tempol induced a dose-dependent vasodilator response in MAB from Wistar rats. These results suggest that Tempol protects the stenotic kidney against chronic ischemic renal injury and prevents renal dysfunction in the 2K1C model, probably through its antioxidant, vasodilator and antihypertensive actions.
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Antioxidantes/uso terapéutico , Óxidos N-Cíclicos/uso terapéutico , Hipertensión/complicaciones , Isquemia/complicaciones , Enfermedades Renales/prevención & control , Riñón/irrigación sanguínea , Animales , Antioxidantes/farmacología , Materiales Biomiméticos/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Caspasa 3/metabolismo , Enfermedad Crónica , Creatinina/sangre , Óxidos N-Cíclicos/farmacología , Dinoprost/análogos & derivados , Dinoprost/metabolismo , Hipertensión/fisiopatología , Riñón/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Glomérulos Renales/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Renina/metabolismo , Marcadores de Spin , Superóxido Dismutasa , Urea/sangre , Vasodilatación/efectos de los fármacosRESUMEN
This work describes a new approach to obtain new ß-vinylporphyrin derivatives through palladium-catalyzed cross-coupling reaction of 2-bromo-5,10,15,20-tetraphenylporphyrinatozinc(II) with N-tosylhydrazones. This is the first report of the use of such synthetic methodology in porphyrin chemistry allowing the synthesis of new derivatives, containing ß-arylvinyl substituents.
RESUMEN
We described the synthesis of a new congener series of 1,2,3-triazolyl-4-oxoquinolines and evaluated their ability to inhibit oseltamivir (OST)-resistant influenza strains. Oxoquinoline derivative 1i was the most potent compound within this series, inhibiting 94% of wild-type (WT) influenza neuraminidase (NA) activity. Compound 1i inhibited influenza virus replication with an EC50 of 0.2µM with less cytotoxicity than OST, and also inhibited different OST-resistant NAs. These results suggest that 1,2,3-triazolyl-4-oxoquinolines represent promising lead molecules for further anti-influenza drug design.
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Antivirales/farmacología , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza B/efectos de los fármacos , Gripe Humana/tratamiento farmacológico , Oseltamivir/farmacología , Quinolonas/farmacología , Triazoles/farmacología , Antivirales/química , Diseño de Fármacos , Farmacorresistencia Viral , Humanos , Virus de la Influenza A/enzimología , Virus de la Influenza B/enzimología , Gripe Humana/virología , Simulación del Acoplamiento Molecular , Neuraminidasa/antagonistas & inhibidores , Neuraminidasa/metabolismo , Quinolonas/química , Triazoles/químicaRESUMEN
As part of a continuing search for new potential anticancer candidates, we describe the synthesis, cytotoxicity and mechanistic evaluation of a series of 4-oxoquinoline-3-carboxamide derivatives as novel anticancer agents. The inhibitory activity of compounds 10-18 was determined against three cancer cell lines using the MTT colorimetric assay. The screening revealed that derivatives 16b and 17b exhibited significant cytotoxic activity against the gastric cancer cell line but was not active against a normal cell line, in contrast to doxorubicin, a standard chemotherapeutic drug in clinical use. Interestingly, no hemolytical activity was observed when the toxicity of 16b and 17b was tested against blood cells. The in silico and in vitro mechanistic evaluation indicated the potential of 16b as a lead for the development of novel anticancer agents against gastric cancer cells.
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Antineoplásicos/química , Antineoplásicos/farmacología , Animales , Antineoplásicos/síntesis química , Línea Celular Tumoral/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Técnicas de Química Sintética , Simulación por Computador , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Eritrocitos/efectos de los fármacos , Hemolíticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Quinolonas/química , Neoplasias Gástricas/tratamiento farmacológicoRESUMEN
The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds' in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC(50) values of 0.4±0.2 µM (3f) and 0.2±0.005 µM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.
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Fármacos Anti-VIH/química , VIH-1/efectos de los fármacos , Nucleósidos/química , Ácidos Fosforosos/química , Quinolonas/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/toxicidad , Humanos , Ácidos Fosforosos/síntesis química , Ácidos Fosforosos/toxicidad , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis, which remains a serious public health problem. The emergence of resistant bacterial strains has continuously increased and new treatment options are currently in need. In this work, we identified a new potential aldehyde-arylhydrazone-oxoquinoline derivative (4e) with interesting chemical structural features that may be important for designing new anti-TB agents. This 1-ethyl-N'-[(1E)-(5-nitro-2-furyl)methylene]-4-oxo-1,4-dihydroquinoline-3-carbohydrazide (4e) presented an in vitro active profile against M. tuberculosis H37Rv strain (minimum inhibitory concentration, MIC = 6.25 µg/mL) better than other acylhydrazones described in the literature (MIC = 12.5 µg/mL) and close to other antitubercular agents currently on the market. The theoretical analysis showed the importance of several structural features that together with the 5-nitro-2-furyl group generated this active compound (4e). This new compound and the analysis of its molecular properties may be useful for designing new and more efficient antibacterial drugs.
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Antituberculosos/aislamiento & purificación , Antituberculosos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Aldehídos/química , Aldehídos/aislamiento & purificación , Aldehídos/farmacología , Antituberculosos/química , Hidrazonas/química , Hidrazonas/aislamiento & purificación , Hidrazonas/farmacología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinolonas/química , Quinolonas/aislamiento & purificación , Quinolonas/farmacologíaRESUMEN
Two different products were obtained by the regiodivergent reaction of benzoquinone derivatives with phenolates and anilines: 3-aryloxybenzoquinone and 2-phenylamino-3-bromobenzoquinone. Calculated density functional theory free energies of reaction values corroborate the experimental observation of the formation of the substitution product in the reaction with phenolates in acetonitrile and the product of addition/oxidation for the reaction with aniline in water. Calculated charges and Fukui functions are similar for C2 and C3 atoms, indicating an equal possibility to suffer a nucleophilic attack. The calculated energy barriers for nucleophilic attack steps indicated that the first steps of the substitution with phenolates and addition/oxidation with anilines are faster, which justifies the formation of the respective products. The natural bond order analysis for the transition states revealed that there is a strong interaction between lone pairs of N and O atoms and the πC2C3 * for the O â C2 and N â C3 attacks and a weak interaction for the O â C3 and N â C2 attacks, which also agrees with experimental observations.
RESUMEN
In this work, a new series of arysulfonylhydrazine-1H-1,2,3-triazole derivatives were synthesized, and their ability to inhibit the in vitro replication of HSV-1 was evaluated. Among the 1,2,3-triazole derivatives, 1-[(5â³-methyl-1â³-(4â´-fluorophenylamino)-1H-1,2,3-triazol-4â³-yl)carbonyl]-2-(4'-methylphenylsulfonyl)hydrazine and 1-[(5'-methyl-1'-(2â³,5â³-dichlorophenylamino)-1H-1,2,3-triazol-4'-yl)carbonyl]-2-(phenylsulfonyl)hydrazine, with IC(50) values of 1.30 and 1.26 µM, respectively, displayed potent activity against HSV-1. Because these compounds have low cytotoxicity, their selectivity indices are high. Under the assay conditions, they have better performance than does the reference compound acyclovir. The structures of all of the compounds were confirmed by one- and two-dimensional NMR techniques ((1)H, (13)C-APT, COSY-(1)H×(1)H and HETCOR (1)J(CH)) and by elemental analysis.
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Antivirales/síntesis química , Herpesvirus Humano 1/efectos de los fármacos , Triazoles/síntesis química , Animales , Antivirales/química , Antivirales/toxicidad , Chlorocebus aethiops , Replicación del ADN/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Triazoles/química , Triazoles/toxicidad , Células VeroRESUMEN
Tuberculosis treatment remains a challenge that requires new antitubercular agents due to the emergence of multidrug-resistant Mycobacterium strains. This paper describes the synthesis, the antitubercular activity and the theoretical analysis of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (8a-b, 8e-f, 8i-j and 8n-o) and new analogues (8c-d, 8g-h, 8l-m and 8p-q). These derivatives were synthesized in good yields and some of them showed a promising antitubercular profile. Interestingly the N-acylhydrazone (NAH) 8n was the most potent against the Mycobacterium tuberculosis H37Rv strain (MIC=2.5 µg/mL) similar to or better than the current drugs on the market. The theoretical structure-activity relationship study suggested that the presence of the furyl ring and the electronegative group (NO(2)) as well as low lipophilicity and small volume group at R position are important structural features for the antitubercular profile of these molecules. NMR spectra, IR spectra and elemental analyses of these substances are reported.
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Antituberculosos/síntesis química , Antituberculosos/farmacología , Hidrazinas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Triazoles/química , Antituberculosos/química , Relación Dosis-Respuesta a Droga , Hidrazinas/síntesis química , Hidrazinas/química , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Herpes simplex virus is an important human pathogen responsible for a range of diseases from mild uncomplicated mucocutaneous infections to life-threatening ones. Currently, the emergence of Herpes simplex virus resistant strains increased the need for more effective and less cytotoxic drugs for Herpes treatment. In this work, we synthesized a series of oxoquinoline derivatives and experimentally evaluated the antiviral activity against acyclovir resistant HSV-1 strain as well as their cytotoxity profile. The most active compound (3b), named here as Fluoroxaq-3b, showed a promising profile with a better cytotoxicity profile than acyclovir. The theoretical analysis of the structure-activity relationship of these compounds revealed some stereoelectronic properties such as lower LUMO energy and lipophilicity, besides a higher polar surface area and number of hydrogen bond acceptor groups as important parameters for the antiviral activity. Fluoroxaq-3b showed a good oral theoretical bioavailability, according to Lipinski rule of five, with a promising profile for further in vivo analysis.
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Antivirales/química , Antivirales/farmacología , Herpes Simple/virología , Herpesvirus Humano 1/efectos de los fármacos , Quinolonas/química , Quinolonas/farmacología , Animales , Antivirales/síntesis química , Línea Celular , Chlorocebus aethiops , Herpes Simple/tratamiento farmacológico , Humanos , Quinolonas/síntesis química , Relación Estructura-Actividad , Células VeroRESUMEN
BACKGROUND: Bovine herpesvirus type 5 is an important agent of meningoencephalitis in cattle and has been identified in outbreaks of bovine neurological disease in several Brazilian states. In recent years, oxoquinoline derivatives have become an important focus in antiviral drug research. METHODS: The cytotoxicity and anti BoHV-5RJ42/01 activity of a set of synthetic 4-oxoquinoline derivatives 4a-k were assayed on Madin-Darby Bovine Kidney cell and antiviral activity by plaque reduction assay. RESULTS: The most promising substance (4h) exhibited CC50 and EC50 values of 1,239 µM ±5.5 and 6.0 µM ±1.5, respectively, with an SI =206. Two other compounds 4j (CC50 = 35 µM ±2 and EC50 = 24 µM ±7.0) and 4k (CC50= 55 µM ±2 and EC50 = 24 µM ±5.1) presented similar inhibitory profile and selectivity indexes of 1.4 and 2.9, respectively. The results of the time-of-addition studies revealed expressive reduction of virus production (≥80%) in different stages of virus replication cycle except for compound 4h that slightly inhibited virus yield in the first 2 h post infection, but it showed expressive virus inhibition after this time. CONCLUSIONS: All three compounds slightly interact with the virus on the virucidal assay and they are not able to block virus attachment and penetration. Antiviral effect of oxoquinoline 4h was more prominent than acyclovir which leads us to suggest compound 4h as a promising molecule for further anti-BoHV-5 drug design.
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4-Quinolonas/farmacología , Antivirales/farmacología , Herpesvirus Bovino 5/efectos de los fármacos , Animales , Perros , Células de Riñón Canino Madin Darby/efectos de los fármacos , Ensayo de Placa Viral , Inactivación de Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
This paper describes the synthesis, antiplatelet and theoretical evaluations of 10 N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (2a-j). These compounds were synthesized, characterized and screened for their in vitro antiplatelet profile against human platelet aggregation using arachidonic acid, adrenaline and ADP as agonists. Among NAH derivatives 2a-j, the compounds 2a, 2c, 2e, 2g and 2h were the most promising molecules with significant antiplatelet activity.
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Hidrazinas/síntesis química , Inhibidores de Agregación Plaquetaria/síntesis química , Triazoles/síntesis química , Humanos , Hidrazinas/química , Hidrazinas/farmacología , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/farmacología , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
The current treatment used against envenomation by Lachesis muta venom still presents several side effects. This paper describes the synthesis, pharmacological and theoretical evaluations of new 1-arylsulfonylamino-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters (8a-f) tested against the hemolytic profile of the L. muta snake venom. Their structures were elucidated by one- and two-dimensional NMR techniques ((1)H, APT, HETCOR (1)J(CH) and (n)J(CH), n=2, 3) and high-resolution electrospray ionization mass spectrometry. The series of triazole derivatives significantly neutralized the hemolysis induced by L. muta crude venom presenting a dose-dependent inhibitory profile (IC(50)=30-83 microM) with 1-(4'-chlorophenylsulfonylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl ester (8e) being the most potent compound. The theoretical evaluation revealed the correlation of the antiophidian profile with the coefficient distribution and density map of the Highest Occupied Molecular Orbitals (HOMO) of these molecules. The elucidation of this new series may help on designing new and more efficient antiophidian molecules.
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Venenos de Crotálidos/toxicidad , Triazoles/síntesis química , Viperidae/metabolismo , Animales , Ésteres/química , Hemólisis , Humanos , Espectroscopía de Resonancia Magnética , Conejos , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Termodinámica , Triazoles/química , Triazoles/farmacologíaRESUMEN
In the present article, we describe the synthesis, anti-HIV1 profile and molecular modeling evaluation of 11 oxoquinoline derivatives. The structure-activity relationship analysis revealed some stereoelectronic properties such as LUMO energy, dipole moment, number of rotatable bonds, and of hydrogen bond donors and acceptors correlated with the potency of compounds. We also describe the importance of substituents R(2) and R(3) for their biological activity. Compound 2j was identified as a lead compound for future investigation due to its: (i) high activity against HIV-1, (ii) low cytotoxicity in PBMC, (iii) low toxic risks based on in silico evaluation, (iv) a good theoretical oral bioavailability according to Lipinski 'rule of five', (v) higher druglikeness and drug-score values than current antivirals AZT and efavirenz.
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Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Quinolonas/síntesis química , Quinolonas/farmacología , Animales , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Infecciones por VIH/tratamiento farmacológico , VIH-1/crecimiento & desarrollo , Humanos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/virología , Modelos Moleculares , Estructura Molecular , Quinolonas/química , Quinolonas/farmacocinética , Relación Estructura-Actividad , Células VeroRESUMEN
In this work an efficient one-pot synthesis of substituted pyrroles 7a-n is described, which involves the in situ formation of dihydrofurans ethyl 5-butoxy-2-methyl-4,5-dihydrofuran-3-carboxylate (4), 1-(5-butoxy-2-methyl-4,5-dihydrofuran-3-yl)ethanone (5) and 5-butoxy-4,5-dihydrofuran-3-carbaldehyde (6) followed by reaction with primary amines.
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BACKGROUND: Leishmaniasis is a neglected public health problem caused by several protozoanspecies of the genus Leishmania. The therapeutic arsenal for treating leishmaniasis is quite limited, raising concerns about the occurrence of resistant strains. Furthermore, most of these drugs were developed more than 70 years ago and suffer from poor efficacy and safety and are not well adapted to the needs of patients. Therefore, research on novel natural or synthetic compounds with antiparasitic activity is urgently needed. In this paper, we evaluated the effect and the mechanism of action of naphthotriazolyl-4-oxoquinolines on promastigotes and intracellular amastigotes of Leishmania amazonensis. MATERIALS AND METHODS: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields via the [3+2] cycloaddition reaction between 1,4-naphtoquinone and azido-4- oxoquinoline derivatives. HMPA at 100°C was established as the best solvent and temperature condition for this reaction. The structures of the compounds were confirmed by spectral analyses (infrared spectroscopy, one- and two-dimensional ¹H and ¹³C NMR spectroscopy, and high-resolution mass spectrometry). The compounds exhibited promising activities with IC50 values ranging from 0.7 to 2.0 µM against intracellular amastigotes of Leishmania amazonensis. The most selective compound was the Npentyl- substituted derivative, which showed a Selectivity Index (SI) of 8.6, making it less toxic than pentamidine (SI 4.5). RESULTS: Our results demonstrated that all compounds, except the N-propyl-substituted derivative, induce ROS production by parasites early in the culture. As a proof of concept, we demonstrated that the most selective compound was able to interfere with sterol biosynthesis in L. amazonensis. CONCLUSION: The naphthotriazolyl-4-oxoquinoline derivatives were obtained in good to moderate yields. These conjugates have potent in vitro antileishmanial activity involving at least two different mechanisms of action, making them promising lead compounds for the development of new therapeutic alternatives for leishmaniasis.