Effect of hydroxyamines derived from lapachol and norlachol against Staphylococcus aureus strains carrying the NorA efflux pump.

Isolated substances and those organically synthesized have stood out over the years for their therapeutic properties, including their antibacterial activity. These compounds may be an alternative to the production of new antibiotics or may have the ability to potentiate the action of preexisting ones. In this context, the objective of this study was to evaluate the in vitro antibacterial and efflux pump inhibitory activity of hydroxyamines derived from lapachol and norlachol, more specifically the compounds 2-(2-Hydroxyethylamino)-3-(3-methyl-2-butenyl)-1,4 dihydro-1,4-naphthalenedione, 2-(2-Hydroxyethylamino)-3-(2-methyl-propenyl)[1,4]naphthoquinone and 2-(3-Hydroxypropylamino)-3-(3-methyl-2-butenyl)-[1,4]naphthoquinone, against Staphylococcus aureus strains carrying the NorA efflux pump mechanism. The substances were synthesized from 2-hydroxy-quinones, lapachol and nor-lapachol, obtaining the corresponding 2-methoxylated derivatives via dimethyl sulfate alkylation in a basic medium, which then reacted chemoselectively with 2-ethanolamine and 3-propanolamine to form the corresponding amino alcohols. All three molecules underwent a virtual structure-based analysis (docking). The antibacterial activity of the substances was measured by determining their Minimum Inhibitory Concentration (MIC) and a microdilution assay was performed to verify efflux pump inhibition using the substances at a sub-inhibitory concentration. The results were subjected to statistical analysis using an analysis of variance (ANOVA) followed by Bonferroni's post hoc test. The substances obtained MIC values ≥1024 µg/mL, however, a significant reduction of their MICs was observed when the substances were associated with norfloxacin and ethidium bromide, with this effect being attributed to efflux pump inhibition. Following a virtual analysis based on its structure (docking), information regarding the affinity of new ligands for the ABC efflux pump were observed, thus contributing to the understanding of their mechanism of molecular interactions and the discovery of functional ligands associated with a reduction in bacterial resistance.

In silico evaluation of the antibacterial and modulatory activity of lapachol and nor-lapachol derivates.

The aim of this research was to investigate the pharmacological properties of 2-(2-hydroxyethylamine)-3-(3-methyl-2-butenyl)-1,4-dihydro-1,4-naphthalenedione, 2-(2-hydroxy-ethylamine)-3-(2-methyl-propenyl)-[1,4]naphthoquinone and 2-(3-hydroxy-propylamine)-3-(3-methyl-2-butenyl)-[1,4]naphthoquinone using computational prediction models, in addition to evaluating the in vitro antibacterial and modulatory activity of these compounds against bacterial ATCC strains and clinical isolates. The substances were synthesized from 2-hydroxy-quinones, lapachol and nor-lapachol obtaining the corresponding 2-methoxylated derivatives via dimethyl sulfate alkylation in a basic medium, these then reacted chemoselectively with 2-ethanolamine and 3-propanolamine to form the corresponding amino alcohols. The antibacterial activity and modulatory activity of the substances were assayed by broth microdilution method to determine the Minimum Inhibitory Concentration (MIC). The molecular structures were analyzed using the ChEMBL database to predict possible pharmacological targets, which pointed to the molecule 2- (2-hydroxy-ethylamine)-3-(2-methyl-propenyl)-[1,4]naphthoquinone as a probable antibacterial agent for the proteins Replicative DNA helicase and RecA. The compounds had a low molecular weight and a small number of rotatable bonds. The MICs of the substances were not clinically significant, however, the association with gentamicin and amikacin reduced the MICs of these antibiotics. In conclusion, the combination of these substances with aminoglycosides may be a therapeutic alternative to bacterial resistance and the reduction of side effects.

Flavonoids induce cell death in Leishmania amazonensis: in vitro characterization by flow cytometry and Raman spectroscopy.

Leishmaniasis comprises a group of infectious diseases with worldwide distribution, of which both the visceral and cutaneous forms are caused by Leishmania parasites. In the absence of vaccines, efficacious chemotherapy remains the basis for leishmaniasis control. The available drugs are expensive and associated with several secondary adverse effects. Due to these limitations, the development of new antileishmanial compounds is imperative, and plants offer various perspectives in this regard. The present study evaluated the in vitro leishmanicidal activity of flavonoids isolated from Solanum paludosum Moric. and investigated the mechanisms of cell death induced by them. These compounds were evaluated in vitro for their antileishmanial activity against Leishmania amazonensis promastigotes and they showed prominent leishmanicidal activity. The EtOAc fraction, gossypetin 3,7,8,4'-tetra-O-methyl ether (1), and kaempferol 3,7-di-O-methyl ether (3) were selected to be used in an in vitro assay against L. amazonensis amastigotes and cell death assays. The flavonoids (1) and (3) presented significant activity against L. amazonensis amastigotes, exhibiting the IC50 values of 23.3 ± 4.5 µM, 34.0 ± 9.6 µM, and 10.5 ± 2.5 µM for the EtOAc fraction, (1), and (3), respectively, without toxic effects to the host cells. Moreover, (1) and (3) induced blocked cell cycle progression at the G1/S transition, ultimately leading to G1/G0 arrest. Flavonoid (3) also induced autophagy. Using Raman spectroscopy in conjunction with principal component analysis, the biochemical changes in the cellular components induced by flavonoids (1) and (3) were presented. The obtained results indicated that the mechanisms of action of (1) and (3) occurred through different routes. The results support that the flavonoids derived from S. paludosum can become lead molecules for the design of antileishmanial prototypes.

Evaluation of acute toxicity of β-lapachone associated with chitosan as a cytoprotective agent / Avaliação da toxicidade aguda da β-lapachona associada à quitosana como agente citoprotetor

ABSTRACT INTRODUCTION: β-lapachone (β-LAP), a potent antitumor agent, has limited therapeutic use due to its low solubility and high toxicity. A possible strategy to overcome these drawbacks may be the use of adjuvants such as chitosan (CS), a cationic polysaccharide with biological properties of biocompatibility and biodegradability. OBJECTIVE: Evaluate the adjuvant action of CS as a cytoprotectant associated with β-LAP, through acute toxicity studies, evaluating histopathological changes in organs such as liver and kidneys. METHODS: The β-LAP-CS conjugate was prepared in a 1:1 ratio, administered orally, with a single dose of β-LAP of 80 mg/kg, in Swiss mice. Histomorphological and histomorphometric analyses of the kidneys and liver were performed. RESULTS: In the histomorphological studies of the tested groups, we observed that the hepatocytes of animals treated with the free drug presented morphological alterations, such as cytoplasmic vacuolization, cellular extravasation, atypical and pyknotic nuclei. In this same group, the kidneys presented granular aspects suggestive of glomerulonephritis. These changes were not found in the control group and in animals treated with CS-conjugated β-LAP. There was no statistical difference in the histomorphometric analyses of the distal tubules and the renal glomeruli between the three groups analyzed, even with evident histomorphological alterations. After histomorphometric studies, it was observed that the area of hepatocytes and their cell nuclei presented a statistically significant difference between the animals treated with free β-LAP and the β-LAP-CS. CONCLUSION: The decrease in β-LAP toxicity after conjugation may be related to the hepatoprotective property of CS.

RESUMO INTRODUÇÃO: A β-lapachona (β-LAP), um potente agente antitumoral, tem uso terapêutico limitado devido a sua baixa solubilidade e elevada toxicidade. Uma possível estratégia para contornar esses inconvenientes pode ser a utilização de adjuvantes como a quitosana (QS), um polissacarídeo catiônico com propriedades biológicas, como biocompatibilidade e biodegradabilidade. OBJETIVO: Avaliar a ação adjuvante da QS como citoprotetor associada à β-LAP por meio de estudos de toxicidade aguda, verificando as alterações histopatológicas em órgãos como fígado e rins. MÉTODOS: Um conjugado da β-LAP-QS foi preparado na proporção 1:1, administrado por via oral, com dose única da β-LAP de 80 mg/kg, em camundongos Swiss. Foram realizadas análises histomorfológicas e histomorfométricas dos rins e do fígado desses animais. RESULTADOS: Nos estudos histomorfológicos dos grupos testados, observamos que os hepatócitos dos animais tratados com a droga livre apresentaram alterações morfológicas, como vacuolização do citoplasma, extravasamento celular, núcleos atípicos e picnóticos. Nesse mesmo grupo, os rins apresentaram aspectos granulosos sugestivos de glomerulonefrite. Essas alterações não foram encontradas no grupo-controle e nos animais tratados com a β-LAP conjugada com QS. Não houve diferença estatística nas análises histomorfométricas dos túbulos distais e dos glomérulos renais entre os três grupos analisados, mesmo com alterações histomorfológicas evidentes. Após estudos histomorfométricos, foi observado que a área dos hepatócitos e seus núcleos celulares apresentaram diferença estatística significativa entre os animais tratados com a β-LAP livre e o conjugado β-LAP-QS. CONCLUSÃO: A diminuição da toxicidade da β-LAP, após ser conjugada, pode estar relacionada com a propriedade hepatoprotetora da QS.

Development of solid dispersions of ß-lapachone in PEG and PVP by solvent evaporation method.

ß-lapachone (ßlap) has shown potential use in various medical applications. However, its poor solubility has limited its systemic administration and clinical applications. The aim of this work is to develop solid dispersions of ßlap using poly (ethylene glycol) (PEG 6000) and polyvinylpyrrolidone (PVP K30) as hydrophilic polymers and evaluate the dissolution rate in aqueous medium. Solid dispersions were prepared by solvent evaporation method using different weight ratios of ßlap and hydrophilic polymer (1:1, 1:2, and 1:3). Characterization performed by differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that ßlap was molecularly dispersed within the polymer matrix. The in vitro dissolution tests showed an enhancement in the dissolution profile of ßlap as solid dispersions prepared in both PVP and PEG, although the former showed better results. The drug:polymer ratio influenced ßlap dissolution rate, as higher amounts of hydrophilic polymer led to enhanced drug dissolution. Thus, this study demonstrated that solid dispersions of ßlap in PVP offers an effective way to overcome the poor dissolution of ßlap.

Evaluation on the leishmanicidal activity of 2-N,N'-dialkylamino-1,4-naphthoquinone derivatives.

Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. In this study was evaluated in vitro leishmanicidal activity of 2-N,N'-dialkylamino-1,4-naphthoquinone derivatives, covering a series of fourteen 2-N-morpholino-, 2-N-thiomorpholino, 2-N-piperidino, 2-N-(N4-methyl)-piperazino naphthoquinones (1a-n) derived from nor-lapachol and lawsone, belong to some other di-alkyaminoderivatives. At the cytotoxicity assay on peritoneal macrophages, the compounds possessing larger alkyl groups and N-methyl-piperazino moiety (1d, 1h, 1i and 1k), showed toxic effects similar to the standard drug used pentamidine. However, the other compounds of the series showed no deleterious effect on the host cell. Meanwhile, these cytotoxic derivatives (1d, 1h and 1i) had pronounced leishmanicidal activity against L. amazonensis promastigotes, and treatments with six other compounds (1d, 1e, 1f, 1h, 1k and 1n) had significant effect leishmanicidal against L. chagasi promastigotes. In the assay against L. chagasi amastigotes, eight compounds (1a, 1b, 1c, 1d, 1h, 1i, 1k and 1m) showed significant activity. Moreover, the compounds (1a, 1b, 1c, and 1m) showed effect against amastigotes of L. chagasi and not being toxic to the host cell. These data show the derivatives as promising substances for research leishmanicidal activity.

Protoflavanones from the Wood Stem of Salvertia convallariodora.

Phytochemical-analysis of the ethyl acetate extract of stem wood of Salvertia convallariodora A. St.-Hil. (Vochysiaceae), a Brazilian Cerrado species, led to the isolation and full characterization of three new non-aromatic B-ring flavanones (1-3) as well as the terpene mixture of sericic acid (4), 24-hydroxytormentic acid (5); 24-hydroxytormentic acid glucosyl ester (6), and sericoside (7), all identified for the first time from S. convallariodora. The structures of the new flavanones (1-3) were established from IR, LC-PDA-qTOF-MS, and NMR spectral data, including 2D NMR experiments.

Evaluation of the orofacial antinociceptive profile of the ethyl acetate fraction and its major constituent, rosmarinic acid, from the leaves of Hyptis pectinata on rodents

ABSTRACT Hyptis pectinata (L.) Poit., Lamiaceae, popularly known as "sambacaitá," is an aromatic shrub largely grown in the Brazilian northeastern. We investigated the antinociceptive effects of the ethyl acetate fraction obtained from the leaves of H. pectinata and of its main constituent rosmarinic acid, on formalin (2%)-, glutamate (25 µM)- and capsaicin (2.5 µg)-induced orofacial nociception in rodents. Male mice were pretreated with ethyl acetate fraction (100, 200 or 400 mg/kg, p.o.), rosmarinic acid (10 or 20 mg/kg, p.o.), morphine (5 mg/kg, i.p.), or vehicle (distilled water + 0.2% Tween 80). Ethyl acetate fraction reduced the nociceptive face-rubbing behavior during the two phase of the formalin test, whereas pretreatment with rosmarinic acid decreased the pain behavior in the second phase. Ethyl acetate fraction produced significant antinociceptive effects in the capsaicin and glutamate tests. This study showed that oral administration of ethyl acetate fraction produced potent antinociceptive effects compared to treatment with rosmarinic acid.

Distinct effects of novel naphtoquinone-based triazoles in human leukaemic cell lines.

OBJECTIVES: The aim of this study was to investigate the cytotoxic effect of new 1,4-naphthoquinone- 1,2,3-triazoles, named C2 to C8 triazole derivatives, towards human cancer cell lines. METHODS: The effect on cell viability was assessed by MTT and propidium iodide assays. The cytotoxic effect of C2 and C3 in K562 and HL-60 cells were analyzed by flow cytometry, DNA fragmentation and reactive oxygen species (ROS) production. Western blot and q-PCR procedures were also performed. KEY FINDINGS: C2 and C3 inhibited both K562 and HL-60 cells growth in a concentration-dependent manner. C2 presented the highest cytotoxic activity with an IC50 of approximately 14 µm and 41 µm for HL-60 and K562 cells, respectively, while being less toxic to normal peripheral blood monocyte cells. Both derivatives induced cellular changes in HL-60 cells, characteristic of apoptosis, such as mitochondrial membrane depolarization, phosphatidylserine externalization, increasing sub-G1 phase, DNA fragmentation, downregulating Bcl-2 protein and upregulating Bax protein. In K562 cells, C2 and C3 induced S-phase arrest of cell cycle, which was associated with upregulation of p21. The effect of these derivatives in HL-60 cells can be related to the ROS intracellular level. CONCLUSION: Taken together our results showed that C2 and C3 triazole derivatives presented the best potential for drug design.

Riparin A, a compound from Aniba riparia, attenuate the inflammatory response by modulation of neutrophil migration.

Inflammation is a local tissue response to attacks characterized by vascular and cellular events, including intense oxidative stress. Riparin A, a compound obtained from Aniba riparia, has been shown to have antioxidant activity and cytotoxicity in vitro. This study was aimed at evaluating the anti-inflammatory effect of riparin A against acute inflammation. The results of our evaluations in various experimental models indicated that riparin A reduced paw edema induced by carrageenan, compound 48/80, histamine, and serotonin. Furthermore, it decreased leukocyte and neutrophil counts, myeloperoxidase activity, thiobarbituric acid reactive substance (TBARS) levels, and cytokine (tumor necrosis factor-α and interleukin-1ß) levels increased by carrageenan-induced peritonitis, and reversed glutathione levels. Riparin A also reduced carrageenan-induced adhesion and rolling of leukocytes on epithelial cells and did not produce gastric-damage as compared with indomethacin. In conclusion, the data show that riparin A reduces inflammatory response by inhibiting vascular and cellular events, modulating neutrophil migration, inhibiting proinflammatory cytokine production, and reducing oxidative stress.

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent.

This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the ß-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol.

Synthesis, leishmanicidal activity and theoretical evaluations of a series of substituted bis-2-hydroxy-1,4-naphthoquinones.

A series of eight substituted bis-2-hydroxy-1,4-naphthoquinone derivatives was synthesized through lawsone condensation with various aromatic and aliphatic aldehydes under mild acidic conditions. The title compounds were evaluated for antileishmanial activity in vitro against Leishmania amazonensis and Leishmania braziliensis promastigotes; six compounds showed good activity without significant toxic effects. The compound with the highest activity was used for an in vivo assay with Leishmania amazonensis.

Synthesis and cytotoxic evaluation of a series of 2-amino-naphthoquinones against human cancer cells.

The cytotoxicity of a series of aminonaphthoquinones resulting from the reaction of suitable aminoacids with 1,4-naphthoquinone was assayed against SF-295 (glioblastoma), MDAMB-435 (breast), HCT-8 (colon), HCT-116 (colon), HL-60 (leukemia), OVCAR-8 (ovarian), NCI-H358M (bronchoalveolar lung carcinoma) and PC3-M (prostate) cancer cells and also against PBMC (peripheral blood mononuclear cells). The results demonstrated that all the synthetic aminonaphthoquinones had relevant cytotoxic activity against all human cancer lines used in this experiment. Five of the compounds showed high cytotoxicity and selectivity against all cancer cell lines tested (IC50 = 0.49 to 3.89 µg·mL-1). The title compounds were less toxic to PBMC, since IC50 was 1.5 to eighteen times higher (IC50 = 5.51 to 17.61 µg·mL-1) than values shown by tumour cell lines. The mechanism of cell growth inhibition and structure-activity relationships remains as a target for future investigations.

Vasorelaxation induced by a new naphthoquinone-oxime is mediated by NO-sGC-cGMP pathway.

It has been established that oximes cause endothelium-independent relaxation in blood vessels. In the present study, the cardiovascular effects of the new oxime 3-hydroxy-4-(hydroxyimino)-2-(3-methylbut-2-enylnaphtalen-1(4H)-one (Oxime S1) derived from lapachol were evaluated. In normotensive rats, administration of Oxime S1 (10, 15, 20 and 30 mg/Kg, i.v.) produced dose-dependent reduction in blood pressure. In isolated aorta and superior mesenteric artery rings, Oxime S1 induced endothelium-independent and concentration-dependent relaxations (10(-8) M to 10(-4) M). In addition, Oxime S1-induced vasorelaxations were attenuated by hydroxocobalamin or methylene blue in aorta and by PTIO or ODQ in mesenteric artery rings, suggesting a role for the nitric oxide (NO) pathway. Additionally, Oxime S1 (30 and 100 µM) significantly increased NO concentrations (13.9 ± 1.6 nM and 17.9 ± 4.1 nM, respectively) measured by nitric oxide microsensors. Furthermore, pre-contraction with KCl (80 mM) prevented Oxime S1-derived vasorelaxation in endothelium-denuded aortic rings. Of note, combined treatment with potassium channel inhibitors also reduced Oxime S1-mediated vasorelaxation suggesting a role for potassium channels, more precisely Kir, Kv and KATP channels. We observed the involvement of BKCa channels in Oxime S1-induced relaxation in mesenteric artery rings. In conclusion, these data suggest that the Oxime S1 induces hypotension and vasorelaxation via NO pathway by activating soluble guanylate cyclase (sGC) and K+ channels.

In vitro antioxidant and cytotoxic activity of some synthetic riparin-derived compounds.

This study aimed to study the in vitro antioxidant activity and cytotoxicity on tumor cells lines of six synthetic substances derived from riparins. All the substances showed antioxidant activity and riparins C, D, E, F presented cell growth inhibition rates greater than 70%, suggesting that these molecules have antitumor properties. These substances also caused greater than 80% releases of cytoplasmic lactate dehydrogenase enzyme (LDH). Although the antioxidant and antitumor properties presented herein require further assessment, the outcomes indicate that these novel riparins are promising biologically active compounds.

1,2,3-triazole-, arylamino- and thio-substituted 1,4-naphthoquinones: potent antitumor activity, electrochemical aspects, and bioisosteric replacement of C-ring-modified lapachones.

1,2,3-Triazole-, arylamino- and thio-substituted naphthoquinones (24, 8, and 2 representatives, respectively) were synthesized in moderate yields and evaluated against several human cancer cell lines (blood, ovarian, breast, central nervous system, colon, and prostate cancers and melanoma), showing, for some of them, IC50 values below 2 µM. The cytotoxic potential of the tested naphthoquinones was also assayed on non-tumor cells such as human peripheral blood mononucluear cells (PBMC) and two murine fibroblast lines (L929 and V79 cells). α-Lapachone- and nor-α-lapachone-based 1,2,3-triazoles and arylamino-substituted naphthoquinones showed potent cytotoxicity against different cancer cell lines. The compounds may represent promising new lead derivatives for anticancer drug development. The electrochemical properties of selected compounds were evaluated in an attempt to correlate them with antitumor activity.

Synthesis and anti-Trypanosoma cruzi activity of naphthoquinone-containing triazoles: electrochemical studies on the effects of the quinoidal moiety.

In our continued search for novel trypanocidal compounds, twenty-six derivatives of para- and ortho-naphthoquinones coupled to 1,2,3-triazoles were synthesized. These compounds were evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease. Compounds 17-24, 28-30 and 36-38 are described herein for the first time. Three of these novel compounds (28-30) were found to be more potent than the standard drug benznidazole, with IC50/24h values between 6.8 and 80.8µM. Analysis of the toxicity to heart muscle cells led to LC50/24h of <125, 63.1 and 281.6µM for 28, 29 and 30, respectively. Displaying a selectivity index of 34.3, compound 30 will be further evaluated in vivo. The electrochemical properties of selected compounds were evaluated in an attempt to find correlations with trypanocidal activity, and it was observed that more electrophilic quinones were generally more potent.

Antileishmanial Phenylpropanoids from the Leaves of Hyptis pectinata (L.) Poit.

Hyptis pectinata, popularly known in Brazil as "sambacaitá" or "canudinho," is an aromatic shrub largely grown in the northeast of Brazil. The leaves and bark are used in an infusion for the treatment of throat and skin inflammations, bacterial infections, pain, and cancer. Analogues of rosmarinic acid and flavonoids were obtained from the leaves of Hyptis pectinata and consisted of two new compounds, sambacaitaric acid (1) and 3-O-methyl-sambacaitaric acid (2), and nine known compounds, rosmarinic acid (3), 3-O-methyl-rosmarinic acid (4), ethyl caffeate (5), nepetoidin A (6), nepetoidin B (7), cirsiliol (8), circimaritin (9), 7-O-methylluteolin (10), and genkwanin (11). The structures of these compounds were determined by spectroscopic methods. Compounds 1-5, and 7 were evaluated in vitro against the promastigote form of L. braziliensis, and the ethanol extract. The hexane, ethyl acetate, and methanol-water fractions were also evaluated. The EtOH extract, the hexane extract, EtOAc, MeOH:H2O fractions; and compounds 1, 2 and 4 exhibited antileishmanial activity, and compound 1 was as potent as pentamidine. In contrast, compounds 3, 5, and 7 did not present activity against the promastigote form of L. braziliensis below 100 µM. To our knowledge, compounds 1 and 2 are being described for the first time.

Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide-alkyne cycloaddition.

Continuing our screening program for novel anti-parasite compounds, we synthesized seven 1,4-naphthoquinones coupled to 1,2,3-triazoles, five nor-ß-lapachone-based 1,2,3-triazoles and ten α-lapachone-based 1,2,3-triazoles. These and other naphthoquinonoid compounds were evaluated for their activity against promastigote forms of antimony-sensitive and -resistant strains of Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis. The toxicity of these compounds to mammalian cells was also examined. The substances were more potent than an antimonial drug, with IC50 values ranging from 1.0 to 50.7 µM. Nor-α-lapachone derivatives showed the highest antileishmanial activity, with selectivity indices in the range of 10-15. These compounds emerged as important leads for further investigation as antileishmanial agents. Additionally, one of these compounds exhibited cross-resistance in Sb-resistant Leishmania and could provide a molecular tool for investigating the multidrug resistance mechanisms in Leishmania parasites.

On the search for potential anti-Trypanosoma cruzi drugs: synthesis and biological evaluation of 2-hydroxy-3-methylamino and 1,2,3-triazolic naphthoquinoidal compounds obtained by click chemistry reactions.

Five 2-hydroxy-3-substituted-aminomethyl naphthoquinones, nine 1,2,3-triazolic para-naphthoquinones, five nor-ß-lapachone-based 1,2,3-triazoles, and several other naphthoquinonoid compounds were synthesized and evaluated against the infective bloodstream form of Trypanosoma cruzi, the etiological agent of Chagas disease, continuing our screening program for new trypanocidal compounds. Among all the substances, 16-18, 23, 25-29 and 30-33 were herein described for the first time and fifteen substances were identified as more potent than the standard drug benznidazole, with IC(50)/24h values in the range of 10.9-101.5 µM. Compounds 14 and 19 with Selectivity Index of 18.9 and 6.1 are important structures for further studies.