13 results on '"Baroni ACM"'
Search Results
2. Neuroprotective Profile of Triazole Grandisin Analogue against Amyloid-Beta Oligomer-Induced Cognitive Impairment.
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Andrade VHB, M Rodrigues EY, Dias NAF, Ferreira GFC, Carvalho DB, das Neves AR, Coronel PMV, Yonekawa MKA, Parisotto EB, Santos EAD, Souza AS, Paredes-Gamero EJ, de Sousa KS, Souza LL, Resstel LBM, Baroni ACM, and Lagatta DC
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- Mice, Male, Animals, Amyloid beta-Peptides metabolism, Memantine pharmacology, Antioxidants pharmacology, Furans pharmacology, Anti-Inflammatory Agents pharmacology, Hippocampus metabolism, Alzheimer Disease pathology, Cognitive Dysfunction chemically induced, Cognitive Dysfunction drug therapy, Lignans pharmacology, Neuroprotective Agents pharmacology
- Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-β oligomers (AβO) in the brain, neuroinflammation, oxidative stress, and cognitive decline. Grandisin, a tetrahydrofuran neolignan, exhibits relevant anti-inflammatory and antioxidant properties. Interestingly, grandisin-based compounds were shown to prevent AβO-induced neuronal death in vitro. However, no study has assessed the effect of these compounds on the AD animal model. This study focuses on a triazole grandisin analogue (TGA) synthesized using simplification and bioisosteric drug design, which resulted in improved potency and solubility compared with the parent compound. This study aimed to investigate the possible in vivo effects of TGA against AβO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AβO (90 μM) or vehicle injections. 24 h after surgery, animals received intraperitoneal treatment with TGA (1 mg/kg) or vehicle, administered on a 14 day schedule. One day after treatment completion, a novel object recognition task (NORT) was performed. Memantine (10 mg/kg) was administered as a positive control. NORT retention sessions were performed on days 8 and 16 after AβO injection. Immediately after retention sessions, animals were euthanized for cortex and hippocampus collection. Specimens were subjected to oxidative stress and cytokine analyses. TGA reduced the level of cortex/hippocampus lipoperoxidation and prevented cognitive impairment in AβO-injected mice. Additionally, TGA reduced tumor necrosis factor (TNF) and interferon-γ (IFN-γ) levels in the hippocampus. By contrast, memantine failed to prevent cortex/hippocampus lipid peroxidation, recognition memory decline, and AβO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AβO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AβO-injected mice. Moreover, TGA exhibited a persistent neuroprotective effect compared to memantine, reflecting an innovative profile of this promising agent against neurodegenerative diseases, such as AD.
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- 2023
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3. 1,4-Diaryl-1,2,3-triazole neolignan-celecoxib hybrids inhibit experimental arthritis induced by zymosan.
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Felipe JL, Bonfá IS, Lossavaro PKMB, Lencina JS, B Carvalho D, Candeloro L, Ferreira GIS, das Neves AR, Souza MIL, Silva-Filho SE, Baroni ACM, and Toffoli-Kadri MC
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- Animals, Celecoxib adverse effects, Zymosan, Hyperalgesia drug therapy, Hydrogen Peroxide, Anti-Inflammatory Agents therapeutic use, Edema drug therapy, Lignans therapeutic use, Arthritis, Experimental chemically induced, Arthritis, Experimental drug therapy, Arthritis, Rheumatoid drug therapy
- Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes cartilage damage. Anti-inflammatories are widely used in the management of RA, but they can have side effects such as gastrointestinal and/or cardiovascular disorders. Studies published by our group showed that the synthesis of hybrid triazole analogs neolignan-celecoxib containing the substituent groups sulfonamide (L15) or carboxylic acid (L18) exhibited anti-inflammatory activity in an acute model of inflammation, inhibited expression of P-selectin related to platelet activation and did not induce gastric ulcer, minimizing the related side effects. In continuation, the present study evaluated the anti-inflammatory effects of these analogs in an experimental model of arthritis and on the functions of one of the important cells in this process, macrophages. Mechanical hyperalgesia, joint edema, leukocyte recruitment to the joint and damage to cartilage in experimental arthritis and cytotoxicity, spread of disease, phagocytic activity and nitric oxide (NO) and hydrogen peroxide production by macrophages were evaluated. Pre-treatment with L15 and L18 reduced mechanical hyperalgesia, joint edema and the influx of leukocytes into the joint cavity after different periods of the stimulus. The histological evaluation of the joint showed that L15 and L18 reduced cartilage damage and there was no formation of rheumatoid pannus. Furthermore, L15 and L18 were non-cytotoxic. The analogs inhibited the spreading, the production of NO and hydrogen peroxide. L15 decreased the phagocytosis. Therefore, L15 and L18 may be potential therapeutic prototypes to treat chronic inflammatory diseases such as RA., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2023
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4. Design, synthesis and antitrypanosomatid activity of 2-nitroimidazole-3,5-disubstituted isoxazole compounds based on benznidazole.
- Author
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Carvalho DB, Costa PAN, Portapilla GB, das Neves AR, Shiguemoto CYK, Pelizaro BI, Silva F, Piranda EM, Arruda CCP, Gaspari PDM, Cardoso IA, Luccas PH, Nonato MC, Lopes NP, de Albuquerque S, and Baroni ACM
- Subjects
- Humans, Isoxazoles chemistry, Structure-Activity Relationship, Cycloaddition Reaction, Antiprotozoal Agents chemistry, Chagas Disease drug therapy, Nitroimidazoles pharmacology, Nitroimidazoles therapeutic use, Trypanosoma cruzi
- Abstract
Chagas disease and leishmaniasis are neglected diseases of high priority as a public health problem. Pharmacotherapy is based on the administration of a few drugs, which exhibit hazardous adverse effects and toxicity to the patients. Thus, the search for new antitrypanosomatid drugs is imperative to overcome the limitations of the treatments. In this work, 46 2-nitroimidazole 3,5-disubstituted isoxazole compounds were synthesized in good yields by [3 + 2] cycloaddition reaction between terminal acetylene (propargyl-2-nitroimidazole) and chloro-oximes. The compounds were non-toxic to LLC-MK2 cells. Compounds 30, 35, and 44 showed in vitro antichagasic activity, 15-fold, 12-fold, and 10-fold, respectively, more active than benznidazole (BZN). Compounds 30, 35, 44, 45, 53, and 61 acted as substrates for the TcNTR enzyme, indicating that this might be one of the mechanisms of action involved in their antiparasitic activity. Piperazine series and 4-monosubstituted compounds were potent against T. cruzi parasites. Besides the in vitro activity observed in compound 45, the in vivo assay showed that the compound only reduced the parasitemia levels by the seventh-day post-infection (77%, p > 0.001) compared to the control group. However, 45 significantly reduced the parasite load in cardiac tissue (p < 0.01) 11 days post-infection. Compounds 49, 52, and 54 showed antileishmanial activity against intracellular amastigotes of Leishmania (L.) amazonensis at the same range as amphotericin B. These findings highlight the antitrypanosomatid properties of 2-nitroimidazole 3,5-disubstituted isoxazole compounds and the possibility in using them as antitrypanosomatid agents in further studies., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest that could in any way influence this work., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
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- 2023
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5. In Vivo Antileishmanial Effect of 3,5-Diaryl-isoxazole Analogues Based on Veraguensin, Grandisin, and Machilin G: A Glance at a Preclinical Study.
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das Neves AR, Carvalho DB, Silva F, Rosalem RF, Pelizaro BI, Castilho PF, Oliveira KMP, Cassemiro NS, Pessatto LR, Paredes-Gamero EJ, Piranda EM, Silva DB, Arruda CCP, and Baroni ACM
- Subjects
- Animals, Mice, Isoxazoles pharmacology, Mice, Inbred BALB C, Lignans pharmacology, Leishmania, Leishmaniasis, Cutaneous drug therapy, Leishmaniasis, Cutaneous pathology, Antiprotozoal Agents pharmacology
- Abstract
New treatment approaches targeting cutaneous leishmaniasis (CL) are required since conventional drugs exhibit limitations due to their several adverse effects and toxicity. In this study, we aimed to evaluate the in vivo intralesional treatment efficacy of five isoxazole derivatives previously synthesized and effective in vitro against intracellular amastigote forms of Leishmania (L.) amazonensis . Among the tested analogues, 7 exhibited relevant in vivo therapeutic effects. The in silico predictions provided interesting information about the toxicity, suggesting the safety of analogue 7 . Experiments performed with Salmonella typhimurium strains (TA98, TA100, and TA102) showed a non-mutagenicity profile of 7 . The treatment of Leishmania -infected BALB/c mice with isoxazole 7 showed remarkably smaller CL lesions and decreased the parasitism (by 98.4%) compared to the control group. Hence, analogue 7 is a promising drug candidate and alternative treatment for CL caused by L. amazonensis .
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- 2023
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6. Repurposing of 5-nitrofuran-3,5-disubstituted isoxazoles: A thriving scaffold to antitrypanosomal agents.
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Carvalho DB, das Neves AR, Portapilla GB, Soares O, Santos LBB, Oliveira JRS, Vianna LS, Judice WAS, Cardoso IA, Luccas PH, Nonato MC, Lopes NP, de Albuquerque S, and Baroni ACM
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- Structure-Activity Relationship, Isoxazoles pharmacology, Isoxazoles chemistry, Drug Repositioning, Trypanosoma cruzi, Nitrofurans pharmacology, Nitrofurans chemistry, Trypanocidal Agents pharmacology, Trypanocidal Agents chemistry
- Abstract
Chagas disease (CD) is a neglected disease caused by the protozoan Trypanosoma cruzi. The two drugs used in the treatment schedules exhibit adverse effects and severe toxicity. Thus, searching for new antitrypanosomal agents is urgent to provide improved treatments to those affected by this disease. 5-Nitrofuran-isoxazole analogs were synthesized by cycloaddition reactions [3+2] between chloro-oximes and acetylenes in satisfactory yields. We analyzed the structure-activity relationship of the analogs based on Hammett's and Hansch's parameters. The 5-nitrofuran-isoxazole analogs exhibited relevant in vitro antitrypanosomal activity against the amastigote forms of T. cruzi. Analog 7s was the trending hit of the series, showing an IC
50 value of 40 nM and a selectivity index of 132.50. A possible explanation for this result may be the presence of an electrophile near the isoxazole core. Moreover, the most active analogs proved to act as an in vitro substrate of type I nitroreductase rather than the cruzain, enzymes commonly investigated in molecular target studies of CD drug discovery. These findings suggest that 5-nitrofuran-isoxazole analogs are promising in the studies of agents for CD treatment., (© 2022 Deutsche Pharmazeutische Gesellschaft.)- Published
- 2023
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7. Green Synthesis of Molecules for the Treatment of Neglected Diseases.
- Author
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Anghinoni JM, Dilelio MC, Shiguemoto CYK, Schumacher RF, Baroni ACM, and Lenardão EJ
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- Humans, Neglected Diseases drug therapy, Chagas Disease drug therapy, Malaria drug therapy
- Abstract
Neglected tropical diseases (NTDs) affect mainly poor and marginalized populations of tropical and subtropical areas in 150 countries. Many of the chemical processes involved in the synthesis of active pharmaceutical ingredients (APIs) are highly polluting and inefficient, both in terms of materials and energy-consuming. In this review, we present the green protocols developed in the last 10 years to access new small molecules with potential applications in the treatment of leishmania, tuberculosis, malaria, and Chagas disease. The use of alternative and efficient energy sources, like microwaves and ultrasound, as well as reactions using green solvents and solvent-free protocols, are discussed in this review., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2023
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8. Anti-inflammatory, ulcerogenic and platelet activation evaluation of novel 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids.
- Author
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Felipe JL, Cassamale TB, Lourenço LD, Carvalho DB, das Neves AR, Duarte RCF, Carvalho MG, Toffoli-Kadri MC, and Baroni ACM
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- Animals, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal chemistry, Anti-Ulcer Agents chemical synthesis, Anti-Ulcer Agents chemistry, Carrageenan, Celecoxib chemistry, Celecoxib pharmacology, Dose-Response Relationship, Drug, Edema chemically induced, Lignans chemistry, Lignans pharmacology, Male, Mice, Molecular Structure, Peritonitis chemically induced, Platelet Activation drug effects, Platelet Aggregation Inhibitors chemical synthesis, Platelet Aggregation Inhibitors chemistry, Rats, Structure-Activity Relationship, Triazoles chemistry, Triazoles pharmacology, Ulcer chemically induced, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Anti-Ulcer Agents pharmacology, Edema drug therapy, Peritonitis drug therapy, Platelet Aggregation Inhibitors pharmacology, Ulcer drug therapy
- Abstract
This study reports the synthesis of novel neolignans-celecoxib hybrids and the evaluation of their biological activity. Analogs8-13(L13-L18) exhibited anti-inflammatory activity, inhibited glycoprotein expression (P-selectin) related to platelet activation, and were considered non- ulcerogenic in the animal model, even with the administration of 10 times higher than the dose used in reference therapy. In silico drug-likeness showed that the analogs are compliant with Lipinski's rule of five. A molecular docking study showed that the hybrids8-13(L13-L18) fitted similarly with celecoxib in the COX-2 active site. According to this data, it is possible to infer that extra hydrophobic interactions and the hydrogen interactions with the triazole core may improve the selectivity towards the COX-2 active site. Furthermore, the molecular docking study with P-selectin showed the binding affinity of the analogs in the active site, performing important interactions with amino acid residues such as Tyr 48. Whereas the P-selectin is a promising target to the design of new anti-inflammatory drugs with antithrombotic properties, a distinct butterfly-like structure of 1,4-diaryl-1,2,3-triazole neolignan-celecoxib hybrids synthesized in this work may be a safer alternative to the traditional COX-2 inhibitors., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2022
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9. Dehydration of D-fructose to 5-hydroxymethyl-2-furfural in DMSO using a hydrophilic sulfonated silica catalyst in a process promoted by microwave irradiation.
- Author
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Barbosa SL, de S Freitas M, Dos Santos WTP, Nelson DL, Klein SI, Clososki GC, Caires FJ, Baroni ACM, and Wentz AP
- Abstract
SiO
2 -SO3 H, with a surface area of 115 m2 /g, pore volumes of 0.38 cm3 g-1 and 1.32 mmol H+ /g, was used as a 10% w/w catalyst for the preparation of 5-hydroxymethyl-2-furfural (HMF) from fructose. A conversion of 100% was achieved in a microwave reactor during 10 min at 150 °C in DMSO, with 100% selectivity for HMF, at a molar ratio of fructose: DMSO equal to 1:56. The catalyst could be re-used three times.- Published
- 2021
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10. Synthesis and Antitrypanosomal Activity of 1,4-Disubstituted Triazole Compounds Based on a 2-Nitroimidazole Scaffold: a Structure-Activity Relationship Study.
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Assunção ELF, Carvalho DB, das Neves AR, Kawasoko Shiguemotto CY, Portapilla GB, de Albuquerque S, and Baroni ACM
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- Animals, Cells, Cultured, Macaca mulatta, Molecular Structure, Nitroimidazoles chemistry, Parasitic Sensitivity Tests, Triazoles chemical synthesis, Triazoles chemistry, Trypanocidal Agents chemical synthesis, Trypanocidal Agents chemistry, Nitroimidazoles pharmacology, Triazoles pharmacology, Trypanocidal Agents pharmacology, Trypanosoma cruzi drug effects
- Abstract
Chagas disease affects 6-8 million people worldwide, remaining a public health concern. Toxicity, several adverse effects and inefficiency in the chronic stage of the disease are the major challenges regarding the available treatment protocols. This work involved the synthesis of twenty-two 1,4-disubstituted-1,2,3-triazole analogues of benznidazole (BZN), by using a click chemistry strategy. Analogues were obtained in moderate to good yields (40-97 %). Antitrypanosomal activity was evaluated against the amastigote forms of Trypanosoma cruzi. Compound 8 a (4-(2-nitro-1H-imidazol-1-yl)methyl)-1-phenyl-1H-1,2,3-triazole) without substituents on phenyl ring showed similar biological activity to BZN (IC
50 =3.0 μM, SI>65.3), with an IC50 =3.1 μM and SI>64.5. Compound 8 o (3,4-di-OCH3 -Ph) with IC50 = 0.65 μM was five-fold more active than BZN, and showed an excellent selectivity index (SI>307.7). Compound 8 v (3-NO2 , 4-CH3 -Ph) with IC50 =1.2 μM and relevant SI>166.7, also exhibited higher activity than BZN. SAR analysis exhibited a pattern regarding antitrypanosomal activity relative to BZN, in compounds with electron-withdrawing groups (Hammett σ+) at position 3, and electron-donating groups (Hammett σ-) at position 4, as observed in 8 o and 8 v. Further research might explore in vivo antitrypanosomal activity of promising analogues 8 a, 8 o, and 8 v. Overall, this study indicates that approaches such as the bioisosteric replacement of amide group by 1,2,3-triazole ring, the use of click chemistry as a synthesis strategy, and design tools like Craig-plot and Topliss tree are promising alternatives to drug discovery., (© 2020 Wiley-VCH GmbH.)- Published
- 2020
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11. Design, synthesis, antileishmanial, and antifungal biological evaluation of novel 3,5-disubstituted isoxazole compounds based on 5-nitrofuran scaffolds.
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Trefzger OS, Barbosa NV, Scapolatempo RL, das Neves AR, Ortale MLFS, Carvalho DB, Honorato AM, Fragoso MR, Shuiguemoto CYK, Perdomo RT, Matos MFC, Chang MR, Arruda CCP, and Baroni ACM
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- Antifungal Agents chemical synthesis, Antifungal Agents chemistry, Antiprotozoal Agents chemical synthesis, Antiprotozoal Agents chemistry, Dose-Response Relationship, Drug, Isoxazoles chemical synthesis, Isoxazoles chemistry, Microbial Sensitivity Tests, Molecular Structure, Nitrofurans chemistry, Parasitic Sensitivity Tests, Structure-Activity Relationship, Antifungal Agents pharmacology, Antiprotozoal Agents pharmacology, Candida drug effects, Drug Design, Isoxazoles pharmacology, Leishmania drug effects, Nitrofurans pharmacology
- Abstract
Nineteen 3,5-disubstituted-isoxazole analogs were synthesized based on nitrofuran scaffolds, by a [3 + 2] cycloaddition reaction between terminal acetylenes and 5-nitrofuran chloro-oxime. The compounds were obtained in moderate to very good yields (45-91%). The antileishmanial activity was assayed against the promastigote and amastigote forms of Leishmania (Leishmania) amazonensis. Alkylchlorinated compounds 14p-r were active on both the promastigote and amastigote forms, with emphasis on compound 14p, which showed strong activity against the amastigote form (IC
50 = 0.6 μM and selectivity index [SI] = 5.2). In the alkyl series, compound 14o stands out with an IC50 = 8.5 μM and SI = 8.0 on the amastigote form. In the aromatic series, the most active compounds were those containing electron-donor groups, such as trimethoxy isoxazole 14g (IC50 = 1.2 μM and SI = 20.2); compound 14h, with IC50 = 7.0 μM and SI = 6.1; and compound 14j containing the 4-SCH3 group, with IC50 = 5.7 μM and SI = 10.2. In addition, the antifungal activity of 19 nitrofuran isoxazoles was evaluated against five strains of Candida (C. albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. glabrata). Eleven isoxazole derivatives were active against C. parapsilosis, and compound 14o was found to be the most active (minimal inhibitory concentration [MIC] = 3.4 μM) for this strain. Compound 14p was active against all the strains tested, with an MIC = 17.5 μM for C. glabrata, lower than that of the fluconazole used as the reference drug., (© 2019 Deutsche Pharmazeutische Gesellschaft.)- Published
- 2020
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12. Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania (Leishmania) amazonensis: A structure-activity relationship comparative study with triazole-neolignan-based compounds.
- Author
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das Neves AR, Trefzger OS, Barbosa NV, Honorato AM, Carvalho DB, Moslaves IS, Kadri MCT, Yoshida NC, Kato MJ, Arruda CCP, and Baroni ACM
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- Animals, Antiprotozoal Agents chemistry, Drug Design, Female, Inhibitory Concentration 50, Isoxazoles pharmacology, Leishmania growth & development, Life Cycle Stages drug effects, Macrophages, Peritoneal parasitology, Mice, Mice, Inbred BALB C, Nitric Oxide metabolism, Structure-Activity Relationship, Antiprotozoal Agents pharmacology, Furans chemistry, Isoxazoles chemistry, Leishmania drug effects, Lignans chemistry, Triazoles chemistry
- Abstract
Isoxazole analogues derived from the neolignans veraguensin, grandisin, and machilin G were previously synthesized with different substitution patterns through the bioisosterism strategy. These compounds were tested on intracellular amastigotes of Leishmania (Leishmania) amazonensis; the derivatives proved to be active against intracellular amastigotes, with IC
50 values ranging from 0.4 to 25 μM. The most active analogues were 4', 14', 15', and 18', with IC50 values of 0.9, 0.4, 0.7, and 1.4 μM, respectively, showing high selectivity indexes (SI = 277.0; 625.0; 178.5 and 357.1). Overall, the isoxazole analogues did not induce nitric oxide (NO) production by infected cells; there was no evidence that NO influences the antileishmanial mechanism of action, except for compound 4'. Trimethoxy groups as substituents seemed to be critical for antileishmanial activity. The SAR study demonstrated that the isoxazole compounds were more active than 1,2,3-triazole compounds with the same substitution pattterns, demonstrating the importance of the bioisosterism strategy in drug design., (© 2019 John Wiley & Sons Ltd.)- Published
- 2019
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13. Design, synthesis and antitrypanosomatid activities of 3,5-diaryl-isoxazole analogues based on neolignans veraguensin, grandisin and machilin G.
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Trefzger OS, das Neves AR, Barbosa NV, Carvalho DB, Pereira IC, Perdomo RT, Matos MFC, Yoshida NC, Kato MJ, de Albuquerque S, Arruda CCP, and Baroni ACM
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- Animals, Antiprotozoal Agents chemical synthesis, Antiprotozoal Agents pharmacology, Cell Survival drug effects, Inhibitory Concentration 50, Isoxazoles chemical synthesis, Isoxazoles pharmacology, Leishmania drug effects, Mice, NIH 3T3 Cells, Structure-Activity Relationship, Trypanosoma cruzi drug effects, Antiprotozoal Agents chemistry, Drug Design, Furans chemistry, Isoxazoles chemistry, Lignans chemistry
- Abstract
Using bioisosterism as a medicinal chemistry tool, 16 3,5-diaryl-isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G were synthesized via 1,3-dipolar cycloaddition reactions, with yields from 43% to 90%. Antitrypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15, 16 and 19 with IC
50 values of 2.0, 3.3 and 9.5 μM against L. amazonensis and IC50 values of 1.2, 2.1 and 6.4 μM on L. braziliensis, respectively. All compounds were noncytotoxic, showing lower cytotoxicity (>250 μM) than pentamidine (78.9 μM). Regarding the structure-activity relationship (SAR), the methylenedioxy group was essential to antileishmanial activity against promastigotes. Replacement of the tetrahydrofuran nucleus by an isoxazole core improved the antileishmanial activity., (© 2018 John Wiley & Sons A/S.)- Published
- 2019
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