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1.
J Med Chem ; 67(4): 2584-2601, 2024 02 22.
Artículo en Inglés | MEDLINE | ID: mdl-38305199

RESUMEN

A series of 28 compounds, 3-nitro-1H-1,2,4-triazole, were synthesized by click-chemistry with diverse substitution patterns using medicinal chemistry approaches, such as bioisosterism, Craig-plot, and the Topliss set with excellent yields. Overall, the analogs demonstrated relevant in vitro antitrypanosomatid activity. Analog 15g (R1 = 4-OCF3-Ph, IC50 = 0.09 µM, SI = >555.5) exhibited an outstanding antichagasic activity (Trypanosoma cruzi, Tulahuen LacZ strain) 68-fold more active than benznidazole (BZN, IC50 = 6.15 µM, SI = >8.13) with relevant selectivity index, and suitable LipE = 5.31. 15g was considered an appropriate substrate for the type I nitro reductases (TcNTR I), contributing to a likely potential mechanism of action for antichagasic activity. Finally, 15g showed nonmutagenic potential against Salmonella typhimurium strains (TA98, TA100, and TA102). Therefore, 3-nitro-1H-1,2,4-triazole 15g is a promising antitrypanosomatid candidate for in vivo studies.


Asunto(s)
Enfermedad de Chagas , Leishmaniasis , Tripanocidas , Trypanosoma cruzi , Humanos , Relación Estructura-Actividad , Enfermedad de Chagas/tratamiento farmacológico , Triazoles/química
2.
ACS Chem Neurosci ; 14(24): 4298-4310, 2023 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-38048522

RESUMEN

Alzheimer's disease (AD) is a neurodegenerative disorder caused by accumulation of amyloid-ß oligomers (AßO) 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 AßO-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 AßO-induced AD. Male C57/Bl6 mice underwent stereotaxic intracerebroventricular AßO (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 AßO 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 AßO-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 AßO-induced increases in TNF and IFN-γ levels in the hippocampus. Thus, memantine was unable to avoid the AßO-induced persistent cognitive impairment. The results showed that TGA may prevent memory impairment by exerting antioxidant and anti-inflammatory effects in AßO-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.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Lignanos , Fármacos Neuroprotectores , Ratones , Masculino , Animales , Péptidos beta-Amiloides/metabolismo , Memantina/farmacología , Antioxidantes/farmacología , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Lignanos/farmacología , Furanos/farmacología , Antiinflamatorios/farmacología , Fármacos Neuroprotectores/farmacología , Hipocampo/metabolismo
3.
Eur J Med Chem ; 260: 115451, 2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-37573209

RESUMEN

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.


Asunto(s)
Antiprotozoarios , Enfermedad de Chagas , Nitroimidazoles , Trypanosoma cruzi , Humanos , Antiprotozoarios/química , Enfermedad de Chagas/tratamiento farmacológico , Isoxazoles/química , Nitroimidazoles/farmacología , Nitroimidazoles/uso terapéutico , Relación Estructura-Actividad , Reacción de Cicloadición
4.
ACS Infect Dis ; 9(5): 1150-1159, 2023 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-37103973

RESUMEN

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.


Asunto(s)
Antiprotozoarios , Leishmania , Leishmaniasis Cutánea , Lignanos , Animales , Ratones , Isoxazoles/farmacología , Lignanos/farmacología , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/patología , Antiprotozoarios/farmacología , Ratones Endogámicos BALB C
5.
Arch Pharm (Weinheim) ; 356(4): e2200472, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36534890

RESUMEN

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 IC50 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.


Asunto(s)
Nitrofuranos , Tripanocidas , Trypanosoma cruzi , Relación Estructura-Actividad , Isoxazoles/farmacología , Isoxazoles/química , Reposicionamiento de Medicamentos , Nitrofuranos/farmacología , Nitrofuranos/química , Tripanocidas/farmacología , Tripanocidas/química
6.
Bioorg Chem ; 119: 105485, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34959176

RESUMEN

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.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antiulcerosos/farmacología , Edema/tratamiento farmacológico , Peritonitis/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Úlcera/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antiulcerosos/síntesis química , Antiulcerosos/química , Carragenina , Celecoxib/química , Celecoxib/farmacología , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Lignanos/química , Lignanos/farmacología , Masculino , Ratones , Estructura Molecular , Peritonitis/inducido químicamente , Activación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/química , Ratas , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , Úlcera/inducido químicamente
7.
ChemMedChem ; 15(21): 2019-2028, 2020 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-32729242

RESUMEN

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 (IC50 =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.


Asunto(s)
Nitroimidazoles/farmacología , Triazoles/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Células Cultivadas , Macaca mulatta , Estructura Molecular , Nitroimidazoles/química , Pruebas de Sensibilidad Parasitaria , Triazoles/síntesis química , Triazoles/química , Tripanocidas/síntesis química , Tripanocidas/química
8.
Arch Pharm (Weinheim) ; 353(2): e1900241, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31840866

RESUMEN

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 (IC50 = 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.


Asunto(s)
Antifúngicos/farmacología , Antiprotozoarios/farmacología , Candida/efectos de los fármacos , Diseño de Fármacos , Isoxazoles/farmacología , Leishmania/efectos de los fármacos , Nitrofuranos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Isoxazoles/síntesis química , Isoxazoles/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Nitrofuranos/química , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad
9.
Chem Biol Drug Des ; 94(6): 2004-2012, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31444858

RESUMEN

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 IC50 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.


Asunto(s)
Antiprotozoarios/farmacología , Furanos/química , Isoxazoles/química , Leishmania/efectos de los fármacos , Lignanos/química , Triazoles/química , Animales , Antiprotozoarios/química , Diseño de Fármacos , Femenino , Concentración 50 Inhibidora , Isoxazoles/farmacología , Leishmania/crecimiento & desarrollo , Estadios del Ciclo de Vida/efectos de los fármacos , Macrófagos Peritoneales/parasitología , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Relación Estructura-Actividad
10.
Chem Biol Drug Des ; 93(3): 313-324, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30354012

RESUMEN

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 IC50 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.


Asunto(s)
Antiprotozoarios/química , Diseño de Fármacos , Furanos/química , Isoxazoles/química , Lignanos/química , Animales , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Supervivencia Celular/efectos de los fármacos , Concentración 50 Inhibidora , Isoxazoles/síntesis química , Isoxazoles/farmacología , Leishmania/efectos de los fármacos , Ratones , Células 3T3 NIH , Relación Estructura-Actividad , Trypanosoma cruzi/efectos de los fármacos
11.
Molecules ; 21(6)2016 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-27331807

RESUMEN

Sixteen 1,4-diaryl-1,2,3-triazole compounds 4-19 derived from the tetrahydrofuran neolignans veraguensin 1, grandisin 2, and machilin G 3 were tested against Leishmania (Leishmania) amazonensis intracellular amastigotes. Triazole compounds 4-19 were synthetized via Click Chemistry strategy by 1,3-dipolar cycloaddition between terminal acetylenes and aryl azides containing methoxy and methylenedioxy groups as substituents. Our results suggest that most derivatives were active against intracellular amastigotes, with IC50 values ranging from 4.4 to 32.7 µM. The index of molecular hydrophobicity (ClogP) ranged from 2.8 to 3.4, reflecting a lipophilicity/hydrosolubility rate suitable for transport across membranes, which may have resulted in the potent antileishmanial activity observed. Regarding structure-activity relationship (SAR), compounds 14 and 19, containing a trimethoxy group, were the most active (IC50 values of 5.6 and 4.4 µM, respectively), with low cytotoxicity on mammalian cells (SI = 14.1 and 10.6). These compounds induced nitric oxide production by the host macrophage cells, which could be suggested as the mechanism involved in the intracellular killing of parasites. These results would be useful for the planning of new derivatives with higher antileishmanial activities.


Asunto(s)
Furanos/química , Leishmaniasis/tratamiento farmacológico , Lignanos/química , Animales , Antiprotozoarios/administración & dosificación , Antiprotozoarios/química , Furanos/administración & dosificación , Humanos , Leishmania/efectos de los fármacos , Leishmania/patogenicidad , Leishmaniasis/parasitología , Lignanos/administración & dosificación , Macrófagos/efectos de los fármacos , Óxido Nítrico/química , Relación Estructura-Actividad
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