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

Neves, Amarith R. das; Trefzger, Ozildéia S.; Barbosa, Natália V.; Honorato, Antônio M.; Carvalho, Diego B.; Moslaves, Iluska Senna Bonfá; Toffoli-Kadri, Mônica Cristina; Yoshida, Norimasa; Kato, Massuo Jorge; Arruda, Carla Cardozo Pinto de; Baroni, Adriano C. M.

doi:10.1111/cbdd.13609

Cited by 19 publications

(21 citation statements)

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“…In the search for new compounds with antileishmanial activity, our research group has synthesized a class of molecules derived from neolignans veraguensin 1, grandisin 2, and machilin G 3, through bioisosteric replacement of the tetrahydrofuran ring by the 1,2,3-triazole core ( Figure 1) [2]. Neolignans are privileged structures in medicinal chemistry since they have different biological activities, among them the antileishmanial [3][4][5][6]. Among 16 synthesized compounds, the triazole hybrid 6 (LASQUIM 25) derived from grandisin 2 and machilin G 3 was highly active against both the flagellated and the intracellular target forms of Leishmania (Leishmania) amazonensis [2,3].…”

Section: Introductionmentioning

confidence: 99%

A Triazole Hybrid of Neolignans as a Potential Antileishmanial Agent by Triggering Mitochondrial Dysfunction

et al. 2019

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In the search for new compounds with antileishmanial activity, we synthesized a triazole hybrid analogue of the neolignans grandisin and machilin G (LASQUIM 25), which was previously found highly active against both promastigotes and intracellular amastigote forms of Leishmania amazonensis. In this work, we investigated the leishmanicidal effects of LASQUIM 25 to identify the mechanisms involved in the cell death of L. amazonensis promastigotes. Transmission electron microscopy (TEM) analysis showed marked effects of LASQUIM 25 (IC50 = 7.2 µM) on the morphology of promastigote forms, notably on mitochondria. The direct action of the triazole derivative on the parasite was noticed over time from 2 h to 48 h, and cells displayed several ultrastructural alterations characteristic of apoptotic cells. Also, flow cytometric analysis (FACS) after TMRE staining detected changes in mitochondrial membrane potential after LASQUIM 25 treatment (64.83% labeling versus 83.38% labeling in nontreated cells). On the other hand, FACS after PI staining in 24 h-treatment showed a slight alteration in the integrity of the cell membrane, a necrotic event (16.76% necrotic cells versus 3.19% staining in live parasites). An abnormal secretion of lipids was observed, suggesting an exocytic activity. Another striking finding was the presence of autophagy-related lysosome-like vacuoles, suggesting an autophagic cell death that may arise as consequence of mitochondrial stress. Taken together, these results suggest that LASQUIM 25 leishmanicidal mechanisms involve some degree of mitochondrial dysregulation, already evidenced by the treatment with the IC50 of this compound. This effect may be due to the presence of a methylenedioxy group originated from machilin G, whose toxicity has been associated with the capacity to generate electrophilic intermediates.

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Section: Introductionmentioning

confidence: 99%

A Triazole Hybrid of Neolignans as a Potential Antileishmanial Agent by Triggering Mitochondrial Dysfunction

et al. 2019

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“…For the synthesis of aryl acetylenes, first, compounds with aromatic substituents were prepared. Aryl acetylenes containing withdrawing and donor electron groups were synthesized by the Sonogashira cross‐coupling reaction between 2‐methyl‐3‐butyn‐2‐ol and aryl bromides or iodides using Pd(PPh 3 ) 2 Cl 2 , CuI in the presence of Et 3 N as the reaction base (Scheme , procedure a) . Subsequently, the compounds were submitted to retro‐Favorski reaction with KOH and the terminal acetylenes 22b–i were obtained in good yields (Scheme , procedure b) .…”

Section: Resultsmentioning

confidence: 99%

“…Phenylacetylene was obtained as a commercially available reagent. Ethynyl‐1,2,3‐trimethoxybenzene 22i was synthesized by the Corey–Fuchs procedure (Scheme , procedures c and d) . The compound 25 was prepared through Sonogashira cross‐coupling reaction between aryl iodide 23 and ethynyltrimethylsilane 24 (Scheme , procedure e) …”

Section: Resultsmentioning

confidence: 99%

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Design, synthesis, antileishmanial, and antifungal biological evaluation of novel 3,5‐disubstituted isoxazole compounds based on 5‐nitrofuran scaffolds

Trefzger

Barbosa

Scapolatempo

et al. 2019

Archiv der Pharmazie

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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 IC 50 = 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 (IC 50 = 1.2 μM and SI = 20.2); compound 14h, with IC 50 = 7.0 μM and SI = 6.1; and compound 14j containing the 4-SCH 3 group, with IC 50 = 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. K E Y W O R D S5-nitrofuran scaffolds, antifungal activity, antileishmanial activity, drug design, isoxazole core *Ozildéia S. Trefzger, Natália V. Barbosa, and Renata L. Scapolatempo contributed equally to this work.

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“…Furthermore, isoxazole derivatives possess various biological activities such as anti-inflammatory [ 21 ], antileishmanial [ 22 ], trypanocidal [ 23 ], antimicrobial [ 24 , 25 ] and antiviral ( Figure 2 , 2-C [ 26 ], 2-D [ 27 ]).…”

Section: Introductionmentioning

confidence: 99%

Design, Microwave-Assisted Synthesis and In Silico Prediction Study of Novel Isoxazole Linked Pyranopyrimidinone Conjugates as New Targets for Searching Potential Anti-SARS-CoV-2 Agents

et al. 2021

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A series of novel naphthopyrano[2,3-d]pyrimidin-11(12H)-one containing isoxazole nucleus 4 was synthesized under microwave irradiation and classical conditions in moderate to excellent yields upon 1,3-dipolar cycloaddition reaction using various arylnitrile oxides under copper(I) catalyst. A one-pot, three-component reaction, N-propargylation and Dimroth rearrangement were used as the key steps for the preparation of the dipolarophiles3. The structures of the synthesized compounds were established by 1H NMR, 13C NMR and HRMS-ES means. The present study aims to also predict the theoretical assembly of the COVID-19 protease (SARS-CoV-2 Mpro) and to discover in advance whether this protein can be targeted by the compounds 4a–1 and thus be synthesized. The docking scores of these compounds were compared to those of the co-crystallized native ligand inhibitor (N3) which was used as a reference standard. The results showed that all the synthesized compounds (4a–l) gave interesting binding scores compared to those of N3 inhibitor. It was found that compounds 4a, 4e and 4i achieved greatly similar binding scores and modes of interaction than N3, indicating promising affinity towards SARS-CoV-2 Mpro. On the other hand, the derivatives 4k, 4h and 4j showed binding energy scores (−8.9, −8.5 and −8.4 kcal/mol, respectively) higher than the Mpro N3 inhibitor (−7.0 kcal/mol), revealing, in their turn, a strong interaction with the target protease, although their interactions were not entirely comparable to that of the reference N3.

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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

Cited by 19 publications

References 32 publications

A Triazole Hybrid of Neolignans as a Potential Antileishmanial Agent by Triggering Mitochondrial Dysfunction

A Triazole Hybrid of Neolignans as a Potential Antileishmanial Agent by Triggering Mitochondrial Dysfunction

Design, synthesis, antileishmanial, and antifungal biological evaluation of novel 3,5‐disubstituted isoxazole compounds based on 5‐nitrofuran scaffolds

Design, Microwave-Assisted Synthesis and In Silico Prediction Study of Novel Isoxazole Linked Pyranopyrimidinone Conjugates as New Targets for Searching Potential Anti-SARS-CoV-2 Agents

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