Synthesis and antimycobacterial activity of (+)‐usnic acid conjugates

Cirillo, Daniela María; Borroni, Emanuele; Festoso, Irene; Monti, Diego; Romeo, Sergio; Mazier, Dominique; Verotta, Luisellá

doi:10.1002/ardp.201800177

Cited by 9 publications

(4 citation statements)

References 44 publications

(56 reference statements)

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“…The secondary metabolite is reported to have severe hepatotoxicity; however years of research have now led to derivatives with improved pharmacological and lower toxicity profiles. Recent reports involved modification of the C-2 group into enaminone and hydrazonyl functionalities, leading to derivatives ( 3 , 4 , Figure ) that targeted various diseases such as cancer, viral and mycobacterial infections, wound healing, and malaria …”

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confidence: 99%

Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents

Bangalore¹,

Krishna

Bollikanda³

et al. 2019

J. Nat. Prod.

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Usnic acid, a product of secondary metabolism in lichens, has displayed a broad range of biological properties such as antitumor, antimicrobial, antiviral, anti-inflammatory, and insecticidal activities. Interested by these pharmacological activities and to tap into its potential, we herein present the synthesis and biological evaluation of new usnic acid enaminone-conjugated 1,2,3triazoles 10−44 as antimycobacterial agents. (+)-Usnic acid was condensed with propargyl amine to give usnic acid enaminone 8 with a terminal ethynyl moiety. It was further reacted with various azides A1−A35 under copper catalysis to give triazoles 10−44 in good yields. Among the synthesized compounds, saccharin derivative 36 proved to be the most active analogue, inhibiting Mycobacterium tuberculosis (Mtb) at an MIC value of 2.5 μM. Analogues 16 and 27, with 3,4-difluorophenacyl and 2-acylnaphthalene units, respectively, inhibited Mtb at MIC values of 5.4 and 5.3 μM, respectively. Among the tested Gram-positive and Gram-negative bacteria, the new derivatives were active on Bacillus subtilis, with compounds 18 [3-(trifluoromethyl)phenacyl] and 29 (N-acylmorpholinyl) showing inhibitory concentrations of 41 and 90.7 μM, respectively, while they were inactive on the other tested bacterial strains. Overall, the study presented here is useful for converting natural (+)-usnic acid into antitubercular and antibacterial agents via incorporation of enaminone and 1,2,3-triazole functionalities.

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confidence: 99%

Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents

Bangalore¹,

Krishna

Bollikanda³

et al. 2019

J. Nat. Prod.

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“… Chemical modifications of the main core scaffold of UA apported in the derivatives described in the literature [ 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. …”

Section: Figurementioning

confidence: 99%

“…Moreover, UA was exploited as a useful intermediate to obtain potent analogs with improved biological profiles [ 11 , 12 , 13 , 14 ]. The chemical modifications introduced in the main scaffold of UA are resumed in Figure 2 [ 13 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. All these chemical modifications preserve the stereochemistry of the UA used as starting material.…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Extraction and HPLC-UV-CD Determination of (S)-usnic Acid in Cladonia foliacea

et al. 2021

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During the years, many usnic acid (UA) conjugates have been synthesized to obtain potent endowed with biological properties. Since (S)-UA is less abundant in nature than (R)-enantiomer, it is difficult to source, thus precluding a deeper investigation. Among the lichens producing UA, Cladonia foliacea is a valuable (S)-UA source. In the present work, we report on a rapid HPLC-UV/PAD-CD protocol suitable for the analysis and the identification of the main secondary metabolites present in C. foliacea extract. Best results were achieved using XBridge Phenyl column and acetonitrile and water, which were both added with formic acid as mobile phase in gradient elution. By combining analytical, spectroscopical, and chiroptical analysis, the most abundant analyte was unambiguously identified as (S)-UA. Accordingly, a versatile microwave-assisted extractive (MAE) protocol, assisted by a design of experiment (DoE), to quantitatively recover (S)-UA was set up. The best result in terms of UA extraction yield was obtained using ethanol and heating at 80 °C under microwave irradiation for 5 min. Starting from 100 g of dried C. foliacea, 420 mg of (S)-UA were achieved. Thus, our extraction method resulted in a suitable protocol to produce (S)-UA from C. foliacea for biological and pharmaceutical investigation or commercial purposes.

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“…This compound was proposed to serve as a food supplement for weight loss, although hepatotoxic effects also were reported (Hsu et al ., ; Sonko et al ., ; Yellapu et al ., ). Nevertheless, usnic acid was shown to exhibit many other beneficial properties, such as being antiviral against hepatitis C and influenza viruses (Shtro et al ., , ; Wei et al ., ), antibacterial against Mycobacterium tuberculosis (Ramos & Almeida da Silva, ; Cirillo et al ., ) and Gram‐positive bacteria including Staphylococcus aureus (Francolini et al ., ; Paudel et al ., ; Pompilio et al ., ; Tozatti et al ., ), anti‐protozoal (Sussmann et al ., ), anti‐helmintic (Araújo et al ., ), anti‐mitotic (al‐Bekairi et al ., ; Cardarelli et al ., ), anti‐inflammatory (Vijayakumar et al ., ), analgesic (Okuyama et al ., ), anti‐cancer (Yang et al ., ) and herbicidal (Romagni et al ., ). Moreover, the compound absorbs UV light making it a potential ingredient in sunscreen products (Legouin et al ., ).…”

Section: Introductionmentioning

confidence: 99%

A facile in vivo procedure to analyze metabolic pathways in intact lichens

et al. 2019

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Lichen secondary metabolites show important biological activities as well as pharmaceutical and chemotaxonomic potential. In order to utilize such substances of interest, detailed knowledge of their biosynthetic pathways is essential. 13 CO 2 -pulse/chase experiments using intact thalli of the lichen Usnea dasopoga resulted in multiple 13 C-labeled isotopologs in amino acids, but not in the dibenzofuran derivative usnic acidone of the best-studied lichen metabolites, with considerable and renewed interest for pharmaceutical and lifestyle applications.Spraying an aqueous solution of [U-13 C 6 ]glucose onto the thalli of U. dasopoga afforded a specific mixture of multiple 13 C-labeled isotopologs in usnic acid. One-and two-dimensional NMR analysis of the crude lichen extract corroborated the polyketide biosynthetic pathway via methylphloroacetophenone but not via phloroacetophenone.With usnic acid as an exemplar, we provide proof-of-principle experiments that can be used in general to study metabolic pathways and fluxes in intact lichens.

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Synthesis and antimycobacterial activity of (+)‐usnic acid conjugates

Cited by 9 publications

References 44 publications

Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents

Usnic Acid Enaminone-Coupled 1,2,3-Triazoles as Antibacterial and Antitubercular Agents

Microwave-Assisted Extraction and HPLC-UV-CD Determination of (S)-usnic Acid in Cladonia foliacea

A facile in vivo procedure to analyze metabolic pathways in intact lichens

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