Synthesis of a Potent Antimalarial Agent through Natural Products Conjugation

Bruno, Michela; Trucchi, Beatrice; Monti, Diego; Romeo, Sergio; Kaiser, Marcel; Verotta, Luisellá

doi:10.1002/cmdc.201200503

Cited by 17 publications

(18 citation statements)

References 42 publications

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“…Furthermore, we synthesized conjugates obtained by addition of aromatic and heterocyclic hydrazines and hydrazides ( PS1 , PS10 , PS17 , PS18 , PS19 ) (Figure ). Usnic acid underwent addition of nitrogen nucleophilic systems in neutral or basic conditions, as described in detail previously . The synthesis and antitubercular activity of conjugate PS19 has been recently described elsewhere …”

Section: Resultsmentioning

confidence: 99%

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

Cirillo

Borroni

Festoso

et al. 2018

Archiv der Pharmazie

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New therapeutics are urgently needed to fight tuberculosis and mycobacteria-related diseases that are a major health hazard especially in poor countries. Natural products have been the source of important antitubercular drugs in the past and still need to receive attention as a potent reservoir of chemical structures. Fifteen known and two new (+)-usnic acid (a benzofurandione formerly isolated from lichens) enamines and hydrazones are here described and tested against sensitive and multidrug-resistant strains of mycobacteria. Among several (+)-usnic acid conjugates, PS14 and PS18 showed potent activity against both susceptible and resistant Mycobacterium tuberculosis strains (MIC values of 1-32 and 2-32 mg/L, respectively) comparable with MIC of other antitubercular drugs already in use for tuberculosis treatment.

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Section: Resultsmentioning

confidence: 99%

“…Synthetic procedures for compounds PS1 , PS4 , PS5 , PS7 , PS10 , PS12 , PS13 , PS14 , PS18 are reported in Ref. while for compounds PS2 , PS6 , PS8 , PS9 , enaminousnic ( BT51 ) are reported in Ref. .…”

Section: Methodsmentioning

confidence: 99%

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

Cirillo

Borroni

Festoso

et al. 2018

Archiv der Pharmazie

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“…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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“…7 The chemical is unique to lichens of the widely distributed genus Usnea , has been extensively studied, and is used in a range of therapeutic capacities, including wound healing, as an expectorant, a pain reliever, and as a preservative among others. 7,9–11 In a microbiological context, UA was found to have antimicrobial, antiviral, and antiprotozoal properties, as well as antiproliferative activity. 12 However, as a compound, UA has limited utility due to rapid metabolism, poor water solubility, lipophilic properties, and hepatotoxicity in mammals.…”

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“…Biochemically, the goal of the conjugations was to increase UA solubility, minimize toxicity, and generate structural diversity off a common UA scaffold. 7 Bruno et al . tested effects of the derivatives against P. falciparum blood stages and found that some of the compounds showed antimalarial activity at lower micromolar concentrations.…”

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A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut

et al. 2016

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The evolution of drug resistance is a recurrent problem that has plagued efforts to treat and control malaria. Recent emergence of artemisinin resistance in Southeast Asia underscores the need to develop novel antimalarials and identify new targetable pathways in Plasmodium parasites. Transmission-blocking approaches, which typically target gametocytes in the host bloodstream or parasite stages in the mosquito gut, are recognized collectively as a strategy that when used in combination with antimalarials that target erythrocytic stages will not only cure malaria but will also prevent subsequent transmission. We tested four derivatives of (+)-usnic acid, a metabolite isolated from lichens, for transmission-blocking activity against Plasmodium falciparum using the standard membrane feeding assay. For two of the derivatives, BT37 and BT122, we observed a consistent dose-response relationship between concentration in the blood meal and oocyst intensity in the midgut. To explore their mechanism of action, we used the murine model Plasmodium berghei and found that both derivatives prevent ookinete maturation. Using fluorescence microscopy, we demonstrated that in the presence of each compound zygote vitality was severely affected, and those that did survive failed to elongate and mature into ookinetes. The observed phenotypes were similar to those described for mutants of specific kinases (NEK2/NEK4) and of inner membrane complex 1 (IMC1) proteins, which are all vital to the zygote-to-ookinete transition. We discuss the implications of our findings and our high-throughput screening approach to identifying next generation, transmission-blocking antimalarials based on the scaffolds of these (+)-usnic acid derivatives.

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Synthesis of a Potent Antimalarial Agent through Natural Products Conjugation

Cited by 17 publications

References 42 publications

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

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

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

A Malaria Transmission-Blocking (+)-Usnic Acid Derivative Prevents Plasmodium Zygote-to-Ookinete Maturation in the Mosquito Midgut

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