Synthesis, SAR, and Docking Studies Disclose 2-Arylfuran-1,4-naphthoquinones as In Vitro

A total of 28 lapachol-related naphthoquinones with four different scaffolds were synthesized and spectroscopically characterized. In vitro antiplasmodial activity was assayed against the chloroquine-resistant Plasmodium falciparum W2 strain by the parasite lactate dehydrogenase (pLDH) method. Cytotoxicity against Hep G2A16 cell was determined by the MTT assay. All compounds disclosed higher in vitro antiplasmodial activity than lapachol. Ortho- and para-naphthoquinones with a furan ring fused to the quinonoid moiety were more potent than 2-hydroxy-3-(1′-alkenyl)-1,4-naphthoquinones, while ortho-furanonaphthoquinones were more cytotoxic. Molecular docking to Plasmodium targets Pfcyt bc1 complex and PfDHOD enzyme showed that five out of the 28 naphthoquinones disclosed favorable binding energies. Furanonaphthoquinones endowed with an aryl moiety linked to the furan ring are highlighted as new in vitro antiplasmodial lead compounds and warrant further investigation

Synthesis by click reactions and antiplasmodial activity of Lupeol 1,2,3-Triazole derivatives.

Lupeol, a triterpene frequently found in Asteraceae plant species, showed moderate to low activity in different strains of Plasmodium falciparum, the most virulent malaria etiological agents. In this work, lupeol was isolated from Parahancornia fasciculata, a plant that is used to treat malaria in the Amazonia region. In the search of more activity lupeol derivatives, five new 1,2,3-triazole hybrid molecules were synthetized by copper-catalyzed azide-alkyne cycloaddition. The antiplasmodial activity of the semi-synthetic compounds were evaluated by the lactate dehydrogenase assay; the lupeol propargyl ether was the only one to disclosing increased activity (half maximal inhibitory concentration-IC50-62.0 ? 1.92 ?mol L-1) in relation to lupeol (IC50 117.00 ?mol L-1). Therefore, this work revealed a new class of interesting lupeol derivatives that can be obtained by linking electron donors to the hydroxy group at C-3

Síntese e atividade antimalárica de derivados 1,2,3-triazólicos do lupeol

Exportado OPUSMade available in DSpace on 2019-08-14T13:54:37Z (GMT). No. of bitstreams: 1 dissert_pronta_final_pdf.pdf: 13325414 bytes, checksum: 40efd83f7fb92c1c8174e54801f735e2 (MD5) Previous issue date: 19A presente dissertação descreve o isolamento de um triterpeno pentacíclico, o lup-20(29)-en-3ß-ol (lupeol), a partir de cascas de Parahancornia fasciculata (Poir.) Benoist (Apocynaceae) e a utilização deste como material de partida para a síntese de híbridos triazólicos. O lupeol foi obtido por percolação exaustiva das cascas da P. fasciculata, coletadas no município de Moju, PA. Tendo em vista a atividade antimalárica desse triterpeno e de derivados triazólicos descritos na literatura, os produtos obtidos poderiam apresentar atividade antimalárica superior àquela descrita para o lupeol. Os híbridos triazólicos do lupeol foram sintetizados por reações de cicloadição catalisadas por Cu (I) (reação "click"), entre um alcino terminal e azidas orgânicas. Dessa forma, o lupeol foi convertido no seu éter propargílico que, por reação "click" com diferentes azidas orgânicas, levou a cinco derivados triazólicos, todos inéditos, que foram denominados TB1 a TB6. Todas as substâncias foram caracterizadas pelos seus espectros no IV, HRMSe RMN de 1H e de 13C. A atividade antimalárica in vitro dos produtos obtidos foi avaliada em culturas de Plasmodium falciparum resistente à cloroquina (clone W2) pelo método da lactato desidrogenase (pLDH). O éter propargílico do lupeol (TB1) foi a substância mais ativa apresentando redução da parasitemia de 81%, na concentração de 50 µg/mL, enquanto que os derivados triazólicos foram menos ativos do que o lupeol, com valores de redução da parasitemia variando de 9% a 26%.This manuscript reports on the isolation of lup-20(29)-en-3-ol (lupeol), a pentacyclic triterpene, from the stem bark of Parahancornia fasciculata (Poir.) Benoist (Apocynaceae) and its use as starting material for the synthesis of triazole hybrids. Lupeol was extracted by exhaustive percolation of P. fasciculata stem bark which was collected in the municipality of Moju, PA. Lupeol is known to present a moderate in vitro antimalarial activity while some synthetic triazole hybrid compounds are reported as good antimalarials what has motivated the present work in the hope that any lupeol triazole derivative might be more active than lupeol. The lupeol triazole hybrids were synthesized by cycloaddtion reactions catalized by Cu (I) (click reaction) between a terminal alkyne and an organic azide. In a first step lupeol was converted to its propagyl ether (TB1) which was submitted to click reactions with different organic azides leading to five new triazole hybrids TB2 - TB6. All the compounds synthesized were characterized by their spectrometric analyses IR, HRMS, 1H and 13C NMR. The in vitro antimalarial activity of the compounds was evaluated against chloroquine resistant Plasmodiumfalciparum (W2 clone) by the lactate dehydrogenase methodology (pLDH). The lupeol propargyl ether was the most active compound causing 81% inhibition of the parasite growth in the concentration of 50 g/mL while the triazole derivatives were less potent than lupeol with inhibition growth ranging from 9% to 26%

Synthesis of triazol derivatives of lupeol with potential antimalarial activity

The goal of this project is synthesize and characterization of derivatives of lupeol and evaluated antimalarial activity. Historically, plants are important source of antimalarial medicines, highlighting quinine (1) (Figure 1), an important      alkaloid from the Cinchona calisaya bark. This compound was an important model for cloroquine  synthesis, a drug that was widely used in malaria treatment. In addition, one of the principal medicines used today is artemisinine, isolated from the Chinese plant Artemisia annua L (2) (Figure 1), and their semi synthetic derivatives (artesunate, artemeter, arteter). However, the malaria parasite has already shown resistance    to most of these current drugs and  the search for new candidates is essential. Lupeol (3) (Figura 1) is a compound that occurs in many plant species and discloses antimalarial, antiinflamatoryl and antitumoral activities. Considering its potential as a lead antimalarial molecule, we focused our work in the synthesis of new lupeol derivatives with increased antimalarial activity(scheme 1).</div