Reactivity studies on chromene derivatives

Dissertação de mestrado em Medicinal Chemistry

Natural chromens and chromene derivatives as potential anti-trypanosomal agents

The aim of the study was to investigate the anti-trypanocidal activities of natural chromene and chromene derivatives. Five chromenes were isolated from Piper gaudichaudianum and P. aduncum, and a further seven derivatives were prepared using standard reduction, methylation and acetylation procedures. These compounds were assayed in vitro against epimastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. The results showed that the most of the compounds, especially those possessing electron-donating groups as substituents on the aromatic ring, showed potent trypanocidal activity. The most active compound, [(2S)-methyl-2-methyl-8-(3 ``-methylbut-2 ``-enyl)-2-(4`-methylpent-3`-enyl)-2H-chromene-6-carboxylate], was almost four times more potent than benznidazole (the positive control) and showed an IC50 of 2.82 mu M. The results reveal that chromenes exhibit significant anti-trypanocidal activities and indicate that this class of natural product should be considered further in the development of new and more potent drugs for use in the treatment of Chagas disease.

Effect of the synthetic coumarin, ethyl 2-oxo-2H-chromene-3-carboxylate, on activity of Crotalus durissus ruruima sPLA2 as well as on edema and platelet aggregation induced by this factor

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A chromene and prenylated benzoic acid from Piper aduncum

In addition to nerolidol, 2',6'-dihydroxy-4'-methoxydihydrochalcone, methyl 2,2-dimethyl-8-(3'-methyl-2'-butenyl)-2H-1-chromene-6-carboxylate, methyl 2,2-dimethyl-2H-1-chromene-6-carboxylate and methyl 8-hydroxy-2,2-dimethyl-2H-1-chromene-6-carboxylate, two new natural products were isolated from the leaves of Piper aduncum, 2,2-dimethyl-2H-1-chromene-6-carboxylic acid and 3-(3',7'-dimethyl-2',6 '-octadienyl)-4-methoxybenzoic acid. The structures of the isolates were established based on analysis of spectroscopic data, including ES-MS. The DNA-damaging activity of the isolated compounds was also investigated against mutant strains of Saccharomyces cerevisiae. (C) 1999 Elsevier B.V. Ltd. All rights reserved.

Circadian rhythm of anti-fungal prenylated chromene in leaves of Piper aduncum

Leaves of Piper aduncum accumulate the anti-fungal chromenes methyl 2,2-dimethyl-2H-1-chromene-6-carboxylate (1) and methyl 2,2-dimethyl-8-(3'-methyl-2'-butenyl)-2H-1-chromene-6-carboxylate (2). The enzymatic formation of 2 from dimethylallyl diphosphate and I was investigated using cell-free extracts of the title plant. An HPLC assay for the prenylation reaction was developed and the enzyme activity measured in the protein extracts. The prenyltransferase that catalyses the transfer of the dimethylallyl group to C-2' of 1 was soluble and required dimethylallyl diphosphate as the prenyl donor. In the leaves, the biosynthesis of the prenylated chromene 2 was time-regulated and prenyltransferase activity depended upon circadian variation. Preliminary characterisation and purification experiments on the prenyltransferase from P. aduncum have been performed. Copyright (C) 2005 John Wiley & Sons, Ltd.

Natural chromenes and chromene derivatives as potential anti-trypanosomal agents

The aim of the study was to investigate the anti-trypanocidal activities of natural chromene and chromene derivatives. Five chromenes were isolated from Piper gaudichaudianum and P. aduncum, and a further seven derivatives were prepared using standard reduction, methylation and acetylation procedures. These compounds were assayed in vitro against epimastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. The results showed that the most of the compounds, especially those possessing electron-donating groups as substituents on the aromatic ring, showed potent trypanocidal activity. The most active compound, [(2S)-methyl-2-methyl-8-(3″-methylbut-2″-enyl)-2- (4′-methylpent-3′-enyl)-2H-chromene-6-carboxylate], was almost four times more potent than benznidazole (the positive control) and showed an IC 50 of 2.82 μM. The results reveal that chromenes exhibit significant anti-trypanocidal activities and indicate that this class of natural product should be considered further in the development of new and more potent drugs for use in the treatment of Chagas disease. © 2008 Pharmaceutical Society of Japan.

Effect of the synthetic coumarin, ethyl 2-oxo-2H-chromene-3-carboxylate, on activity of Crotalus durissus ruruima sPLA2 as well as on edema and platelet aggregation induced by this factor

We show that ethyl 2-oxo-2H-chromene-3-carboxylate (EOCC), a synthetic coumarin, irreversibly inhibits phospholipase A(2) (sPLA2) from Crotalus durissus ruruima venom (sPLA2r) with an IC(50) of 3.1 +/- 0.06 nmol. EOCC strongly decreased the V(max) and K(m), and it virtually abolished the enzyme activity of sPLA2r as well as sPLA2s from other sources. The edema induced by 5PLA2r + EOCC was less than that induced by 5PLA2r treated with p-bromophenacyl bromide, which was more efficient at neutralizing the platelet aggregation activity of native 5PLA2r. Native 5PLA2r induced platelet aggregation of 91.54 +/- 9.3%, and sPLA2r +/- EOCC induced a platelet aggregation of 18.56 +/- 6.5%. EOCC treatment also decreased the myotoxic effect of sPLA2r. Mass spectrometry showed that EOCC formed a stable complex with sPLA2r, which increased the mass of native 5PLA2r from 14,299.34 da to 14,736.22 Da. Moreover, the formation of this complex appeared to be involved in the loss of 5PLA2r activity. Our results strongly suggest that EOCC can be used as a pharmacological agent against the 5PLA2 in Crotalus durissus sp. venom as well as other sPLA2s. (C) 2010 Elsevier Ltd. All rights reserved.

Composition and screening of antifungal activity against Cladosporium sphaerospermum and Cladosporium cladosporioides of essential oils of leaves and fruits of Piper species

This study investigated the composition and antifungal activity against Cladosporium sphaerospermum and Cladosporium cladosporioides of essential oils of leaves of Piper cernuum, Piper diospyrifolium, Piper crassinervium, Piper solmsianum and Piper umbelata and fruits of P. cernuum and P. diospyrifolium. The essentials oils were analyzed by GC-MS and submitted of the antifungal activity tests. The essential oils of fruits from P. cernuum and leaves of P. crassinervium and P. solmsianum showed potential antifungal activity against C. sphaerospermum and C. cladosporioides. In addition, this is the first report of the composition of essential oils of fruits of P. cernuum and P. diospyrifolium.

Intraspecific variability of dihydrochalcone, chromenes and benzoic acid derivatives in leaves of Piper aduncum L. (Piperaceae)

Chemical analysis carried out in leaves of 18 specimens of Piper aduncum L. (Piperaceae) occurring at Ripasa Reserve, Araraquara, SP, Brazil indicated two distinct populations when investigated over a period of 14 months (January 2000 to February 2001) and then submitted to cluster analysis. The two groups were characterized by accumulation of prenylated benzoic acids, chromenes and dihydrochalcone, respectively. A total of seven compounds were identified by HPLC analysis and compared with standards including two prenylated benzoic acid [aduncumene (1) and 3-(3'-7'-dimethyl-2'-6'-octadienyl)-4-methoxy-benzoic acid (5)], four chromenes [methyl 2,2-dimethyl-8-(3'-methyl-2'-butenyl)-2H-1-chromene-6-carboxylate (4), methyl 2,2-dimethyl-2H-1-chromene-6-carboxylate (2b), methyl 8-hydroxy-2,2-dimethyl-2H-1-chromene-6-carboxylate (3) and 2,2-dimethyl-2H-1-chromene-6-carboxylic acid (2a)] and one dihydrochalcone [2',6'-dihydroxy-4'-methoxy-dihydrochalcone (6)].

Reações de inserção intramolecular de diazo compostos polifuncionais catalisadas por ródio(II): síntese de oxetan-3-ona-2-carboxilato e outros heterociclos funcionalizados

gamma-Hydroxy-alpha-diazo-beta-ketoesters are key intermediates in the chemistry of penicilin-based antibiotics and natural products. The method developed here for the synthesis of ethyl 2-diazo-4-hydroxy-3-oxo-butanoate 17 (in two steps from the diazo mercurial 2) compares very favorably with those reported in the literature for similar compounds. The Rh2(OAc)4-mediated intramolecular OH-insertion reaction of the diazo hydroxy ester 17 was investigated, furnishing the oxetan-3-one-2-carboxilate 18 in good yield. When the diazo ester lacks a free hydroxyl group as in the case of the phenoxy diazo ester 11 an intramolecular CH-insertion takes place, affording the 2H-chromene 20 in almost quantitative yield. The behavior of other functionalized diazo esters towards Rh2(OAc)4 was also investigated.

Antifungal derivatives from Piper mollicomum and P. lhotzkyanum (Piperaceae)

Bioguided fractionation of the extracts from leaves of Piper mollicomum and Piper lhotzkyanum against the fungi Cladosporium cladosporioides and C. sphaerospermum afforded seven bioactive compounds, four being chromenes: methyl 2,2-dimethyl-2H-chromene-6-carboxylate, methyl 8-hydroxy-2,2-dimethyl-2H-chromene-6-carboxylate, 2-methyl-2-[4'-methyl-3'-pentenyl]-2H-1-benzopyran-6-carboxylic acid, 2,2-dimethyl-2H-chromene-6-carboxylic acid, one a dihydrochalcone: 2',6'-dihydroxy-4'-methoxydihydrochalcone, and two flavanones: 7-methoxy-5,4'-dihydroxy-flavanone and 7,4'-dimethoxy-5-hydroxy-flavanone. The structures of the bioactive isolated derivatives were elucidated by interpretation of their NMR data [¹H and 13C (BBD, DEPT 135º)], and mass spectral data as well as by comparison with data described in the literature.

One-pot three component reaction involving cyclohexyl isocyanide for the synthesis of furo[3,4-b]chromenes

On stirring an equimolar mixture of 4-oxo-4H-chromene-3-carbaldehyde, ninhydrin and cyclohexyl isocyanide in CH(2)Cl(2)-MeOH (7: 1) at room temperature produces 3-cyclohexylimino-1-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-1,3-dihydro-9H-furo[3,4-b]chromen-9-one which on hydrolysis produces 1-(2-hydroxy-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-1H-furo[3,4-b]chromene-3,9-dione. The structure of the latter compound was confirmed by single crystal X-ray diffraction

Composition and antifungal activity against Candida albicans, Candida parapsilosis, Candida krusei and Cryptococcus neoformans of essential oils from leaves of Piper and Peperomia species

This study was addressed to investigate the composition and antifungal activity of essential oils from leaves of Piperaceae species (Piper aduncum, Piper amalago, Piper cernuum, Piper diospyrifolium, Piper crassinervium, Piper gaudichaudianum, Piper solmsianum, Piper regnellii, Piper tuberculatum, Piper umbelata and Peperomia obtusifolia) against Candida albicans, C. parapsilosis, C. krusei and Cryptococcus neoformans. The essential oils from P. aduncum, P. gaudichaudianum and P. solmsianum showed the highest antifungal activity against Cryptococcus neoformans with the MIC of 62.5, 62.5 and 3.9 mg.mL-1, respectively. The oil from P. gaudichaudianum showed activity against C. krusei with MIC of 31.25 mg.mL-1.

Sequestration of prenylated benzoic acid and chromenes by Naupactus bipes (Coleoptera: Curculionidae) feeding on Piper gaudichaudianum (Piperaceae)

The curculionid beetle Naupactus bipes (Germar, 1824) (Coleoptera: Curculionidae: Brachycerinae) has shown feeding preference for leaves of Piper gaudichaudianum, demonstrating an unexpected specificity for an insect considered to be a generalist. The leaves of P. gaudichaudianum contain the prenylated chromenes gaudichaudianic acid (4, major compound) and its methyl ester (5) in addition to a chromene (3) lacking one prenyl residue. In addition to 4, roots contain the chromone methyl ester (1) and methyl taboganate (2, major compound). Feeding on roots, larvae of N. bipes sequester exclusively the root-specific compounds 1 and 2. Adult beetles sequester the leaf-specific chromenes 3 and 4, but were found to also contain compounds 1 and 2 that are absent in leaves. Therefore, it is suggested that 1 and 2 are sequestered by larvae and can be found in the body of adult insects after long-term storage. In addition, 3 and 4, the major compounds in leaves were found to be associated with the eggs.

Absolute Configuration and Selective Trypanocidal Activity of Gaudichaudianic Acid Enantiomers

Gaudichaudianic acid, a prenylated chromene isolated from Piper gaudichaudianum, has been described as a potent trypanocidal compound against the Y-strain of Trypanosoma cruzi. We herein describe its isolation as a racemic mixture followed by enantiomeric resolution using chiral HPLC and determination of the absolute configuration of the enantiomers as (+)-S and (-)-R by means of a combination of electronic and vibrational circular dichroism using density functional theory calculations. Investigation of the EtOAc extract of the roots, stems, and leaves from both adult specimens and seedlings of P. gaudichaudianum revealed that gaudichaudianic acid is biosynthesized as a racemic mixture from the seedling stage onward. Moreover, gaudichaudianic acid was found exclusively in the roots of seedlings, while it is present in all organs of the adult plant. Trypanocidal assays indicated that the (+)-enantiomer was more active than its antipode. Interestingly, mixtures of enantiomers stowed a synergistic effect, with the racemic mixture being the most active.