RESUMO
BACKGROUND: Chagas disease and leishmaniasis affect a significant portion of the Latin American population and still lack efficient treatments. In this context, natural products emerge as promising compounds for developing more effective therapies, aiming to mitigate side effects and drug resistance. Notably, species from the Amaryllidaceae family emerge as potential reservoirs of antiparasitic agents due to the presence of diverse biologically active alkaloids. PURPOSE: To assess the anti-Trypanosoma cruzi and anti-Leishmania infantum activity of five isolated alkaloids from Hippeastrum aulicum Herb. (Amaryllidaceae) against different life stages of the parasites using in silico and in vitro assays. Furthermore, molecular docking was employed to evaluate the interaction of the most active alkaloids. METHODS: Five natural isoquinoline alkaloids isolated in suitable quantities for in vitro testing underwent preliminary in silico analysis to predict their potential efficacy against Trypanosoma cruzi (amastigote and trypomastigote forms) and Leishmania infantum (amastigote and promastigote forms). The in vitro antiparasitic activity and mammalian cytotoxicity were investigated with a subsequent comparison of both analysis (in silico and in vitro) findings. Additionally, this study employed the molecular docking technique, utilizing cruzain (T. cruzi) and sterol 14α-demethylase (CYP51, L. infantum) as crucial biological targets for parasite survival, specifically focusing on compounds that exhibited promising activities against both parasites. RESULTS: Through computational techniques, it was identified that the alkaloids haemanthamine (1) and lycorine (8) were the most active against T. cruzi (amastigote and trypomastigote) and L. infantum (amastigote and promastigote), while also revealing unprecedented activity of alkaloid 7methoxy-O-methyllycorenine (6). The in vitro analysis confirmed the in silico tests, in which compound 1 presented the best activities against the promastigote and amastigote forms of L. infantum with half-maximal inhibitory concentration (IC50) 0.6 µM and 1.78 µM, respectively. Compound 8 exhibited significant activity against the amastigote form of T. cruzi (IC50 7.70 µM), and compound 6 demonstrated activity against the trypomastigote forms of T. cruzi and amastigote of L. infantum, with IC50 values of 89.55 and 86.12 µM, respectively. Molecular docking analyses indicated that alkaloids 1 and 8 exhibited superior interaction energies compared to the inhibitors. CONCLUSION: The hitherto unreported potential of compound 6 against T. cruzi trypomastigotes and L. infantum amastigotes is now brought to the forefront. Furthermore, the acquired dataset signifies that the isolated alkaloids 1 and 8 from H. aulicum might serve as prototypes for subsequent structural refinements aimed at the exploration of novel leads against both T. cruzi and L. infantum parasites.
Assuntos
Alcaloides , Amaryllidaceae , Isoquinolinas , Leishmania infantum , Simulação de Acoplamento Molecular , Trypanosoma cruzi , Trypanosoma cruzi/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Amaryllidaceae/química , Alcaloides/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Isoquinolinas/farmacologia , Isoquinolinas/química , Isoquinolinas/isolamento & purificação , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Humanos , Antiparasitários/farmacologia , Antiparasitários/química , Antiparasitários/isolamento & purificação , Antiprotozoários/farmacologia , Antiprotozoários/química , Antiprotozoários/isolamento & purificaçãoRESUMO
Reactions involving C(sp3)-H bonds of azaarenes have been widely studied in recent years as they allow direct functionalization of these N-heterocycles without the use of harsh reaction conditions. In this work, we describe the C(sp3)-H functionalization of 4-methylquinazolines and 1-benzylisoquinolines, employing α-substituted ß-nitrostyrenes catalyzed by inexpensive copper acetate. Under the optimized condition, 21 pyrrolo[1,2-c]quinazolines, as well as an imidazo[1,2-c]quinazoline and 4 pyrrolo[2,1-a]isoquinolines, were obtained in moderate to good yields. Furthermore, the biological activity of the pyrrolo[1,2-c]quinazolines was evaluated against Plasmodium falciparum, and promising results were obtained.
Assuntos
Antimaláricos , Quinazolinas , Cobre/farmacologia , Cobre/química , Isoquinolinas/química , CatáliseRESUMO
Benzophenanthridines belong to the benzylisoquinolic alkaloids, representing one of the main groups of this class. These alkaloids include over 120 different compounds, mostly in plants from the Fumariaceae, Papaveraceae, and Rutaceae families, which confer chemical protection against pathogens and herbivores. Industrial uses of BZD include the production of environmentally friendly agrochemicals and livestock food supplements. However, although mainly considered toxic compounds, plants bearing them have been used in traditional medicine and their medical applications as antimicrobials, antiprotozoals, and cytotoxic agents have been envisioned. The biosynthetic pathways for some BZD have been established in different species, allowing for the isolation of the genes and enzymes involved. This knowledge has resulted in a better understanding of the process controlling their synthesis and an opening of the gates towards their exploitation by applying modern biotechnological approaches, such as synthetic biology. This review presents the new advances on BDZ biosynthesis and physiological roles. Industrial applications, mainly with pharmacological approaches, are also revised.
Assuntos
Benzofenantridinas/biossíntese , Alcaloides/biossíntese , Alcaloides/química , Alcaloides/farmacologia , Benzofenantridinas/química , Benzofenantridinas/farmacologia , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/farmacologia , Vias Biossintéticas , Desenvolvimento de Medicamentos , Isoquinolinas/química , Isoquinolinas/farmacologia , Medicina Tradicional , Fenômenos Fisiológicos Vegetais , Relação Estrutura-AtividadeRESUMO
As part of our continuing efforts to discover new bioactive compounds from endophytic fungal sources, we have investigated the extract of the Paraphaeosphaeria sporulosa F03 strain. The study led to the isolation of four new 3-methyl-isoquinoline alkaloids (1: â-â4: ) and four known polyketides (5: â-â8: ). The structures of compounds 1: â-â4: were elucidated by 1D and 2D NMR experiments and HRMS analysis. The absolute configuration of 4: was determined by comparison of its experimental electronic circular dichroism spectrum with calculated data. Compounds 1: â-â4: exhibited antifungal activity with minimal inhibitory concentration values ranging from 6.25â-â50 µg/mL against six Candida species but they did not present any cytotoxic activity against the human tumor cell lines A549 (lung), MCF-7 (breast), and HepG2 (hepatocellular). In addition, compound 4: exhibited antiplasmodial activity in the low micromolar range (IC50 = 4 µM).
Assuntos
Alcaloides , Antimaláricos , Eriocaulaceae , Policetídeos , Antifúngicos/farmacologia , Antimaláricos/farmacologia , Ascomicetos , Endófitos/química , Humanos , Isoquinolinas/química , Isoquinolinas/farmacologia , Estrutura Molecular , Extratos Vegetais , Policetídeos/química , Policetídeos/farmacologiaRESUMO
Diclinanona calycina R. E. Fries popularly known as "envira", is a species of the Annonaceae family endemic to Brazil. In our ongoing search for bioactive compounds from Annonaceae Amazon plants, the bark of D. calycina was investigated by classical chromatography techniques that yielded thirteen compounds (alkaloids and flavonoids) described for the first time in D. calycina as well as in the genus Diclinanona. The structure of these isolated compounds were established by extensive analysis using 1D/2D-NMR spectroscopy in combination with MS. The isolated alkaloids were identified as belonging to the subclasses: simple isoquinoline, thalifoline (1); aporphine, anonaine (2); oxoaporphine, liriodenine (3); benzyltetrahydroisoquinolines, (S)-(+)-reticuline (4); dehydro-oxonorreticuline (3,4-dihydro-7-hydroxy-6-methoxy-1-isoquinolinyl)(3-hydroxy-4-methoxyphenyl)-methanone) (5); (+)-1S,2R-reticuline Nß-oxide (6); and (+)-1S,2S-reticuline Nα-oxide (7); tetrahydroprotoberberine, coreximine (8); and pavine, bisnorargemonine (9). While the flavonoids belong to the benzylated dihydroflavones, isochamanetin (10), dichamanetin (11), and a mixture of uvarinol (12) and isouvarinol (13). Compound 5 is described for the first time in the literature as a natural product. The cytotoxic activity of the main isolated compounds was evaluated against cancer and non-cancerous cell lines. Among the tested compounds, the most promising results were found for the benzylated dihydroflavones dichamanetin (10), and the mixture of uvarinol (12) and isouvarinol (13), which presented moderate cytotoxic activity against the tested cancer cell lines (<20.0 µg·mL-1) and low cytotoxicity against the non-cancerous cell line MRC-5 (>25.0 µg·mL-1). Dichamanetin (11) showed cytotoxic activity against HL-60 and HCT116 with IC50 values of 15.78 µg·mL-1 (33.70 µmol·L-1) and 18.99 µg·mL-1 (40.56 µmol·L-1), respectively while the mixture of uvarinol (12) and isouvarinol (13) demonstrated cytotoxic activity against HL-60, with an IC50 value of 9.74 µg·mL-1, and HCT116, with an IC50 value of 17.31 µg·mL-1. These cytotoxic activities can be attributed to the presence of one or more hydroxybenzyl groups present in these molecules as well as the position in which these groups are linked. The cytotoxic activities of reticuline, anonaine and liriodenine have been previously established, with liriodenine being the most potent compound.
Assuntos
Alcaloides/química , Annonaceae/química , Flavonas/química , Isoquinolinas/química , Casca de Planta/química , Alcaloides/farmacologia , Aporfinas/química , Aporfinas/farmacologia , Brasil , Linhagem Celular Tumoral , Dioxóis/química , Dioxóis/farmacologia , Flavanonas/farmacologia , Flavonas/farmacologia , Células HCT116 , Células HL-60 , Células Hep G2 , Humanos , Isoquinolinas/farmacologia , Células MCF-7 , Extratos Vegetais , Folhas de Planta/químicaRESUMO
In this work, we describe how stereochemically complex polycyclic compounds can be generated by applying a synthetic sequence comprising an intramolecular Ugi reaction followed by a Pictet-Spengler cyclization on steroid-derived scaffolds. The resulting compounds, which combine a fragment derived from a natural product and a scaffold not found in nature. are both structurally distinct and globally similar to natural products at the same time, and interrogate an alternative region of the chemical space. One of the new compounds showed significant antiproliferative activity on HepG2 cells through a caspase-independent cell-death mechanism, an appealing feature when new antitumor compounds are searched.
Assuntos
Antineoplásicos/farmacologia , Produtos Biológicos/farmacologia , Caspases/metabolismo , Isoquinolinas/farmacologia , Piperazinas/farmacologia , Esteroides/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Estereoisomerismo , Esteroides/síntese química , Esteroides/químicaRESUMO
Structure-based molecular networking is useful as a dereplication strategy to identify known molecules, unknown close analogues, or compound families. On the other hand, the ligand fishing assay is a remarkable alternative to accelerate the screening process and to overcome the drawbacks of laborious experiments usually adopted in natural product research. The combination of these approaches contributes to high productivity in disclosing active metabolites and a decrease in lead time identification. To provide a valuable data base for the alkaloids of A. salzmannii bark herein we disclose thirty-one isoquinoline alkaloids including benzyltetrahydroisoquinolines, aporphines, proaporphines, and protoberberines. Among these, twenty-six have not been described for A. salzmannii including the unprecedented alkaloid N,O-dimethylcoclaurine N-oxide. In addition, norcoclaurine (1), norreticuline (13), N,O-dimethylcoclaurine N-oxide (15), and N-acetylasimilobine (24) are now reported for the first time as ligand for acetylcholinesterase.
Assuntos
Acetilcolinesterase/metabolismo , Alcaloides/análise , Annona/química , Cromatografia de Afinidade/métodos , Extratos Vegetais/química , Alcaloides/química , Alcaloides/metabolismo , Enzimas Imobilizadas/metabolismo , Isoquinolinas/análise , Isoquinolinas/química , Isoquinolinas/metabolismo , Espectrometria de Massas/métodos , Casca de Planta/químicaRESUMO
Streptomyces venezuelae is well known to produce various secondary metabolites, including chloramphenicol, jadomycin, and pikromycin. Although many strains have been classified as S. venezuelae species, only a limited number of strains have been explored extensively for their genomic contents. Moreover, genomic differences and diversity in secondary metabolite production between the strains have never been compared. Here, we report complete genome sequences of three S. venezuelae strains (ATCC 10712, ATCC 10595, and ATCC 21113) harboring chloramphenicol and jadomycin biosynthetic gene clusters (BGC). With these high-quality genome sequences, we revealed that the three strains share more than 85% of total genes and most of the secondary metabolite biosynthetic gene clusters (smBGC). Despite such conservation, the strains produced different amounts of chloramphenicol and jadomycin, indicating differential regulation of secondary metabolite production at the strain level. Interestingly, antagonistic production of chloramphenicol and jadomycin was observed in these strains. Through comparison of the chloramphenicol and jadomycin BGCs among the three strains, we found sequence variations in many genes, the non-coding RNA coding regions, and binding sites of regulators, which affect the production of the secondary metabolites. We anticipate that these genome sequences of closely related strains would serve as useful resources for understanding the complex secondary metabolism and for designing an optimal production process using Streptomyces strains.
Assuntos
Cloranfenicol/biossíntese , Genômica , Isoquinolinas/metabolismo , Streptomyces/classificação , Streptomyces/metabolismo , Cloranfenicol/química , Cloranfenicol/metabolismo , Isoquinolinas/química , Estrutura Molecular , Streptomyces/química , Streptomyces/genéticaRESUMO
A multicomponent diversity-oriented synthesis of new highly emissive tetracyclic isoquinolines that target specific organelles is described. The title compounds were prepared via a three-step protocol starting with an Ugi four-component reaction, followed by either an intramolecular alkyne hydroarylation and subsequent alkene isomerization or through a Pomeranz-Fritsch-type cyclization with a final intramolecular Heck reaction. Subcellular localization studies of these compounds using green channel confocal microscopy revealed remarkable and distinctive distribution patterns in live cells, showing an unprecedented high selectivity and imaging contrast. The differentiated organelle visualization-including localizers for mitochondria, lysosomes, Golgi apparatus, endoplasmic reticulum, and plasma membrane-was achieved by varying the nature of the tetracyclic system and substituent pattern, changing the original four-component set in the starting Ugi reaction.
Assuntos
Corantes Fluorescentes/química , Isoquinolinas/síntese química , Isoquinolinas/metabolismo , Frações Subcelulares/metabolismo , Células HeLa , Humanos , Isoquinolinas/químicaRESUMO
In the search for new quinoid compounds endowed with potential anticancer activity, the synthesis of novel heterodimers containing the cytotoxic 7-phenylaminoisoquinolinequinone and 2-phenylaminonaphthoquinone pharmacophores, connected through methylene and ethylene spacers, is reported. The heterodimers were prepared from their respective isoquinoline and naphthoquinones and 4,4'-diaminodiphenyl alkenes. The access to the target heterodimers and their corresponding monomers was performed both through oxidative amination reactions assisted by ultrasound and CeCl3·7H2O catalysis "in water". This eco-friendly procedure was successfully extended to the one-pot synthesis of homodimers derived from the 7-phenylaminoisoquinolinequinone pharmacophore. The electrochemical properties of the monomers and dimers were determined by cyclic and square wave voltammetry. The number of electrons transferred during the oxidation process, associated to the redox potential EI1/2, was determined by controlled potential coulometry.