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1.
Med Hypotheses ; 144: 109988, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32540603

RESUMO

Pentoxifylline (PTX) is a phosphodiesterase inhibitor that increases cyclic adenosine monophosphate levels, which in turn activate protein kinase, leading to a reduction in the synthesis of proinflammatory cytokines to ultimately influence the renin-angiotensin system (RAS) in vitro by inhibiting angiotensin 1 receptor (AT1R) expression. The rheological, anti-inflammatory, and renin-angiotensin axis properties of PTX highlight this drug as a therapeutic treatment alternative for patients with COVID-19 by helping reduce the production of the inflammatory cytokines without deleterious effects on the immune system to delay viral clearance. Moreover, PTX can restore the balance of the immune response, reduce damage to the endothelium and alveolar epithelial cells, improve circulation, and prevent microvascular thrombosis. There is further evidence that PTX can improve ventilatory parameters. Therefore, we propose repositioning PTX in the treatment of COVID-19. The main advantage of repositioning PTX is that it is an affordable drug that is already available worldwide with an established safety profile, further offering the possibility of immediately analysing the result of its use and associated success rates. Another advantage is that PTX selectively reduces the concentration of TNF-α mRNA in cells, which, in the case of an acute infectious state such as COVID-19, would seem to offer a more strategic approach.

2.
Molecules ; 25(7)2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32260146

RESUMO

The Cactaceae family is an important source of triterpenes and sterols. The wide uses of those plants include food, gathering, medicinal, and live fences. Several studies have led to the isolation and characterization of many bioactive compounds. This review is focused on the chemistry and biological properties of sterols and triterpenes isolated mainly from some species with columnar and arborescent growth forms of Mexican Cactaceae. Regarding the biological properties of those compounds, apart from a few cases, their molecular mechanisms displayed are not still fully understand. To contribute to the above, computational chemistry tools have given a boost to traditional methods used in natural products research, allowing a more comprehensive exploration of chemistry and biological activities of isolated compounds and extracts. From this information an in silico bioprospection was carried out. The results suggest that sterols and triterpenoids present in Cactaceae have interesting substitution patterns that allow them to interact with some bio targets related to inflammation, metabolic diseases, and neurodegenerative processes. Thus, they should be considered as attractive leads for the development of drugs for the management of chronic degenerative diseases.

3.
BMC Chem ; 13(1): 22, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31384771

RESUMO

Background: Mangroves plants and their endophytes represent a natural source of novel and bioactive compounds. In our ongoing research on mangrove endophytes from the Panamanian Pacific Coast, we have identified several bioactive endophytic fungi. From these organisms, an isolate belonging to the genus Zasmidium (Mycosphaerellaceae) showed 91.3% of inhibition against α-glucosidase enzyme in vitro. Results: Zasmidium sp. strain EM5-10 was isolated from mature leaves of Laguncularia racemosa, and its crude extract showed good inhibition against α-glucosidase enzyme (91.3% of inhibition). Bioassay-guided fractionation of the crude extract led to obtaining two active fractions: L (tripalmitin) and M (Fungal Tryglicerides Mixture). Tripalmitin (3.75 µM) showed better inhibitory activity than acarbose (positive control, IC50 217.71 µM). Kinetic analysis established that tripalmitin acted as a mixed inhibitor. Molecular docking and molecular dynamics simulations predicted that tripalmitin binds at the same site as acarbose and also to an allosteric site in the human intestinal α-glucosidase (PDB: 3TOP). Conclusions: Zasmidium sp. strain EM5-10 represents a new source of bioactive substances that could possess beneficial properties for human health.

4.
J Nat Prod ; 82(4): 823-831, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30840453

RESUMO

The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (-)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure-activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10-16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species ( L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABAA receptors (α1ß2γ2s) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.

5.
Molecules ; 24(2)2019 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-30658415

RESUMO

Infection from multidrug resistant bacteria has become a growing health concern worldwide, increasing the need for developing new antibacterial agents. Among the strategies that have been studied, biofilm inhibitors have acquired relevance as a potential source of drugs that could act as a complement for current and new antibacterial therapies. Based on the structure of 2-alkyl-3-hydroxy-4-quinolone and N-acylhomoserine lactone, molecules that act as mediators of quorum sensing and biofilm formation in Pseudomonas aeruginosa, we designed, prepared, and evaluated the biofilm inhibition properties of long chain amide derivatives of 2-amino-4-quinolone in Staphylococcus aureus and P. aeruginosa. All compounds had higher biofilm inhibition activity in P. aeruginosa than in S. aureus. Particularly, compounds with an alkyl chain of 12 carbons exhibited the highest inhibition of biofilm formation. Docking scores and molecular dynamics simulations of the complexes of the tested compounds within the active sites of proteins related to quorum sensing had good correlation with the experimental results, suggesting the diminution of biofilm formation induced by these compounds could be related to the inhibition of these proteins.


Assuntos
4-Quinolonas/química , Amidas/síntese química , Amidas/farmacologia , Biofilmes/efeitos dos fármacos , Simulação por Computador , Amidas/química , Domínio Catalítico , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Percepção de Quorum/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia
6.
Biomolecules ; 8(4)2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-30360548

RESUMO

An increasing occurrence of resistance in insect pests and high mammal toxicity exhibited by common pesticides increase the need for new alternative molecules. Among these alternatives, bioinsecticides are considered to be environmentally friendly and safer than synthetic insecticides. Particularly, plant extracts have shown great potential in laboratory conditions. However, the lack of studies that confirm their mechanisms of action diminishes their potential applications on a large scale. Previously, we have reported the insect growth regulator and insecticidal activities of secondary metabolites isolated from plants of the Calceolaria genus. Herein, we report an in silico study of compounds isolated from Calceolaria against acetylcholinesterase, prophenoloxidase, and ecdysone receptor. The molecular docking results are consistent with the previously reported experimental results, which were obtained during the bioevaluation of Calceolaria extracts. Among the compounds, phenylethanoid glycosides, such as verbascoside, exhibited good theoretical affinity to all the analyzed targets. In light of these results, we developed an index to evaluate potential multitarget insecticides based on docking scores.


Assuntos
Calceolariaceae/química , Simulação por Computador , Inibidores Enzimáticos/toxicidade , Glicosídeos/toxicidade , Praguicidas/toxicidade , Acetilcolinesterase/química , Animais , Drosophila melanogaster/química , Inibidores Enzimáticos/química , Glucosídeos/química , Glicosídeos/química , Humanos , Simulação de Acoplamento Molecular , Praguicidas/química , Fenóis/química , Receptores de Esteroides/química
7.
Chem Cent J ; 9(1): 53, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26435737

RESUMO

BACKGROUND: Panama has an extensive mangrove area and it is one of the countries with the highest biodiversity in America. Mangroves are widely used in traditional medicine, nevertheless, there are very few studies that validates their medicinal properties in America. Given the urgent need for therapeutic options to treat several diseases of public health importance, mangrove ecosystem could be an interesting source of new bioactive molecules. This study was designed to evaluate the potential of Pelliciera rhizophorae as a source of bioactive compounds. RESULTS: The present investigation was undertaken to explore the possible antiparasitic potential and α-glucosidase inhibition by compounds derived from the Panamanian mangrove Pelliciera rhizophorae. Bioassay-guided fractionation of the crude extract led to the isolation of ten chemical compounds: α-amyrine (1), ß-amyrine (2), ursolic acid (3), oleanolic acid (4), betulinic acid (5), brugierol (6) iso-brugierol (7), kaempferol (8), quercetin (9), and quercetrin (10). The structures of these compounds were established by spectroscopic analyses including APCI-HR-MS and NMR. Compounds 4 (IC50 = 5.3 µM), 8 (IC50 = 22.9 µM) and 10 (IC50 = 3.4 µM) showed selective antiparasitic activity against Leishmania donovani, while compounds 1 (IC50 = 19.0 µM) and 5 (IC50 = 18.0 µM) exhibited selectivity against Tripanosoma cruzi and Plasmodium falciparum, respectively. Moreover, compounds 1-5 inhibited α-glucosidase enzyme in a concentration-dependent manner with IC50 values of 1.45, 0.02, 1.08, 0.98 and 2.37 µM, respectively. Their inhibitory activity was higher than that of antidiabetic drug acarbose (IC50 217.7 µM), used as a positive control. Kinetic analysis established that the five compounds acted as competitive inhibitors. Docking analysis predicted that all triterpenes bind at the same site that acarbose in the human intestinal α-glucosidase (PDB: 3TOP). CONCLUSIONS: Three groups of compounds were isolated in this study (triterpenes, flavonols and dithiolanes). Triterpenes and flavones showed activity in at least one bioassay (antiparasitic or α-glucosidase). In addition, only the pentacyclic triterpenes exhibited a competitive type of inhibition against α-glucosidase.

8.
J Mol Graph Model ; 62: 18-25, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26342572

RESUMO

Triterpenes and sterols are good candidates for the development of anti-inflammatory drugs and use in chemoprevention or chemotherapy of cancer via the interaction with therapeutic targets related to inflammation, such as COX-1 and -2; LOX-5; MPO, PLA2 and i-NOS. In this study, we use molecular docking to evaluate the potential binding of a database of selected sterol and triterpenoid compounds with several skeletons against enzymes related to inflammation to propose structural requirements beneficial for anti-inflammatory activity that can be used for the design of more potent and selective anti-inflammatory and antitumor drugs. Our results suggest that the substitution pattern is important and that there is an important relationship between the class of sterol or triterpenoid skeleton and enzyme binding.


Assuntos
Anti-Inflamatórios/química , Esteróis/química , Triterpenos/química , Vias Biossintéticas , Domínio Catalítico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Ciclo-Oxigenase 1/química , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Óxido Nítrico Sintase Tipo II/química , Peroxidase/química , Ligação Proteica , Relação Estrutura-Atividade
9.
Anticancer Res ; 32(12): 5159-65, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23225412

RESUMO

BACKGROUND: D3CLP (9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinoline) is a potent cytotoxic thiazolo[5,4-b]quinoline synthetic derivative that induces apoptosis of leukemia cells, while it displays low toxicity towards non-tumoral cells. The aim of this study was to determine if D3CLP can enhance the cytotoxicity of other antineoplastic drugs. MATERIALS AND METHODS: Leukemia, breast and cervical cancer cell lines were exposed to D3CLP-alone or in combination with imatinib, tamoxifen or cisplatin, respectively. Cell viability after treatment was evaluated by the MTT assay, and cell death by the TUNEL assay. The effects of combined treatments were analyzed by combination index and isobolographic analysis. RESULTS: Antiproliferative activity results indicate that D3CLP in combination with antineoplastic drugs induced a synergistic effect, at 3:1 and 1:1 ratios for D3CLP plus imatinib in K-562 leukemia cells, and at a 3:1 ratio for D3CLP with cisplatin in HeLa cells, as determined by their combination index. Furthermore, isobolographic analysis demonstrated a significant synergism for a 3:1 combination ratio of D3CLP with cisplatin in HeLa cells. In addition, TUNEL assay suggests cell death by apoptosis of HeLa cells after treatment with D3CLP and its combination with cisplatin at a 3:1 ratio. CONCLUSION: Overall the results indicate that D3CLP, in combined preparation with antineoplastic drugs, is a good candidate for pre-clinical studies in the treatment of different carcinoma cell types.


Assuntos
Aminoquinolinas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Cisplatino/farmacologia , Tiazóis/farmacologia , Neoplasias do Colo do Útero/tratamento farmacológico , Aminoquinolinas/administração & dosagem , Benzamidas , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Fragmentação do DNA/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Células HeLa , Humanos , Mesilato de Imatinib , Células K562 , Células MCF-7 , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Tamoxifeno/administração & dosagem , Tamoxifeno/farmacologia , Tiazóis/administração & dosagem , Neoplasias do Colo do Útero/patologia
10.
Eur J Med Chem ; 46(6): 2102-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21420205

RESUMO

Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalates to DNA and inhibits topoisomerase II in vitro inducing cell death. The clinical use of m-Amsa and other neoplastic drugs is limited due to side effects and drug resistance. In the present study we evaluated one thiazolo[5,4-b]quinoline derivate, 9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinoline (D3CLP), considered isosteric with 9-anilinoacridines, in order to determine its relative cytotoxic activity in tumoral versus non-tumoral cells, as well as the cell death mechanism induced by D3CLP on K-562 human leukemia cells. D3CLP was found to be four times more cytotoxic to tumor cells than Peripheral Blood Monocyte Cells (PBMCs). On the other hand, D3CLP induces cell death without previous cell cycle arrest at any phase, as shown by flow cytometry after 12 h of exposure to this compound. Interestingly, we detected a subdiploid peak 24 h after treatment. Signs of apoptosis were evident, as detected by TUNEL positive cells, chromatin condensation and nuclear fragmentation. Effector caspases activation were assessed with peak activity at 24 h after treatment (as detected by fluorometry assays), at which time a subdiploid peak was found in flow cytometry histograms. All data are consistent with the induction of apoptotic cell death in K-562 cells via effector caspases activation. In conclusion, the significant cytotoxicity of D3CLP together with the cell death type it produces, justifies further experimental and preclinical evaluation of this compound in the effort to find new and highly specific anti-tumor agents against leukemia cells.


Assuntos
Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Inibidores de Caspase , Inibidores de Cisteína Proteinase/farmacologia , Tiazóis/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Humanos , Células K562 , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Células Tumorais Cultivadas
11.
Bioorg Med Chem ; 17(9): 3266-77, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19364657

RESUMO

Some novel 9-anilinothiazolo[5,4-b]quinoline derivatives were synthesized and their cytotoxic activities were examined. The inhibition of some of the most active compounds over human topoisomerase II (Topo II) activity was assessed with the kDNA decatenation assay. The novel compounds differ in the substituents attached to the anilino ring, a dialkylamino alkylamino group, a saturated heterocyclic moiety, a methylthio group at position 2 and a fluorine atom present or absent at 7-position. According to the data, compounds with a diethylaminopropylamino group and a chlorine atom at 4'-position of the anilino ring were the most cytotoxic. The molecular models of all compounds indicated a correlation between hydrophobicity and cytotoxic activity although the direction and magnitude of the dipole moment also had a significant influence on its cytotoxicity. The 2-dialkylaminoalkylamino substituent is flexible and is known to facilitate the crossing of cell membranes; thus, this last barrier may be a limiting step in the mechanisms mediating the cytotoxicity. On the other hand, the activity of 2-methylthio derivatives seems to rely more on the electronic effects brought about by the substitution of the aniline ring. The synthesis, cytotoxicity against cancer cell lines, in vitro inhibition of human topoisomerase II, molecular modeling and the preliminary analysis of structure-activity relationships are presented.


Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Inibidores da Topoisomerase II , Compostos de Anilina/síntese química , DNA/genética , DNA/metabolismo , DNA Topoisomerases Tipo II/química , DNA Topoisomerases Tipo II/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Células K562 , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Quinolinas/síntese química , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia
12.
J Mol Graph Model ; 27(8): 900-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19269869

RESUMO

Although 9-anilinoacridines are among the best studied antitumoral intercalators, there are few studies about the effect of isosteric substitution of a benzene moiety for a heterocycle ring in the acridine framework. According to these studies, this approach may lead to effective cytotoxic agents, but good cytotoxic activity depends on structural requirements in the aniline ring which differ from those in 9-anilinoacridines. The present paper deals with molecular modeling studies of some 9-anilino substituted tricyclic compounds and their intercalation complexes (in various DNA sequences) resulting from docking the compounds into various DNA sequences. As expected, the isosteric substitution in 9-anilinoacridines influences the LUMO energy values and orbital distribution, the dipole moment, electrostatic charges and the conformation of the anilino ring. Other important differences are observed during the docking studies, for example, changes in the spatial arrangement of the tricyclic nucleus and the anilino ring at the intercalation site. Semiempirical calculations of the intercalation complexes show that the isosteric replacement of a benzene ring in the acridine nucleus affects not only DNA affinity but also base pair selectivity. These findings explain, at least partially, the different structural requirements observed in several 9-anilino substituted tricyclic compounds for cytotoxic activity. Thus, the data presented here may guide the rational design of new agents with different DNA binding properties and/or a cytotoxic profile by isosteric substitution of known intercalators.


Assuntos
DNA/química , Compostos Heterocíclicos com 3 Anéis/química , Substâncias Intercalantes/química , Acridinas/química , Simulação por Computador , Modelos Moleculares , Estrutura Molecular
13.
Bioorg Med Chem ; 16(3): 1142-9, 2008 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-18035542

RESUMO

A series of novel alkylamino and 9-anilinothiazolo[5,4-b]quinolines were synthesized as potential antitumoral agents. The in vitro cytotoxicity of these compounds was evaluated on several cell lines. The inclusion of electron-withdrawn/acceptor hydrogen-bond groups at position 3' of the anilino ring and the presence of an alkylamino chain on the tricyclic framework (regardless of its position) seem to be structural features relevant to cytotoxic activity.


Assuntos
DNA/genética , Quinolinas/síntese química , Quinolinas/toxicidade , Tiazóis/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Quinolinas/química , Relação Estrutura-Atividade
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