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1.
RSC Adv ; 8(34): 18938-18951, 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-35539652

RESUMO

Curcumin has been transformed to several diversely substituted bis-pyrrolizidino/thiopyrrolizidino oxindolo/acenaphthyleno curcuminoids via a sequential azomethine ylide cycloaddition reaction using isatins/acenaphthoquinone and proline/thioproline as the reagents. The products were separated via extensive chromatography and characterized by 1D/2D NMR and HRMS analysis.

2.
J Nat Prod ; 80(5): 1347-1353, 2017 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-28493718

RESUMO

Neem (Azadirachta indica) is a well-known medicinal and insecticidal plant. Although previous studies have reported the antiulcer activity of neem leaf extract, the lead compound is still unidentified. The present study reports tamarixetin 3-O-ß-d-glucopyranoside (1) from a methanol extract of neem leaves and its gastroprotective activity in an animal model. Compound 1 showed significant protection against indomethacin-induced gastric ulceration in mice in a dose-dependent manner. Moreover, ex vivo and circular dichroism studies confirmed that 1 inhibited the enzyme matrix metalloproteinase-9 (MMP-9) activity with an IC50 value of ca. 50 µM. Molecular docking and dynamics showed the binding of 1 into the pocket of the active site of MMP-9, forming a coordination complex with the catalytic zinc, thus leading to inhibition of MMP-9 activity.


Assuntos
Antiulcerosos/farmacologia , Azadirachta/química , Dissacarídeos/isolamento & purificação , Dissacarídeos/farmacologia , Indometacina/farmacologia , Metaloproteinase 9 da Matriz/química , Quercetina/análogos & derivados , Animais , Antiulcerosos/química , Dissacarídeos/química , Indometacina/química , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Fitoterapia , Folhas de Planta , Quercetina/química , Quercetina/isolamento & purificação , Quercetina/farmacologia
3.
Org Lett ; 17(18): 4440-3, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26331906

RESUMO

Curcumin has been transformed to racemic curcuminoids via an azomethine ylide cycloaddition reaction using isatin/acenaphthoquinone and proline as the reagents. The products were characterized by extensive 1D/2D NMR analysis and single-crystal X-ray crystallographic studies. The enantiomers of one racemic product were separated by HPLC on a Chiralcel OD-H column and were indeed confirmed by the CD spectra of the separated enantiomers.


Assuntos
Compostos Azo/química , Curcumina/análogos & derivados , Curcumina/síntese química , Alcaloides de Pirrolizidina/síntese química , Tiossemicarbazonas/química , Cromatografia Líquida de Alta Pressão , Cristalografia por Raios X , Curcumina/química , Reação de Cicloadição , Indóis/química , Isatina/química , Conformação Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Oxindóis , Alcaloides de Pirrolizidina/química , Estereoisomerismo
4.
Mol Divers ; 19(2): 251-61, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25749788

RESUMO

Withaferin-A (WA) has attracted the attention of chemists as well as biologists due to its interesting structure and various bio-activities. In light of the promising biological importance of WA as well as pyrrolidine-2-spiro-3'-oxindole ring system, we became interested in the synthesis of a combined motif involving both the ring systems via the 1,3-dipolar cycloaddition of WA at Δ(2)-bond of the α,ß-unsaturated carbonyl system. We now report a facile, atom-economic synthesis of novel spiro-pyrrolizidino-oxindole adducts of withaferin-A (10 compounds) via the intermolecular cycloaddition of azomethine ylides generated in situ from proline and isatins/acenaphthoquinone. The reaction is highly chemo, regio, and stereoselective affording the cis-fused products with ß-orienting hydrogen. The structures were determined by 1D/2D NMR spectroscopic data analysis and unequivocally confirmed by X-ray crystallographic analysis in some cases. Bioevaluation of the compounds against six cancer lines (e.g., CHO, HepG2, HeLa, HEK 293, MDCK-II, and Caco-2) identified 4 promising potential anticancer compounds.


Assuntos
Vitanolídeos/química , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Reação de Cicloadição , Humanos , Indóis , Conformação Molecular , Estrutura Molecular , Oxindóis , Compostos de Espiro , Estereoisomerismo , Vitanolídeos/síntese química , Vitanolídeos/toxicidade
5.
Curr Top Med Chem ; 15(11): 1013-26, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25786506

RESUMO

Isolation of andrographolide from Andrographis paniculata, preparation of a library of derivatives via 1,3-dipolar cycloaddition of andrographolide with azomethine ylides generated from isatin derivatives or acenaphthoquinone and seconday α-amino acids, evaluation of the anticancer potential of the products, quantitative structure activity relationship studies and pharmacokinetic parameter determination have been described. 2D QSAR studies revaled that steric effects and van der Waals interactions play major roles in the determination of antiproliferative activity of these derivatives. 3D QSAR study predicted that the benzyl substitution at N20 position may be important for higher steric interaction. Pharmacokinetic studies with two most potent analogues revealed moderate chemical stability but poor aqueous solubility, metabolic stability and permeability with significant CYP3A4 inhibition.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Diterpenos/química , Relação Quantitativa Estrutura-Atividade , Andrographis/química , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral/efeitos dos fármacos , Técnicas de Química Sintética , Diterpenos/isolamento & purificação , Interações Medicamentosas , Ensaios de Seleção de Medicamentos Antitumorais , Estabilidade de Medicamentos , Células HeLa/efeitos dos fármacos , Células Hep G2/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Ratos , Solubilidade
6.
Nat Prod Res ; 29(19): 1850-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25674969

RESUMO

Phytochemical investigation of the plant Clerodendrum phlomidis Linn. F. (Lamiaceae) has now led to the isolation of two new flavonoid glycosides (1, 2) together with six known compounds identified as pectolinaringenin (3), pectolinaringenin-7-O-ß-D-glucopyranoside (4), 24ß-ethylcholesta-5,22E,25-triene-3ß-ol (5), 24ß-ethylcholesta-5,22E,25-triene-3ß-O-ß-D-glucopyranoside (6), (2S,3S,4R,10E)-2-[(2'R)-2'-hydroxytetracosanoylamino]-10-octadecene-1,3,4-triol (7) and andrographolide (8) mainly by spectroscopic analysis. Compounds 4 and 6-8 are reported for the first time from C. phlomidis.


Assuntos
Clerodendrum/química , Flavonoides/química , Glicosídeos/química , Flavonoides/isolamento & purificação , Glicosídeos/isolamento & purificação , Estrutura Molecular , Folhas de Planta/química , Plantas Medicinais/química
7.
Nat Prod Res ; 29(3): 253-61, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25348942

RESUMO

Aervalanata possesses various useful medicinal and pharmaceutical activities. Phytochemical investigation of the plant has now led to the isolation of a new 2α,3α,15,16,19-pentahydroxy pimar-8(14)-ene diterpenoid (1) together with 12 other known compounds identified as ß-sitosterol (2), ß-sitosterol-3-O-ß-D-glucoside (3), canthin-6-one (4), 10-hydroxycanthin-6-one (aervine, 5), 10-methoxycanthin-6-one (methylaervine, 6), ß-carboline-1-propionic acid (7), 1-O-ß-D-glucopyranosyl-(2S,3R,8E)-2-[(2'R)-2-hydroxylpalmitoylamino]-8-octadecene-1,3-diol (8), 1-O-(ß-D-glucopyranosyl)-(2S,3S,4R,8Z)-2-[(2'R)-2'-hydroxytetracosanoylamino]-8(Z)-octadene-1,3,4-triol (9), (2S,3S,4R,10E)-2-[(2'R)-2'-hydroxytetracosanoylamino]-10-octadecene-1,3,4-triol (10), 6'-O-(4″-hydroxy-trans-cinnamoyl)-kaempferol-3-O-ß-D-glucopyranoside (tribuloside, 11), 3-cinnamoyltribuloside (12) and sulfonoquinovosyldiacylglyceride (13). Among these, six compounds (8-13) are reported for the first time from this plant. Cytotoxicity evaluation of the compounds against five cancer cell lines (CHO, HepG2, HeLa, A-431 and MCF-7) shows promising IC50 values for compounds 4, 6 and 12.


Assuntos
Abietanos/química , Amaranthaceae/química , Abietanos/isolamento & purificação , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/isolamento & purificação , Humanos , Concentração Inibidora 50 , Estrutura Molecular
8.
Beilstein J Org Chem ; 10: 692-700, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24778721

RESUMO

A new series of pyrrolo[3',4':3,4]pyrrolo[1,2-a]furoquinolines/phenanthrolines and pyrrolo[1,2-a]phenanthrolines were efficiently built up from an 8-hydroxyquinoline derivative or phenanthroline via 1,3-dipolar cycloaddition reaction involving non-stabilized azomethine ylides, generated in situ from the parent furo[3,2-h]quinoliniums/phenanthroliums, in presence of a copper(II) chloride-phenanthroline catalytic system. The methodology combines general applicability with high yields.

9.
J Ethnopharmacol ; 149(1): 335-43, 2013 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-23838474

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Different parts of Indian ethnomedicinal plant Shorea robusta is traditionally used for several ailments including wounds and burn by different tribal groups, since ages. Here we have validated, for the first time, the effectiveness and the possible mechanism of action of young leaf extracts of Shorea robusta, used by two distinct tribes of India, and its isolated compounds as a topical formulation in three wound models in rats. MATERIALS AND METHODS: Bioactivity-guided study of the active extract resulted in the isolation of two known compounds. The prepared ointment containing extracts (2.5 and 5%, w/w), fractions (5% w/w) and isolated compounds (0.25% w/w) were evaluated on excision, incision and dead space wound models in rats by the rate of wound closure, period of epithelialisation, tensile strength, granulation tissue weight, hydroxyproline content and histopathology. RESULTS: The animals treated with the extracts and fractions (5%) showed significant reduction in wound area 96.55 and 96.41% with faster epithelialisation (17.50 and 17.86), while the isolated compounds bergenin and ursolic acid heal the wound faster, but complete epithelialisation with 100% wound contraction was evident with 5% povidone-iodine group on 18th post-wounding day. Moreover, the tensile strength of incision wound, granuloma tissue weight, and hydroxyproline content was significantly increased in both the extract and compound(s) treated animals. Furthermore, the tissue histology of animals treated with the isolated compound(s) showed complete epithelialisation with increased collagenation, similar to povidone-iodine group. CONCLUSION: Thus, our results validated the traditional use of Shorea robusta young leaves in wound management.


Assuntos
Dipterocarpaceae/química , Etnofarmacologia , Extratos Vegetais/uso terapêutico , Cicatrização/efeitos dos fármacos , Administração Tópica , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Estabilidade de Medicamentos , Índia , Dose Letal Mediana , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade , Folhas de Planta/química , Ratos , Ratos Wistar , Testes de Irritação da Pele , Testes de Toxicidade Aguda , Ferimentos Penetrantes/tratamento farmacológico
10.
Contraception ; 88(1): 133-40, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23290431

RESUMO

BACKGROUND: An alarming increase in global population is the root cause of poverty, malnutrition, sexually transmitted infections (STIs) and many other social problems. Microbicidal spermicides possessing dual function of contraception and STI protection can effectively combat this problem, and their development is of utmost importance at present. STUDY DESIGN: A major metabolite isolated from Shorea robusta resin was spectroscopically characterized as asiatic acid. Spermicidal efficacy of the isolate was evaluated in vitro by a modified Sander-Cramer test. The mode of spermicidal action was assessed by (a) double fluoroprobe staining, (b) hypoosmotic swelling test and (c) scanning electron microscopy. Antimicrobial efficacy was assessed by disc diffusion and broth dilution methods using human isolates of bacteria (Escherichia coli ATCC 25938 and Pseudomonas aeruginosa 71) and fungus (Candida tropicalis). RESULTS: The minimum effective concentration of asiatic acid that induced instantaneous immobilization of rat spermatozoa in vitro was 125 mcg/mL. The mechanism of action involved disruption of sperm plasma membrane. The microbicidal efficacy was found to be moderate for vaginal pathogens, with no effect on normal vaginal flora. CONCLUSION: Asiatic acid possesses appreciable spermicidal and microbicidal potential and may be explored as an effective microbicidal spermicide.


Assuntos
Anti-Infecciosos Locais/farmacologia , Dipterocarpaceae/química , Descoberta de Drogas , Resinas Vegetais/química , Infecções Sexualmente Transmissíveis/prevenção & controle , Espermicidas , Espermatozoides/efeitos dos fármacos , Animais , Anti-Infecciosos Locais/isolamento & purificação , Candida tropicalis/efeitos dos fármacos , Candida tropicalis/crescimento & desenvolvimento , Candida tropicalis/isolamento & purificação , Membrana Celular/efeitos dos fármacos , Membrana Celular/ultraestrutura , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/isolamento & purificação , Humanos , Índia , Masculino , Testes de Sensibilidade Microbiana , Triterpenos Pentacíclicos/isolamento & purificação , Triterpenos Pentacíclicos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/isolamento & purificação , Ratos , Ratos Sprague-Dawley , Infecções Sexualmente Transmissíveis/microbiologia , Infecções Sexualmente Transmissíveis/transmissão , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermicidas/isolamento & purificação , Espermatozoides/ultraestrutura
11.
ACS Comb Sci ; 15(1): 41-8, 2013 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-23167870

RESUMO

Dispiro-pyrrolidino/pyrrolizidino fused oxindoles/acenaphthoquinones have been derived from andrographolide via azomethine ylide cycloaddition to the conjugated double-bond under microwave (MW) irradiation. The reactions are chemo-, stereo-, and regioselective in nature. Change in amino acid from sarcosine/N-benzyl glycine to l-proline changes the regiochemistry. A representative library of 40 compounds along with in vitro anticancer evaluation is reported.


Assuntos
Diterpenos/química , Diterpenos/síntese química , Micro-Ondas , Ciclização , Reação de Cicloadição , Estrutura Molecular , Bibliotecas de Moléculas Pequenas
12.
Antimicrob Agents Chemother ; 56(1): 432-45, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22024817

RESUMO

Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 µM). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.


Assuntos
Aminoquinolinas/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmania donovani/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Proteínas de Protozoários/antagonistas & inibidores , Quinaldinas/administração & dosagem , Administração Oral , Aminoquinolinas/síntese química , Animais , Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/síntese química , Apoptose/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Resistência a Medicamentos , Glutationa/antagonistas & inibidores , Concentração Inibidora 50 , Injeções Intraperitoneais , Leishmania donovani/crescimento & desenvolvimento , Leishmaniose Visceral/microbiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Proteínas de Protozoários/metabolismo , Quinaldinas/síntese química , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo
13.
Reprod Biol Endocrinol ; 9: 102, 2011 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-21801392

RESUMO

BACKGROUND: Sperm immobilizing activity and plausible mechanism of action of Chenopodium album seed decoction (CAD) have been elucidated in our earlier studies. The present study has been carried out to explore the safety standards of CAD along with microbicidal properties as prerequisite for its use as a topically applicable vaginal contraceptive. METHODS: The safety standards of CAD were assessed by a) Hemolytic index determination using rabbit erythrocytes, to set the doses of the other experiments, b) Dermal irritancy test using refined version of Draize scoring system on rabbits, c) Possible effect on local tissues and reproductive performance in female rats after fourteen daily single dose application, d) PCNA staining- to evaluate the effect of CAD on vaginal tissue proliferation, e) TUNEL assay- to examine its ability to induce in situ apoptosis in the vaginal tissue sections of the treated animals, and f) Microbicidal activity- to explore the effect of CAD on the growth of Lactobacillus acidophilus and Candida albicans. RESULTS: In vitro irritation studies on rabbit erythrocytes revealed the hemolytic index of CAD to be 8.2 mg/ml. The dermal irritation test showed it to be a non-irritant even at higher doses. Intra vaginal application of CAD in rat vagina for 14 consecutive days caused slight reversible inflammation on vaginal epithelial cells at doses as high as 82 mg/ml. However, at this dose level it neither had any adverse effect on vaginal tissue proliferation nor did it cause in situ apoptosis as evident from PCNA staining and TUNEL assay. Fertility and fecundity were restored 4-15 days after withdrawal of CAD application. At dose level 10 times that of its spermicidal MEC (minimum effective concentration), CAD did not block the growth of Lactobacillus, although the size of individual colony was marginally reduced. However, growth of the pathogenic fungus Candida albicans was completely inhibited with 20 mg/ml of CAD. CONCLUSION: The overall result evolved from the study strengthens the candidature of CAD as a safe microbicidal spermicide. It is almost non-irritant to rabbit skin and rat vaginal tissues at doses 10 fold higher than its hemolytic index. The effect of CAD on Lactobacillus culture was not highly encouraging but it prevented the growth of the fungal pathogen Candida albicans at 20 mg/ml of CAD.


Assuntos
Chenopodium album/química , Eritrócitos/efeitos dos fármacos , Extratos Vegetais/toxicidade , Sementes/toxicidade , Espermicidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Olho/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Lactobacillus acidophilus/efeitos dos fármacos , Coelhos , Ratos , Ratos Sprague-Dawley , Vagina/efeitos dos fármacos , Vagina/patologia , Vaginite/induzido quimicamente
14.
Biomed Pharmacother ; 65(6): 387-94, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21715129

RESUMO

Multidrug resistance (MDR) mediated by the over expression of drug efflux protein P-glycoprotein (P-gp) is one of the major impediments to successful treatment of cancer. P-gp acts as an energy-dependent drug efflux pump and reduces the intracellular concentration of structurally unrelated drugs inside the cells. Therefore, there is an urgent need for development of new compound that are less toxic and effective against drug resistance in cancer. Preclinical studies have shown that quinoline derivatives possess anticancer activities. Here, we report the antitumor potential of quinoline derivative, 2-(2-Methyl-quinolin-4ylamino)-N-phenyl acetamide (S4). To evaluate the cytotoxic potential of S4, we used four different cell lines (Hela, HCT-116, CCRF-CEM, and CEM/ADR 5000) in vitro, and showed that S4 kills doxorubicin resistant T lymphoblastic leukemia cell, CEM/ADR 5000 in a concentration dependent manner while others remains unaffected. Moreover, S4 induces apoptosis in CEM/ADR 5000 cells through generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyle-cysteine (NAC) completely blocks ROS generation and, subsequently, abrogates S4 induced apoptosis. Furthermore, in vivo treatment with S4 significantly increases the life span of swiss albino mice bearing sensitive and doxorubicin resistant subline of Ehrlich ascites carcinoma. In addition, intraperitoneal application of S4 in mice does not show any systemic toxicity at concentrations that in preliminary trials in a mice Ehrlich ascites carcinoma model. Therefore, present report provides evidence that S4, a quinoline derivative, may be a promising new therapeutic agent against drug resistant cancers.


Assuntos
Acetanilidas/farmacologia , Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Acetanilidas/administração & dosagem , Acetanilidas/efeitos adversos , Acetanilidas/uso terapêutico , Aminoquinolinas/administração & dosagem , Aminoquinolinas/efeitos adversos , Aminoquinolinas/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Ehrlich/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Feminino , Humanos , Masculino , Camundongos , Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Testes de Toxicidade Crônica
15.
Chem Asian J ; 6(6): 1390-7, 2011 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-21433298

RESUMO

For two indole and oxindole bioactive molecules, low-order room-temperature X-ray data were used to generate aspherical electron density (ED) distributions by application of the invariom formalism. An analysis of the ED using the quantum theory of atoms in molecules (QTAIM) was carried out, which allowed for quantitatively examining bond orders and charge separations in various parts of the molecules. The inspection of electrostatic potentials (ESPs) and Hirshfeld surfaces provided additional information on the intermolecular interactions. Thus, reactive regions of the molecules could be identified, covalent and electrostatic contributions to interactions could be visualized, and the forces causing the crystal packing scheme could be rationalized. As the used invariom formalism needs no extra experimental effort compared to routine X-ray analysis, its wide application is recommended because it delivers information far beyond the normally obtained steric properties. In this way, complementary contributions to drug design can be given as is demonstrated for indoles in this study, which are involved in the metabolism of plants and animals as well as in cancer therapy.


Assuntos
Indóis/química , Alcaloides de Pirrolizidina/química , Temperatura Baixa , Cristalografia por Raios X , Elétrons , Ligação de Hidrogênio , Conformação Molecular , Oxindóis , Teoria Quântica , Eletricidade Estática
16.
Eur J Med Chem ; 46(6): 2132-40, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21440339

RESUMO

A number of indolizines and pyrrolo[1,2-a]quinolines/isoquinolines were prepared from phenacyl pyridinium, quinolinium and isoquinolinium salts derived from the reaction of the heterocycles with 2-bromo acetophenone with alkynes and alkenes using amberlite-IRA-402 (OH) ion exchange resin as the base. Antibacterial and antifungal studies were carried out against thirteen bacterial and four fungal strains, which revealed that three derivatives (4a, 4b, 7a) out of fifteen are effective against all the thirteen strains and one derivative, 10, showed dual antibactericidal and antifungal efficacy.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Fungos/efeitos dos fármacos , Resinas de Troca Iônica/química , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Indolizinas/síntese química , Indolizinas/química , Indolizinas/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/química , Isoquinolinas/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 19(16): 4786-9, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19564109

RESUMO

Syntheses of 3,3-diheteroaromatic oxindole derivatives has been achieved by coupling indole-2,3-dione (isatin) with differently substituted indoles and pyrrole in presence of I(2) in i-PrOH. The in vitro spermicidal potentials and the mode of spermicidal action of the synthesized analogues were evaluated and the derivative, 3,3-bis (5-methoxy-1H-indol-3-yl) indolin-2-one (3d) exhibited most significant activity.


Assuntos
Indóis/química , Indóis/síntese química , Espermicidas/síntese química , Animais , Indóis/farmacologia , Microscopia Eletrônica de Transmissão , Oxindóis , Ratos , Espermicidas/química , Espermicidas/farmacologia
18.
Eur J Med Chem ; 44(2): 845-53, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18538452

RESUMO

A one-pot synthesis of some novel bis-quinolines has been achieved under phase transfer catalyzed conditions using 8-hydroxy quinoline derivatives as substrates. The synthesized analogues were evaluated for antileishmanial activity against Leishmania donovani promastigotes and amastigotes. The entire bis-quinolines showed efficacy in both in vitro and in vivo studies. Compound 5 (1,1-bis-[(5-chloro-8-quinolyl)oxy]methane) exhibited the most significant activity. Compounds 4 (1,1-bis-[(8-quinolyl)oxy]methane) and 9 (1,5-bis-[(2-methyl-8-quinolyl)oxy]pentane) also demonstrated significant leishmanicidal efficacy against established visceral leishmaniasis in BALB/c model. Ultrastructural studies of promastigotes treated with compound 5, demonstrated membrane blebbing, chromatin condensation and vacuolization in the parasites and the flagellated parasites became round shaped after treatment. Moreover, in vitro antibacterial activity of compound 5 against several bacterial strains revealed its promising efficacy. The findings suggested that 1,1-bis-[(5-chloro-8-quinolyl)oxy]methane (5) is a bright candidate to be considered as lead compound for leishmanicidal drug.


Assuntos
Antibacterianos/química , Antiprotozoários/química , Leishmaniose Visceral/tratamento farmacológico , Quinolinas/síntese química , Animais , Catálise , Leishmania donovani/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Testes de Sensibilidade Parasitária , Quinolinas/farmacologia , Relação Estrutura-Atividade
19.
Indian J Pharmacol ; 41(4): 176-81, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20523869

RESUMO

UNLABELLED: In drug discovery research, the compounds should not only to be potent and selective but also must possess acceptable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) to increase success rate in clinical studies. OBJECTIVE: Exploration of drug-like properties of 2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide, a potent antileishmanial compound by performing some in vitro ADME experiments along with validation of such studies. MATERIALS AND METHODS: Experimental protocols were established and validated for stability (in PBS pH7.4, simulated gastric and intestinal fluid), solubility, permeability, distribution coefficient (Log D), plasma protein binding and metabolism by rat liver microsomes by using spectrophotometer or HPLC. Methods were considered valid if the results of the standard compounds matched with reported results or within acceptable range or with proper ranking (high-medium-low). RESULTS: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 +/- 6.42 muM. The parallel artificial membrane permeability assay (PAMPA) indicated its medium permeability (Log Pe = -5.53 +/- 0.01). The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and -1.33, respectively. The plasma protein binding study by the equilibrium dialysis method was observed to be 78.82 +/- 0.13% while metabolism by Phase-I enzymes for 1 hour at 37 degrees C revealed that 36.07 +/- 4.15% of the compound remained after metabolism. CONCLUSION: The methods were found to be very useful for day-to-day ADME studies. All the studies with the antileishmanial compound ascertained that the compound bears optimum pharmacokinetic properties to be used orally as a potential drug for the treatment of leishmaniasis.

20.
Int J Antimicrob Agents ; 32(4): 349-54, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18674886

RESUMO

2-(2-Methyl-quinoline-4ylamino)-N-(2-chlorophenyl)-acetamide, a novel anilidoquinoline derivative, was synthesised and evaluated for its therapeutic efficacy in treating Japanese encephalitis. The compound showed significant antiviral and antiapoptotic effects in vitro. Significant decreases in viral load (P<0.01) combined with an increase in survival was observed in Japanese encephalitis virus-infected mice treated with 2-(2-methyl-quinoline-4ylamino)-N-(2-chlorophenyl)-acetamide.


Assuntos
Acetamidas/uso terapêutico , Antivirais/uso terapêutico , Vírus da Encefalite Japonesa (Espécie)/patogenicidade , Encefalite Japonesa/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Quinolinas/uso terapêutico , Acetamidas/química , Acetamidas/farmacologia , Acetanilidas/síntese química , Acetanilidas/química , Acetanilidas/farmacologia , Acetanilidas/uso terapêutico , Aminoquinolinas/síntese química , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Aminoquinolinas/uso terapêutico , Animais , Antivirais/química , Antivirais/farmacologia , Linhagem Celular Tumoral , Vírus da Encefalite Japonesa (Espécie)/efeitos dos fármacos , Encefalite Japonesa/virologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Quinolinas/síntese química , Quinolinas/química , Quinolinas/farmacologia , Resultado do Tratamento
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