RESUMO
A series of phenyl carboxyl esters 5a-d derived from N-(cyclopropylmethyl)normetazocine was synthesized and evaluated for its selectivity at mu, kappa, and delta opioid receptors. Compound 5a, although 43 times less potent than the reference compound U50488, was specific for kappa receptors, having no detectable affinity for either mu or delta receptors. Greater binding affinity was seen with the diastereoisomer having the 1'R,2'S stereochemistry in the cyclopropyl ring of the nitrogen substituent, which was only 12 times less active than U50488. Antinociceptive activity in the mouse tail flick was only slightly lower than that of U50488 (ED50 = 7.66 vs 4.52 mg/kg). Naloxone fully prevented antinociception induced by (1'R,2'S)-5a at the doses of 2.0 mg/kg. Compound (1'R,2'S)-5a is one of the most kappa-selective non-peptide compounds reported to date. The implications of these results in terms of requirements for kappa ligands are discussed.
Assuntos
Ciclazocina/análogos & derivados , Receptores Opioides kappa/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Ciclazocina/síntese química , Ciclazocina/metabolismo , Ciclazocina/farmacologia , Desenho de Fármacos , Ésteres/síntese química , Ésteres/farmacologia , Cobaias , Ligação de Hidrogênio , Técnicas In Vitro , Ligantes , Masculino , Camundongos , Modelos Moleculares , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Receptores Opioides kappa/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of (+)-cis-N-normetazocine derivatives has been described, and their affinities for sigma1, sigma2, and phencyclidine (PCP) sites and opioid, muscarinic (M2), dopamine (D2), and serotonin (5-HT2) receptors were evaluated. The effect of the N-substitution with a substituted ethylamino spacer was investigated. Compounds 8c-11c displayed high affinities for sigma1 sites and for opioid receptors. Substitution of the second basic nitrogen either with alkyl or cycloalkyl substituents give compounds (1a-6a) with high affinity and selectivity for sigma1 binding sites. Compounds 1a-5a were further characterized in vivo, and their agonist/antagonist activity was evaluated. In mouse, compound 1a and 2a as well as haloperidol suppressed in a dose-related manner the stereotyped behavior induced by (+)-SKF 10,047. Compounds 3a-5a and (+)-pentazocine do not affect the stereotyped behavior induced by ip injection of (+)-SKF 10,047. Therefore, from this series of compounds we identified potent and selective sigma1 ligands which might prove useful to unveil the functional role of sigma1 sites.
Assuntos
Benzomorfanos/farmacologia , Receptores sigma/antagonistas & inibidores , Animais , Benzomorfanos/síntese química , Benzomorfanos/química , Benzomorfanos/metabolismo , Encéfalo/metabolismo , Cobaias , Ligantes , Masculino , Camundongos , Ensaio Radioligante , Ratos , Receptor Muscarínico M2 , Receptores de Dopamina D2/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Opioides/metabolismo , Receptores de Serotonina/metabolismo , Receptores sigma/agonistas , Receptores sigma/metabolismo , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Previous research showed that berberine-containing Berberis species synthesise the substances 5'-methoxyhydnocarpin-D (5'-MHC-D) and pheophorbide a, which have no antimicrobial activity but inhibit the expression of multidrug resistant efflux pumps (MDRs) in Staphylococcus aureus and potentiate the action of berberine. The MDR pumps extrude synthetic and natural antimicrobials from bacterial cells. We searched for these compounds in Berberis aetnensis C. Presl. (Berberidaceae), an endemic plant of the volcano Mount Etna. This work confirms the presence of pheophorbide a and permits us to hypothesise the presence of 5'-MHC-D in leaf extracts. In fact, the activity of ciprofloxacin was improved when two chromatographic fractions isolated from leaf extracts were added. These results are indicative of the presence of MDR pump inhibitors. Moreover, crude extracts were tested on several micro-organisms and showed antimicrobial activity mainly against Gram-positive bacteria and yeasts.
Assuntos
Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Berberis , Clorofila/análogos & derivados , Antibacterianos/administração & dosagem , Antibacterianos/química , Proteínas de Bactérias/antagonistas & inibidores , Berberina/administração & dosagem , Berberina/química , Berberina/isolamento & purificação , Berberina/farmacologia , Candida/efeitos dos fármacos , Clorofila/administração & dosagem , Clorofila/química , Clorofila/isolamento & purificação , Clorofila/farmacologia , Ciprofloxacina/administração & dosagem , Interações Medicamentosas , Flavonoides/administração & dosagem , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Estrutura Molecular , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Extratos Vegetais/farmacologia , Staphylococcus aureus/efeitos dos fármacosRESUMO
The methylation of 2H-pyridazino [4,5-b][1,4]benzothiazin-1(10H)-one-5,5-dioxide 2 and the oxidation of 2-methyl-2H-pyridazino[4,5-b][1,4]benzothiazin-1(10H)-one 3 produced the same compound 4. On the contrary, in the 2-dialkylaminoalkylic series, the dialkylamino-alkylation and the oxidation reactions, carried out on compounds 2 and 8 respectively, afforded derivatives 7 and 9. In addition, the behaviour to the oxidation of the corresponding 10-methyl and 10-dialkylaminoalkyl analogues is also described. The synthesized compounds were tested for their analgesic, antiexudative and anti-inflammatory activities. The pharmacological results showed that in general dialkylaminoalkyl derivatives are more active than methyl derivatives. In particular, compounds 7 b, 9 b and 11 c exhibited an analgesic activity comparable to that of phenylbutazone; moreover 10-substituted compounds 11 a, 11 b and 11 c, screened p.o. as anti-inflammatory agents in rats, resulted equipotent to phenylbutazone and more active than 2-substituted isomers. These activities are coupled with a high LD50 and a very low ulcerogenic potential.
Assuntos
Analgésicos/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Piridazinas/síntese química , Tiazinas/síntese química , Animais , Comportamento Animal/efeitos dos fármacos , Fenômenos Químicos , Química , Exsudatos e Transudatos/efeitos dos fármacos , Dose Letal Mediana , Masculino , Camundongos , Fenilbutazona/farmacologia , Fenilbutazona/toxicidade , Piridazinas/farmacologia , Piridazinas/toxicidade , Ratos , Ratos Endogâmicos , Úlcera Gástrica/induzido quimicamente , Tiazinas/farmacologia , Tiazinas/toxicidadeRESUMO
The dialkylamino-alkylation of 3H-pyridazino[4,5-b][1,4]benzothiazin-4(10H)-one-5,5-dioxide 5 produced the 3-dialkylaminoalkyl-derivatives 6. To the same compounds we arrived by selective reduction of the corresponding N-oxides 4, derived from the oxidation of the 3-dialkylaminoalkyl-3H-pyridazino[4,5-b][1,4]benzothiazin-4( 10H)-ones 3. Similarly, the oxidation of the 10-dialkylaminoalkyl analogues 8 afforded the corresponding derivatives 9. The synthesized compounds were tested, as hydrochlorides, for their analgesic and anti-inflammatory activities. The results showed that many of these compounds possess a very good analgesic activity, superior to that of phenylbutazone, apparently not related to the position and the peculiarities of the aminoalkylic side-chain. The anti-inflammatory activity was moderate, comparable only for 4 c to that of phenylbutazone. In the most active compounds a very low ulcerogenic potential and a high LD50 have been observed.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Piridazinas/síntese química , Tiazinas/síntese química , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/toxicidade , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Piridazinas/farmacologia , Piridazinas/toxicidade , Ratos , Ratos Sprague-Dawley , Espectrofotometria Infravermelho , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/patologia , Relação Estrutura-Atividade , Tiazinas/farmacologia , Tiazinas/toxicidadeRESUMO
Some pyrimidines, pyrazolo[3,4-d]pyrimidines and imidazo[4,5-d]pyrimidines bearing the 5-nitro- and 5-aminothienyl-2-sulfide functionalities on the pyrimidine nucleus were synthesized and evaluated for their antifungal activity against several strains of yeasts and dermatophytes. 4-Amino-2-pyrimidinyl-5'-nitro-2'-thienylsulfide (Va) resulted active against both yeasts and dermatophytes (about 30 fold less potent than Miconazole). Compds. (II b), (V b) and (VIII b) showed only a slight activity against dermatophytes, while the other compounds were inactive.
Assuntos
Antifúngicos/síntese química , Imidazóis/síntese química , Pirazóis/síntese química , Pirimidinas/síntese química , Acetilação , Fenômenos Químicos , Química , Fungos/efeitos dos fármacos , Imidazóis/farmacologia , Testes de Sensibilidade Microbiana , Pirazóis/farmacologia , Pirimidinas/farmacologiaRESUMO
The synthesis and the in vitro receptor affinity for sigma 1 and opiod receptors of the two diastereoisomers of (+)-cis-MPCB namely, (+)-cis-(1'S,2'R)-6,11-Dimethyl-1,2,3,4,5,6 -hexahydro-3-[[2'-(methoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2 ,6 -methano-3-benzazocin-8-ol, (1'S,2'R)6a and (+)-cis-(1'R,2'S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-3- [[2-(methoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2,6-methano-3-+ ++benzazocin-8 -ol, (1'R,2'S)6a are reported. Affinities of (1'S,2'R)6a and (1'R,2'S)6a were compared with those of the (-)-cis-diastereoisomers of MPCB(1), and of its p-Cl phenyl derivative CCB(2). The (+)-cis-N-normetazocine derivatives showed higher affinity for the sigma 1 sites, labeled with [3H]-(+)-pentazocine than the corresponding (-)-cis- analogs. In particular, compound (1'S,2'R)6a showed a Ki = 66.7 nM for sigma 1 receptor, associated with a good selectivity for sigma 1 with respect to kappa, mu, delta opioid receptors subtypes (Ki = > 1,000 nM). Analysis of the data seem to support the hypothesis that the (+)-cis-N-normetazocine nucleus posses a specific enantioselectivity for sigma 1 sites, when supporting bulkier N-substituents functionalized with a carboxy ester group.
Assuntos
Ciclazocina/análogos & derivados , Receptores Opioides/metabolismo , Receptores sigma/metabolismo , Animais , Encéfalo/metabolismo , Ciclazocina/química , Ciclazocina/metabolismo , Cobaias , Isomerismo , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeAssuntos
Adjuvantes Imunológicos/uso terapêutico , Timopentina/uso terapêutico , Uremia/tratamento farmacológico , Ensaios Clínicos Controlados como Assunto , Humanos , Contagem de Leucócitos , Valores de Referência , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Uremia/imunologiaAssuntos
Aciclovir/uso terapêutico , Antivirais/uso terapêutico , Citomegalovirus/patogenicidade , Hepatite Viral Humana/tratamento farmacológico , Adulto , Anticorpos Antivirais/sangue , Citomegalovirus/isolamento & purificação , Feminino , Hepatite Viral Humana/virologia , Humanos , Imunoglobulina M/sangue , Masculino , Resultado do TratamentoRESUMO
2,4-Dimethyl-1-oxo-1,2-dihydro-3-carbazoyl-isoquinoline (II), 1-chloro-, 1-methoxy-3-carbazoyl-4-methylisoquinoline (VI, X) and a series of their hydrazonic derivatives have been synthesized and tested in vitro for antibacterial and antifungal activities. 1-(1-Chloro-4-methyl-3-isoquinolinoyl)-2-(5-nitro-2-furfurylide ne) hydrazine (VII h) proved to be the most effective in the series (MIC 0.78 micrograms/ml) and was more potent than furazolidone against several strains of S.aureus; the same compound also showed a moderate antifungal activity.
Assuntos
Anti-Infecciosos/síntese química , Antifúngicos/síntese química , Carbazóis/síntese química , Isoquinolinas/síntese química , Antibacterianos , Anti-Infecciosos/farmacologia , Antifúngicos/farmacologia , Bactérias/efeitos dos fármacos , Candida/efeitos dos fármacos , Carbazóis/farmacologia , Fenômenos Químicos , Química , Isoquinolinas/farmacologia , Testes de Sensibilidade Microbiana , Espectrofotometria InfravermelhoRESUMO
3-[2-(5-Nitro-2-furyl)vinylen]-2-isoxazoline (VIII) and 3-nitro-, 3-amino- and 3-acylaminostyryl-2-isoxazolines have been synthesized and tested for antibacterial activity. Compound (VIII) showed potent antibacterial activity in vitro against several strains of S. aureus and E. coli (two to eight times more active than furazolidone). None of the styryl derivatives exhibited significant activity.
Assuntos
Antibacterianos/síntese química , Isoxazóis/síntese química , Oxazóis/síntese química , Escherichia coli/efeitos dos fármacos , Isoxazóis/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Compostos de Vinila/síntese química , Compostos de Vinila/farmacologiaRESUMO
Some new di(nitrothienyl)- and di(acetylaminothienyl)sulfones were synthesized. Compounds (I)-(VI) were active against several Gram-positive bacteria, in vitro. Di(5-acetylamino-2-thienyl)sulfone (VII) showed a mild antimalarial activity against a drug-sensitive strain of P. berghei in mice.
Assuntos
Antibacterianos/síntese química , Antimaláricos/síntese química , Sulfonas/síntese química , Animais , Antimaláricos/uso terapêutico , Bactérias/efeitos dos fármacos , Malária/tratamento farmacológico , Camundongos , Testes de Sensibilidade Microbiana , Plasmodium berghei/efeitos dos fármacos , Sulfonas/farmacologiaRESUMO
Hemodialysis patients were screened and monitored for HBV markers and at renal unit (identification EDTA 13ND) Palermo. Eighty-five patients received the hepatitis B vaccine (Haevac B Pasteur); fifty-three were followed up for more than three years; they received one of the three following schedules: 5 micrograms at 0, 1, 2 and 14 months; 5 micrograms at 0, 1, 2, 3, and 14 or 10 micrograms at 0, 1, 2, and 14 months. The best result was obtained by third schedule with a sero-conversion to anti-HBs of 83% at one month after the booster doses; and with the same percentage of anti-HBs positivity two years after the booster dose. During the study time (January 1984, March 1989) no new HBV events in patients and in the hemodialysis staff, who was also on monitoring, were observed.
Assuntos
Vacinas contra Hepatite B/administração & dosagem , Hepatite B/prevenção & controle , Diálise Renal , Adolescente , Adulto , Idoso , Feminino , Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Antígenos de Superfície da Hepatite B/sangue , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/imunologia , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
A new series of 5-(4-halobenzoyl)-4-amino-3-(2-dialkylamino-ethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives has been synthetized. The compounds were evaluated for antifungal activity on yeast and dermatophytes. The compound (VI b) resulted about thirty times less potent than miconazole on dermatophytes.
Assuntos
Antifúngicos/síntese química , Tiazóis/síntese química , Tiofenos/síntese química , Benzoatos/síntese química , Benzoatos/farmacologia , Fenômenos Químicos , Química , Tiazóis/farmacologia , Tiofenos/farmacologiaRESUMO
Compounds having 2-methoxynaphthalene as their parent nucleus were synthesized and evaluated for antiinflammatory effect according to the carrageenin paw edema method in rats. The synthetic routes for the preparation of isomeric 1,2- and 2,6-disubstituted derivatives are described. Replacement of the alpha-methylacetic moiety in naproxen by 4-hydroxybutyric acid side chain did not cause loss of activity.