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1.
Acta Pharmacol Sin ; 44(1): 221-233, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35676531

RESUMO

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.


Assuntos
Inibidores da Fosfodiesterase 5 , Hipertensão Arterial Pulmonar , Humanos , Masculino , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirimidinonas , Biotransformação , Fezes , Administração Oral
2.
Acta Pharmacol Sin ; 43(12): 3130-3138, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35296780

RESUMO

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.


Assuntos
COVID-19 , Nucleosídeos , Humanos , SARS-CoV-2 , Voluntários Saudáveis , Método Duplo-Cego , Área Sob a Curva , China , Administração Oral , Relação Dose-Resposta a Droga
3.
Acta Pharmacol Sin ; 42(7): 1195-1200, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33041326

RESUMO

Remdesivir (RDV) exerts anti-severe acute respiratory coronavirus 2 activity following metabolic activation in the target tissues. However, the pharmacokinetics and tissue distributions of the parent drug and its active metabolites have been poorly characterized to date. Blood and tissue levels were evaluated in the current study. After intravenous administration of 20 mg/kg RDV in mice, the concentrations of the parent drug, nucleotide monophosphate (RMP) and triphosphate (RTP), as well as nucleoside (RN), in the blood, heart, liver, lung, kidney, testis, and small intestine were quantified. In blood, RDV was rapidly and completely metabolized and was barely detected at 0.5 h, similar to RTP, while its metabolites RMP and RN exhibited higher blood levels with increased residence times. The area under the concentration versus time curve up to the last measured point in time (AUC0-t) values of RMP and RN were 4558 and 136,572 h∙nM, respectively. The maximum plasma concentration (Cmax) values of RMP and RN were 2896 nM and 35,819 nM, respectively. Moreover, RDV presented an extensive distribution, and the lung, liver and kidney showed high levels of the parent drug and metabolites. The metabolic stabilities of RDV and RMP were also evaluated using lung, liver, and kidney microsomes. RDV showed higher clearances in the liver and kidney than in the lung, with intrinsic clearance (CLint) values of 1740, 1253, and 127 mL/(min∙g microsomal protein), respectively.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Nucleosídeos/metabolismo , Nucleotídeos/metabolismo , Polifosfatos/metabolismo , Distribuição Tecidual/fisiologia , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/farmacologia , Alanina/farmacocinética , Alanina/farmacologia , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , COVID-19/metabolismo , Rim/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Camundongos , SARS-CoV-2/efeitos dos fármacos , Tratamento Farmacológico da COVID-19
4.
Acta Pharmacol Sin ; 42(3): 482-490, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32581257

RESUMO

TPN729 is a novel phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction in men. Our previous study shows that the plasma exposure of metabolite M3 (N-dealkylation of TPN729) in humans is much higher than that of TPN729. In this study, we compared its metabolism and pharmacokinetics in different species and explored the contribution of its main metabolite M3 to pharmacological effect. We conducted a combinatory approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolite identification, and examined pharmacokinetic profiles in monkeys, dogs, and rats following TPN729 administration. A remarkable species difference was observed in the relative abundance of major metabolite M3: i.e., the plasma exposure of M3 was 7.6-fold higher than that of TPN729 in humans, and 3.5-, 1.2-, 1.1-fold in monkeys, dogs, and rats, respectively. We incubated liver S9 and liver microsomes with TPN729 and CYP3A inhibitors, and demonstrated that CYP3A was responsible for TPN729 metabolism and M3 formation in humans. The inhibitory activity of M3 on PDE5 was 0.78-fold that of TPN729 (The IC50 values of TPN729 and M3 for PDE5A were 6.17 ± 0.48 and 7.94 ± 0.07 nM, respectively.). The plasma protein binding rates of TPN729 and M3 in humans were 92.7% and 98.7%, respectively. It was astonishing that the catalyzing capability of CYP3A4 in M3 formation exhibited seven-fold disparity between different species. M3 was an active metabolite, and its pharmacological contribution was equal to that of TPN729 in humans. These findings provide new insights into the limitation and selection of animal model for predicting the clinical pharmacokinetics of drug candidates metabolized by CYP3A4.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Inibidores da Fosfodiesterase 5/metabolismo , Pirimidinonas/metabolismo , Sulfonamidas/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Citocromo P-450 CYP3A/farmacocinética , Cães , Humanos , Macaca fascicularis , Masculino , Espectrometria de Massas , Microssomos Hepáticos/metabolismo , Inibidores da Fosfodiesterase 5/sangue , Inibidores da Fosfodiesterase 5/farmacocinética , Pirimidinonas/sangue , Pirimidinonas/farmacocinética , Ratos Sprague-Dawley , Especificidade da Espécie , Sulfonamidas/sangue , Sulfonamidas/farmacocinética
5.
Acta Pharmacol Sin ; 41(9): 1167-1177, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32737471

RESUMO

Human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) and there is no cure currently. The 3CL protease (3CLpro) is a highly conserved protease which is indispensable for CoVs replication, and is a promising target for development of broad-spectrum antiviral drugs. In this study we investigated the anti-SARS-CoV-2 potential of Shuanghuanglian preparation, a Chinese traditional patent medicine with a long history for treating respiratory tract infection in China. We showed that either the oral liquid of Shuanghuanglian, the lyophilized powder of Shuanghuanglian for injection or their bioactive components dose-dependently inhibited SARS-CoV-2 3CLpro as well as the replication of SARS-CoV-2 in Vero E6 cells. Baicalin and baicalein, two ingredients of Shuanghuanglian, were characterized as the first noncovalent, nonpeptidomimetic inhibitors of SARS-CoV-2 3CLpro and exhibited potent antiviral activities in a cell-based system. Remarkably, the binding mode of baicalein with SARS-CoV-2 3CLpro determined by X-ray protein crystallography was distinctly different from those of known 3CLpro inhibitors. Baicalein was productively ensconced in the core of the substrate-binding pocket by interacting with two catalytic residues, the crucial S1/S2 subsites and the oxyanion loop, acting as a "shield" in front of the catalytic dyad to effectively prevent substrate access to the catalytic dyad within the active site. Overall, this study provides an example for exploring the in vitro potency of Chinese traditional patent medicines and effectively identifying bioactive ingredients toward a specific target, and gains evidence supporting the in vivo studies of Shuanghuanglian oral liquid as well as two natural products for COVID-19 treatment.


Assuntos
Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus , Medicamentos de Ervas Chinesas , Flavanonas , Flavonoides , Pandemias , Pneumonia Viral , Replicação Viral/efeitos dos fármacos , Administração Oral , Animais , Antivirais/química , Antivirais/farmacologia , Betacoronavirus/fisiologia , COVID-19 , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Ensaios Enzimáticos , Flavanonas/química , Flavanonas/farmacocinética , Flavonoides/química , Flavonoides/farmacocinética , Humanos , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , SARS-CoV-2 , Células Vero , Replicação Viral/fisiologia
6.
Yao Xue Xue Bao ; 51(12): 1809-21, 2016 12.
Artigo em Zh | MEDLINE | ID: mdl-29908532

RESUMO

Epidemiology indicates that schizophrenia affects approximately 8‰ of the world's population. The atypical (second and third generation) antipsychotics generally endowed with D(2)/5-HT(2A) receptors antagonism properties are commonly used as first-line drugs for the treatment of schizophrenia presently. They have been proven effective in the treatment of positive and negative symptoms of schizophrenia, but they are largely ineffective in the treatment of cognitive deficit. Moreover, the atypical antipsychotics are usually associated with cardiovascular and metabolic side effects such as QT prolongation and weight gain. To develop more potent antipsychotics with fewer side effects, more targets have been identified such as D(3), glutamate, H(3) receptors and PDE10A in recent years. Herein, the research progress of antipsychotics is reviewed.


Assuntos
Antipsicóticos/farmacologia , Esquizofrenia/tratamento farmacológico , Antipsicóticos/efeitos adversos , Humanos , Aumento de Peso
7.
Eur J Pharm Sci ; 191: 106598, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37783378

RESUMO

Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.


Assuntos
COVID-19 , Inibidores de Proteases , Adulto , Humanos , Antivirais/efeitos adversos , Inibidores Enzimáticos , Voluntários Saudáveis , Inibidores de Proteases/efeitos adversos , Ritonavir/uso terapêutico , SARS-CoV-2
8.
Yao Xue Xue Bao ; 45(3): 289-99, 2010 Mar.
Artigo em Zh | MEDLINE | ID: mdl-21351503

RESUMO

Influenza is a major threat to millions of people worldwide. Vaccines and antiviral agents are two main options available to reduce the impact of the influenza virus, while anti-influenza agents are the most effective means to prevent the transmission of the highly contagious virus and to treat the epidemics of disease. At present, four anti-influenza agents have been approved by the FDA for the treatment of influenza, including two M2 protein ion channel inhibitors-amantadine and rimantadine and two neuraminidase inhibitors-zanamivir and oseltamivir. Arbidol hydrochloride, launched in Russia, is a potent inhibitor of influenza virus, too. Neuraminidase inhibitors could be classified generally by structure into six different kinds: sialic acid derivatives, benzoic acid derivatives, cyclohexene derivatives, cyclopentane derivatives, pyrrolidine derivatives and natural products. In this paper, recent progress in the research of the action mechanisms and structure-activity relationships of these anti-influenza virus agents were reviewed.


Assuntos
Antivirais , Neuraminidase/antagonistas & inibidores , Orthomyxoviridae/efeitos dos fármacos , Proteínas da Matriz Viral/antagonistas & inibidores , Ácidos Carbocíclicos , Amantadina/síntese química , Amantadina/química , Amantadina/farmacologia , Amantadina/uso terapêutico , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Ciclopentanos/síntese química , Ciclopentanos/química , Ciclopentanos/farmacologia , Ciclopentanos/uso terapêutico , Guanidinas/síntese química , Guanidinas/química , Guanidinas/farmacologia , Guanidinas/uso terapêutico , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Indóis/uso terapêutico , Influenza Humana/tratamento farmacológico , Neuraminidase/síntese química , Neuraminidase/química , Neuraminidase/farmacologia , Neuraminidase/uso terapêutico , Oseltamivir/síntese química , Oseltamivir/química , Oseltamivir/farmacologia , Oseltamivir/uso terapêutico , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Pirrolidinas/uso terapêutico , Rimantadina/síntese química , Rimantadina/química , Rimantadina/farmacologia , Rimantadina/uso terapêutico , Relação Estrutura-Atividade , Proteínas da Matriz Viral/síntese química , Proteínas da Matriz Viral/química , Proteínas da Matriz Viral/farmacologia , Proteínas da Matriz Viral/uso terapêutico , Zanamivir/síntese química , Zanamivir/química , Zanamivir/farmacologia , Zanamivir/uso terapêutico
9.
J Pharm Biomed Anal ; 191: 113634, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32987249

RESUMO

A simple, rapid and accurate method for quantitative analysis of a highly selective phosphodiesterase-5 inhibitor (PDE5), TPN171 by high performance liquid chromatography and tandem mass spectrometry in human plasma was proposed and validated successfully using D3-TPN171 as internal standards (ISTD). An aliquot of 100 µL of plasma was mixed with internal standard and was precipitated with acetonitrile. Gradient elution was performed on a ACQUITY HSS T3 column (50 × 2.1 mm, 1.8 µm) coupled with a ACQUITY column in-line filter at 40℃, by 5 mM ammonium acetate in water containing 0.1 % formic acid and 0.1 % formic acid in acetonitrile as the mobile phase. The total analytical run time was 3.5 min. The analyte was monitored using multiple reaction monitoring (MRM) scan in positive polarity mode. The ion transition was m/z 442.2→113.2 and 445.2→116.2 for TPN171 and D3-TPN171 respectively. The method was validated for specificity, sensitivity, precision, accuracy, and other analytical parameters. The results found were satisfactory over the linear calibration range of 1-500 ng/mL. Within-day precisions ranged from 1.8 to 7.3 %, and between-day precisions from 2.3 to 4.9 %, accuracies were 95.5-99.8 %.The validated method was successfully applied to determine the plasma concentration after oral administration of 10 mg TPN171 in six healthy volunteers.


Assuntos
Pirimidinonas , Espectrometria de Massas por Ionização por Electrospray , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
10.
Yao Xue Xue Bao ; 43(4): 323-34, 2008 Apr.
Artigo em Zh | MEDLINE | ID: mdl-18664191

RESUMO

Intracellular signal transduction plays an important role in the process of cellular metabolism, segmentation, differentiation, biological behaviour and cell death. Overactive signal transduction relates to tumor development and progression. Signaling pathways operated by protein tyrosine kinases (PTKs) will be illuminated here briefly. The Ras/Raf/MAPK and PI-3K/Akt pathways through receptor protein tyrosine kinases (RTKs), the Src, Bcr-Abl and JAK/STAT pathways by non-receptor protein tyrosine kinases (nrPTKs) are shown separately. Antitumor agents targeting the key proteins involved in the above five signalling routes are also summarized in this review.


Assuntos
Antineoplásicos/farmacologia , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Proteínas ras/metabolismo , Quinases da Família src/metabolismo
11.
Acta Crystallogr Sect E Struct Rep Online ; 64(Pt 6): o969, 2008 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-21202698

RESUMO

The title compound, C(11)H(14)N(2)O·H(2)O, crystallizes with one formula unit in the asymmetric unit. The seven-membered ring has a chair conformation with the C=O group turned away from the benzene ring. N-H⋯O and O-H⋯O hydrogen bonds are present in the crystal structure.

12.
Curr Med Chem ; 14(28): 2996-3002, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18220736

RESUMO

Tetrahydroprotoberberines (THPBs) represent a series of compounds extracted from the Chinese herb Corydalis ambigua and various species of Stephania. THPBs, dependent on the presence of hydroxyl groups in its structure, are divided into three types: nonhydroxyl-THPBs, monohydroxyl-THPBs and dihydroxyl-THPBs. THPBs are identified as a new category of dopamine receptor ligands. Among all THPBs, dihydroxyl-THPBs attracted particular attention because of their dual actions on dopamine (DA) receptors. They exhibit D(1) receptor agonistic activity while acting as D(2) receptor antagonists. This unique pharmacological profile made dihydroxyl-THPBs such as l-stepholidine (l-SPD) potential agents in the treatment of drug addiction, Parkinson's disease, and especially, schizophrenia. Clinical studies have shown that co-administration of l-SPD with a typical antipsychotic drug significantly enhances the therapeutic effects and remarkably reduces the tardive dyskinesia induced by the typical antipsychotic drug used with schizophrenic patients. Moreover, l-SPD alone was shown to have therapeutic value without inducing significant extrapyramidal side effects and also seemed to reduce the negative symptoms of schizophrenia. This is confirmed in experimental studies using animal models of schizophrenia, in which l-SPD improved social interaction and cognitive function, inhibited hyperactivity in schizophrenic animals. This review discusses the chemistry, pharmacology and clinical implications of l-THPBs in the drug development for psychosis and neurobiological diseases.


Assuntos
Alcaloides de Berberina/química , Alcaloides de Berberina/farmacologia , Berberina/análogos & derivados , Transtornos Mentais/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Berberina/química , Berberina/farmacologia , Berberina/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Dopamina/metabolismo , Humanos , Receptores Dopaminérgicos/metabolismo
13.
Guang Pu Xue Yu Guang Pu Fen Xi ; 27(5): 863-7, 2007 May.
Artigo em Zh | MEDLINE | ID: mdl-17655090

RESUMO

The ultraviolet spectrum (UV), infrared spectrum (IR), nuclear magnetic resonance (NMR) and mass spectrum (MS) of aripiprazole, a new antipsychotic drug, were reported and interpreted. The structure of aripiprazole in solution was studied according to the UV spectra detected in solution with different pH values. The vibrations of functional groups of this compound in IR and the isotopic ion peaks in MS were discussed. Moreover, the 2D-NMR techniques, including 1H-1H correlation spectroscopy (1H-1H cosy), heteronuclear single-quantum coherence (HSQC), and heteronuclear multiple-bond correlation (HMBC), were used to deduce the structure of this compound. All the 1H NMR and 13C NMR signals were assigned. Especially, the ten different methylenes in this structure were analyzed according to the chemical shifts, coupling constants and correlations in 2D-NMR spectrum. By all these spectral techniques, the structure of aripiprazole was identified.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Piperazinas/análise , Quinolonas/análise , Espectrofotometria Infravermelho/métodos , Espectrofotometria Ultravioleta/métodos , Aripiprazol , Estrutura Molecular
14.
Guang Pu Xue Yu Guang Pu Fen Xi ; 25(2): 232-4, 2005 Feb.
Artigo em Zh | MEDLINE | ID: mdl-15852863

RESUMO

Fluorescence spectroscopy has achieved great successes in the study on the interaction of drugs and DNA in both quantitative analysis and qualitative analysis. While the fluorescence probe technique can be used to measure the intensity of drugs-DNA interaction, because the injected drugs can change the fluorescence intensity of the probe. In this paper, the authors use berberine as a probe to measure the interaction intensity between some anticancer drugs and DNA, calculate the constant D and determine the effects of those drugs. In addition, the authors point out that this method can not be efficient for certain drug solution.


Assuntos
Antineoplásicos/química , Berberina/química , DNA/química , Espectrometria de Fluorescência/métodos , Fluoruracila/química , Cinética , Mitomicinas/química , Reprodutibilidade dos Testes
15.
Bioorg Med Chem Lett ; 17(17): 4942-6, 2007 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-17601733

RESUMO

Crystal structure of the imiquimod has been determined by single crystal X-ray analysis, imiquimod crystallizes in orthorhombic space group P2(1)2(1)2(1) and the molecules are linked along the c axis by the strong N-H ... N hydrogen bonds. A density functional theory (DFT) study on the electronic properties of imiquimod and its synthetic intermediates has been performed at B3LYP/6-31G* level, while taking solvent effects into account. Both the single configuration interaction (CIS) method and the time-dependent DFT (TDDFT) approaches have been used to calculate the electronic absorption spectra, and there is a good agreement between the calculated and experimental UV-visible absorption spectra. The fluorescence emission spectra of these three compounds in solution have also been measured, the relatively low fluorescence intensity is attributed to a chlorine-modulated heavy atom effect that enhances intersystem crossing between excited singlet and triplet states, and the relatively high fluorescence intensity of imiquimod results from an extended pi-conjugated system which enhances S(1)-->S(0) radiant transition.


Assuntos
Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/farmacologia , Aminoquinolinas/síntese química , Aminoquinolinas/farmacologia , Cristalização , Cristalografia por Raios X , Desenho de Fármacos , Elétrons , Ligação de Hidrogênio , Imiquimode , Modelos Químicos , Conformação Molecular , Estrutura Molecular , Oscilometria , Solventes/química , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta/métodos , Raios Ultravioleta
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